A Randomized, Subject- and Evaluating Investigator-blinded, Controlled, Multicenter, Split-face, Comparison Clinical Investigation to Evaluate Effectiveness and Safety of Princess FILLER Lidocaine in the Correction of Nasolabial Folds
Phase: NA
Conditions: Dermatological Non-Disease
Sponsor: Croma-Pharma GmbH

 
 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
A randomized, subject- and evaluating investigator-blinded, controlled, multicenter, 
split-face, comparison clinical investigation to evaluate effectiveness and safety of 
Princess® FILLER Lidocaine in the correction of nasolabial folds 
 
  
 
Clinical investigation plan no.:
CPH-301-201200F 
Sponsor:
Croma-Pharma GmbH 
Industriezeile 6 
2100 Leobendorf, Austria 
 
 
 
Clinical investigation plan version:
Version 7.0 
Clinical investigation plan date:
15 Mar 2021 
 
 
 
 
STRICTLY CONFIDENTIAL 
The information contained herein is the property of Croma-Pharma GmbH and may not be 
produced, published, or disclosed to others without prior written authorization of Croma-
Pharma GmbH, except that this document may be disclosed to the appropriate Institutional 
Review Board/Independent Ethics Committee under the condition that it is kept confidential.
NCT03990883

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PRINCIPAL 
INVESTIGATOR 
AGREEMENT 
PAGE 
FOR 
THE 
CLINICAL 
INVESTIGATIONAL PLAN 
I agree: 
 To assume responsibility for the proper conduct of the clinical investigation at this site, 
and to conduct the clinical investigation in compliance with this clinical investigational 
plan (CIP), any future amendments, and with any other clinical investigation conduct 
procedures provided by the sponsor or authorized representatives, as well as in accordance 
with the clinical investigation agreement, respective laws and regulations, including GCP, 
and all applicable regulatory requirements. 
 Not to implement any deviations from or changes to the CIP (including CIP amendments) 
without instructions and agreement from the sponsor and prior review and favorable 
opinion from the Ethics Committee and approval from the Competent Authority, if 
applicable, except where necessary to eliminate an immediate hazard to the subject(s), or 
for administrative aspects of the clinical investigation (where permitted by all applicable 
regulatory requirements). 
 That I am familiar with the appropriate use of the investigational medical device (IMD) 
as described in this CIP and any other information provided by the sponsor including, but 
not limited to, the current Investigator’s Brochure or equivalent document provided by 
the sponsor. 
 To ensure that all persons assisting me with the clinical investigations are adequately 
informed about the IMDs and of their clinical investigation-related duties and functions. 
 That I have been informed that certain regulatory authorities require the sponsor to obtain 
and supply details about the investigator’s ownership interest in the sponsor or the clinical 
investigation product, and more generally about his/her financial ties with the sponsor. 
The sponsor will use and disclose the information solely for the purpose of complying 
with regulatory requirements. 
 To keep any information related to this clinical investigation and any results of it as strictly 
confidential. I agree that this information will not be used for any other purpose other than 
the conduct of this clinical investigation. 
 
Investigator's name: ________________________________________________________________ 
 
Investigator's address:_______________________________________________________________ 
 
 
 
 
  _______________________________________________________________ 
 
Governing IRB ____________________________________________________________________ 
 
 
    ____________________________________________________________________ 
 
Investigator's signature: _____________________________________________________________ 
 
 
Date: ____________________________________________________________________________ 
 

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Table of contents 
 
 
Page 
SPONSOR SIGNATURE PAGE ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 5 
1 
ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 10 
2 
CLINICAL INVESTIGATION SYNOPSIS .............................................................. 12 
Primary outcome measure: .......................................................................................... 19 
Secondary outcome measures: ..................................................................................... 19 
Additional outcome measures:..................................................................................... 20 
2.1 
Schedule of Clinical Investigation Procedures and Assessments .......... 32 
3 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE OF THE 
CLINICAL INVESTIGATION ................................................................................... 36 
4 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................. 39 
4.1 
Background Information Regarding Dermal Fillers .............................. 39 
4.2 
Clinical Condition/Indication ................................................................... 43 
4.3 
Description of the Investigational Medical Devices ................................ 43 
4.3.1 
Princess  FILLER Lidocaine ....................................................................... 43 
4.3.2 
Juvéderm® Ultra XC .................................................................................... 45 
4.4 
Non-clinical and Clinical Summaries ....................................................... 45 
4.4.1 
Pre-clinical Experience and Biocompatibility ............................................. 45 
4.4.2 
Clinical experience ....................................................................................... 46 
4.4.3 
Clinical Summary ........................................................................................ 46 
4.5 
Clinical investigation Rationale ................................................................ 48 
5 
CLINICAL INVESTIGATION PURPOSE AND OBJECTIVES ........................... 49 
5.1 
Purpose ........................................................................................................ 49 
5.2 
Primary Objective ...................................................................................... 49 
5.3 
Secondary Objectives ................................................................................. 49 
5.4 
Additional Objectives ................................................................................ 49 
5.5 
Safety Objectives ........................................................................................ 50 
6 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND 
CLINICAL INVESTIGATION ................................................................................... 51 

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6.1 
Potential Risks ............................................................................................ 51 
6.2 
Potential Benefits ....................................................................................... 52 
6.3 
Risk / Benefit Rationale ............................................................................. 52 
7 
DESIGN OF THE CLINICAL INVESTIGATION................................................... 54 
7.1 
Description of the Clinical Investigation Design ..................................... 54 
7.2 
Population to be Studied ........................................................................... 55 
7.3 
Outcome Measures ..................................................................................... 56 
7.3.1 
Effectiveness Outcome Measures ................................................................ 56 
7.3.1.1 
Primary outcome measure: ...................................................................................... 56 
7.3.1.2 
Secondary Outcome Measures: ............................................................................... 56 
7.3.1.3 
Additional Outcome Measures: ............................................................................... 56 
7.3.2 
Safety Outcome Measures ........................................................................... 58 
7.4 
Subject Identification ................................................................................. 58 
7.5 
Screening Failures ...................................................................................... 58 
7.6 
Randomization and Blinding .................................................................... 59 
8 
INVESTIGATIONAL MEDICAL DEVICES ........................................................... 61 
8.1 
Packaging and Labeling ............................................................................ 61 
8.2 
Storage and Handling ................................................................................ 61 
8.3 
Administration of the Device .................................................................... 61 
8.3.1 
Preparation of Administration ...................................................................... 61 
8.3.2 
Injection Technique ..................................................................................... 62 
8.3.3 
Touch-up treatment ...................................................................................... 63 
8.3.4 
Applied volume of the device ...................................................................... 63 
8.4 
Precautions and Warnings, Prohibited Medications/Treatments and 
Restrictions ................................................................................................. 64 
8.4.1 
Precautions and Warnings ............................................................................ 64 
8.4.2 
Prohibited Medications/Treatments ............................................................. 65 
8.4.3 
Restrictions .................................................................................................. 65 
8.5 
Rescue Medication ..................................................................................... 66 
8.6 
Medical Device Accountability ................................................................. 66 
9 
SUBJECT SELECTION, WITHDRAWAL AND DISCONTINUATION ............. 67 
9.1 
Inclusion and Exclusion Criteria – Screening/Baseline .......................... 67 
9.1.1 
Inclusion Criteria ......................................................................................... 67 

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9.1.2 
Exclusion Criteria ........................................................................................ 67 
9.2 
Inclusion and Exclusion Criteria – Repeat-treatment ............................ 69 
9.2.1 
Inclusion Criteria ......................................................................................... 69 
9.2.2 
Exclusion Criteria ........................................................................................ 69 
9.3 
Subject Withdrawal and Discontinuation ............................................... 71 
9.4 
Subject Enrollment, Number and Duration of Subject’s Participation 71 
10 
CLINICAL INVESTIGATION PROCEDURES AND ASSESSMENTS ............... 73 
10.1 
Nasolabial Folds-Severity Rating Scale (NLF-SRS) ............................... 73 
10.2 
Global Aesthetic Improvement Scale (GAIS) .......................................... 74 
10.3 
Subject Satisfaction using Face-Q Questionnaires ................................. 75 
10.3.1 
Satisfaction with Outcome ........................................................................... 75 
10.3.2 
Appraisal of Nasolabial Folds ...................................................................... 75 
10.4 
Subject's Evaluation of Pain ..................................................................... 76 
10.5 
Injection Volume ........................................................................................ 76 
10.6 
Time to Repeat-Treatment ........................................................................ 76 
10.7 
Clinical Photography ................................................................................. 77 
10.8 
Visual Examinations .................................................................................. 77 
10.8.1 
Snellen Visual Acuity .................................................................................. 77 
10.8.2 
Confrontational Visual Fields ...................................................................... 78 
10.8.3 
Ocular Motility ............................................................................................. 79 
10.8.4 
Abnormal Visual Examinations ................................................................... 79 
10.9 
Other Assessments ..................................................................................... 80 
10.10 
Factors that may Compromise the Outcome ........................................... 83 
10.11 
Schedule of the Clinical Investigation ...................................................... 83 
10.11.1 
Screening (Visit 1) ....................................................................................... 83 
10.11.2 
Baseline (Visit 2) ......................................................................................... 84 
10.11.3 
Phone Contact after Visit 2 .......................................................................... 84 
10.11.4 
Week 2 (Visit 3a) ......................................................................................... 85 
10.11.5 
Phone Contact after Visit 3a ........................................................................ 85 
10.11.6 
Week 4 (Visit 3b) ......................................................................................... 85 
10.11.7 
Week 6 (Visit 3c) ......................................................................................... 86 
10.11.8 
Week 12 (Visit 4) and Week 24 (Visit 5) .................................................... 86 
10.11.9 
Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or Visit 7c - Evaluation .. 87 

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10.11.10 
Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or Visit 7c - Repeat-
Treatment ..................................................................................................... 88 
10.11.11 
Phone Contact after Visit 6, Visit 7 or Visit 7c ........................................... 88 
10.11.12 
Week 40 (Visit 8a), Week 52 (Visit 8b) or Visit 8c .................................... 88 
10.11.13 
Week 48 (Visit 9a), Week 60 (Visit 9b) or Visit 9c .................................... 89 
10.12 
Early Termination ..................................................................................... 89 
10.13 
Time-Windows ........................................................................................... 90 
10.14 
Medical Care upon Termination of the Clinical Investigation .............. 90 
11 
MONITORING PLAN ................................................................................................. 91 
12 
ASSESSMENT OF SAFETY ....................................................................................... 92 
12.1 
Definitions of Adverse Events and Adverse Device Effects ................... 92 
12.2 
Documentation of Adverse Events ........................................................... 94 
12.3 
Assessment of Adverse Events .................................................................. 95 
12.3.1 
Assessment of Causality .............................................................................. 95 
12.3.2 
Assessment of Severity ................................................................................ 97 
12.3.3 
Adverse Event Outcome .............................................................................. 97 
12.4 
Adverse Event Monitoring and Assessment ............................................ 98 
12.4.1 
Unanticipated Adverse Device Effects Reporting ..................................... 100 
12.5 
Adverse Events/Serious Adverse Events Follow-up ............................. 101 
12.6 
Visual Examinations ................................................................................ 102 
12.7 
Device Deficiencies ................................................................................... 102 
12.7.1 
Definition of a Device Deficiency ............................................................. 102 
12.7.2 
Recording and Reporting of Device Deficiencies ..................................... 102 
12.7.3 
Handling of Deficient Medical Devices .................................................... 102 
13 
ASSESSMENT OF EFFECTIVENESS .................................................................... 103 
14 
STATISTICAL CONSIDERATIONS ...................................................................... 104 
14.1 
Analysis Sets ............................................................................................. 104 
14.2 
Statistical Analyses ................................................................................... 104 
14.3 
Sample Size Calculation .......................................................................... 107 
15 
DATA HANDLING AND RECORD KEEPING ..................................................... 107 
15.1 
Electronic Case Report Forms ................................................................ 107 
15.2 
Data Management Procedures ................................................................ 108 
15.3 
Data Retention .......................................................................................... 108 

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15.4 
Clinical Investigation Report .................................................................. 109 
16 
REGULATORY AND ETHICAL CONSIDERATIONS ....................................... 110 
16.1 
Ethical Conduct of the Investigation ...................................................... 110 
16.2 
Institutional Review Board (IRB) ........................................................... 110 
16.3 
Insurance .................................................................................................. 110 
16.4 
Informed Consent Process ...................................................................... 110 
16.5 
Subject Confidentiality ............................................................................ 111 
17 
AMENDMENTS TO AND DEVIATIONS FROM THE CIP ................................ 113 
17.1 
Amendments ............................................................................................. 113 
17.2 
Deviations .................................................................................................. 113 
18 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION ...................................................................................................... 114 
19 
PUBLICATION POLICY .......................................................................................... 115 
20 
REFERENCES ............................................................................................................ 116 
21 
REVISION HISTORY ............................................................................................... 120 
22 
APPENDICES ............................................................................................................. 128 
22.1 
Appendix 1: ............................................................................................... 128 
22.2 
Appendix 2: ............................................................................................... 130 
22.3 
Appendix 3: ............................................................................................... 133 
 
Table of Tables 
Table 1: 
Nasolabial Folds-Severity Rating Scale (NLF-SRS) ........................................ 74 
Table 2: 
Global Aesthetic Improvement Scale ............................................................... 75 
 
Table of Figures 
Figure 1: Standard Snellen Hanging Wall Chart ...................................................................... 78 
 

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1 
Abbreviations and definition of terms 
 
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ASADE 
Anticipated serious adverse device effect 
BDDE 
1,4-butanediol diglycidyl ether 
CE 
European Conformity 
CFR 
Code of Federal Regulations 
CIP 
Clinical investigation plan 
CRA 
Clinical research associate 
eCRF 
Electronic case report form 
EU 
European Union 
FACE-Q 
Patient-reported outcome questionnaires measuring experience and 
outcomes of aesthetic facial procedures 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSFV 
First subject first visit 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good clinical practice 
HA 
Hyaluronic acid 
HIPAA 
Health insurance portability and accountability act 
IRB 
Institutional review board 
ICF 
Informed consent form 
IFU 
Instructions for use 
IMD 
Investigational medical device 
ISO 
International Organization for Standardization 
LSLV 
Last subject last visit 

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MedDRA 
Medical disctionary for regulatory activities 
NLF(s) 
Nasolabial fold(s) 
NLF-SRS 
Nasolabial Folds-Severity Rating Scale 
NPRS 
Numeric Pain Rating Scale 
PPS 
Per-protocol set 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SOC 
System organ class 
SOP 
Standard operating procedure 
UADE 
Unanticipated adverse device effect 
US/USA 
United States of America 
UV 
Ultraviolet 
 
 

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2 
Clinical Investigation Synopsis  
INVESTIGATIONAL MEDICINAL PRODUCT  
Clinical 
investigation 
Sponsor 
Croma-Pharma GmbH 
Industriezeile 6 
2100 Leobendorf, Austria 
Name of 
Investigational 
Medical Device 
Crosslinked Hyaluronic Acid (HA) 2.3% + 0.3% Lidocaine 
Hydrochloride i.d. (Trade name: Princess® FILLER Lidocaine) 
CLINICAL CONDITION(S)/INDICATION(S) 
Moderate to severe facial wrinkles and folds, such as nasolabial folds (NLFs)  
PROTOCOL 
IDENTIFIER  
CPH-301-201200F 
PROTOCOL 
TITLE 
A randomized, subject- and evaluating investigator-blinded, 
controlled, 
multi-center, 
split-face, 
comparison 
clinical 
investigation to evaluate effectiveness and safety of Princess® 
FILLER Lidocaine in the correction of nasolabial folds  
Short title 
FILIDO 
CLINICAL 
INVESTIGATION 
PHASE 
Pivotal  
PLANNED CLINICAL INVESTIGATION PERIOD 
Initiation 
Anticipated Q1 to Q2 2019 (FSFV) 
Primary 
Completion 
Anticipated Q3 2021 (LSLV) 
Clinical 
investigation 
Completion 
Anticipated Q4 2021 
Duration 
The duration of the clinical investigation will be a maximum of 
104 weeks for each participating subject, including the temporary 
hold on repeat-treatment. The total expected duration of the 

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clinical investigation (FSFV to LSLV) is up to 24 months with an 
expected recruitment period of about 20 weeks. 
CLINICAL INVESTIGATION OBJECTIVES AND PURPOSE 
Clinical 
investigation 
Purpose 
To demonstrate the effectiveness and safety of Princess® FILLER
Lidocaine in the correction of moderate to severe NLFs  
Objectives 
Primary objective: 
To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs in comparison to Juvéderm® Ultra 
XC, based on the independent blinded evaluating investigator live 
assessment using the Nasolabial Folds Severity Rating Scale NLF-
SRS at Week 24 after initial treatment, relative to Baseline 
assessments  
 
Secondary objectives: 
1. To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs and compared to Juvéderm® 
Ultra XC, based on the independent blinded photographic 
reviewers assessments of photographs from Baseline and 
Week 24 after initial treatment 
2. To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs and compared to Juvéderm® 
Ultra XC, based on the treating investigator live assessments at 
Week 24 after initial treatment, relative to Baseline assessments 
3. To evaluate aesthetic improvement over Baseline after 
treatment using a Global Aesthetic Improvement Score (GAIS), 
based on the independent blinded evaluating investigator 
assessment at Week 24 after initial treatment 

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4. To evaluate aesthetic improvement over Baseline after 
treatment using GAIS, based on the subject assessment at 
Week 24 after initial treatment 
Additional objectives: 
1. To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs compared with Juvéderm® Ultra 
XC, based on the independent blinded evaluating investigator 
live assessments at Week 12, 36, 48 and the post 
repeat-treatment hold follow-up visit (Visit 7c) after initial 
treatment relative to Baseline assessments 
2. To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs compared to Juvéderm® Ultra 
XC, based on the independent blinded photographic reviewers 
assessments of photographs from Baseline and Week 12, 36, 48 
and Visit 7c after initial treatment 
3. To assess the effectiveness of Princess® FILLER Lidocaine in 
reducing the severity of NLFs compared with Juvéderm® Ultra 
XC, based on the treating investigator live assessments at 
Week 12, 36, 48 and Visit 7c after initial treatment relative to 
Baseline assessments 
4. To evaluate aesthetic improvement over Baseline after 
treatment using GAIS, based on the independent blinded 
evaluating investigator assessments at Week 12, 36, 48 and 
Visit 7c after initial treatment 
5. To evaluate aesthetic improvement over Baseline after 
treatment using GAIS, based on the subject assessments at 
Week 12, 36, 48 and Visit 7c after initial treatment 

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6. To assess subject satisfaction with aesthetic outcome after 
treatment at Week 12, 24, 36, 48 and Visit 7c after initial 
treatment 
7. To assess subject appearance appraisal of NLFs after treatment 
at Week 12, 24, 36, 48 and Visit 7c after initial treatment 
compared to Baseline 
8. To evaluate subject’s perception of pain after initial and repeat-
treatment with Princess® FILLER Lidocaine and Juvéderm® 
Ultra XC  
9. Time from initial to repeat-treatment for each treatment group 
10. To assess injection volume (initial, touch-up and repeat-
treatments, separate assessments) needed for optimal correction 
for Princess® FILLER Lidocaine and Juvéderm® Ultra XC 
Safety objectives: 
Frequency, severity, seriousness and causal relationship of adverse 
events (AEs), adverse device effects (ADEs), serious adverse 
eents (SAEs) and serious adverse device effects (SADEs) during 
the entire clinical investigation period including subject 
complaints will be recorded in the subject diaries during four 
weeks after initial-, touch-up-treatments, in comparison with 
Juvéderm® Ultra XC. Frequency, severity, seriousness and causal 
relationship of AEs, ADEs, SAEs and SADEs during the entire 
clinical investigation period including subject complaints will be 
recorded in the subject diaries during four weeks after repeat-
treatments, for Princess® FILLER Lidocaine 
CLINICAL INVESTIGATION DESIGN 
Clinical 
Investigation Type 
Interventional  
Control Type 
Non-inferiority clinical investigation  
Indication Type 
Treatment  

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Blinding/Masking 
Subject- and independent evaluating investigator-blinded 
Design 
The clinical investigation is a randomized, subject- and 
independent evaluating investigator-blinded, active treatment 
controlled, multicenter, paired (split-face) clinical investigation.  
The clinical investigation will comprise two treatment groups as 
follows:  
 Group A: 
 Princess® FILLER Lidocaine on left NLF  
 Juvéderm® Ultra XC on right NLF 
 Group B:  
 Juvéderm® Ultra XC on left NLF 
 Princess® FILLER Lidocaine on right NFL 
Eligible subjects will be randomized at Baseline (Visit 2) in a 1:1 
ratio to Group A or Group B; according to the randomization 
scheme. The subjects of each group will undergo bilateral 
treatments with Princess® FILLER Lidocaine and Juvéderm® 
Ultra XC for the correction of moderate to severe NLFs. 
Baseline Severity of NLFs will be determined at Screening by the 
treating investigator in conjunction with the independent blinded 
evaluating investigator. 
Subjects will be blinded to the treatment administered (they will 
be blindfolded during the administration of devices). The treating 
investigator and the independent blinded evaluating investigator 
will independently assess treatment effect in correction of the 
NLFs using the Nasolabial Folds Severity Rating Scale 
(NLF-SRS). Independent blinded photographic reviews will be 
done for the same time points.  
The treatment will be administered at the Baseline visit (Day 0) 
after randomization. The left NFL will be treated first and the right 
NLF thereafter. Subjects will return for effectiveness follow-up 
assessments two, twelve and 24 weeks after the initial treatment. 

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At the first follow-up visit (Week 2), a touch-up treatment may be 
done if an optimal aesthetic correction has not been achieved after 
initial treatment, as evaluated by the treating investigator. A touch-
up treatment will be performed using the same type of device as 
initially applied.  
On Week 36 and/or Week 48 after initial treatment, an evaluation 
for repeat-treatment will take place; subjects will be offered an 
optional repeat-treatment (Visit 6 or 7), if in the opinion of the 
treating investigator, they have returned to sufficient severity of 
NLFs that would have qualified them for enrollment into the 
clinical investigation initially. The subjects do NOT have to return 
to their Baseline severity to be permitted to receive a repeat-
treatment. At Week 36, an evaluation for repeat-treatment will 
take place; subjects qualifying for a repeat-treatment will receive 
it during the same visit (Visit 6) and will come back for a safety 
follow-up visit four and twelve weeks later (Week 40/Visit 8a and 
Week 48/Visit 9a). For these subjects, Visit 9a will be their end of 
study visit. Subjects which are not qualifying for a repeat-
treatment at Week 36 will be evaluated again at Week 48 (Visit 7); 
qualified subjects will then receive a repeat-treatment during 
Visit 7 and will be followed-up for safety four and twelve weeks 
later (Week 52/Visit 8b and Week 60/Visit 9b). For these subjects, 
Visit 9b will be their end of study visit. Subjects, who do not 
qualify for any retreatment, will have their end of study visit at 
Visit 7. The repeat-treatment will be performed with Princess® 
FILLER Lidocaine on both NLFs. 
Follow-up visits for effectiveness will be performed at Week 2, 
12, 24, 36 and/or 48 after initial treatment. Follow-up visits for 
safety will be performed at Week 2, 4, 6 (only if touch-up 
treatment occurred at Week 2), 12, 24, 36/48 and 48/60 after initial 
treatment. In addition, subjects will be contacted by phone on 

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Day 3 (±24 hours) after initial, touch-up and repeat-treatments for 
a safety check-up. Also at the end of each treatment session, 
subjects will receive a diary to record the injection site reactions, 
as well as the incidence of serious adverse events associated with 
unintended intravascular injection over the following (four weeks 
after initial-, touch-up- and repeat-treatments. 
Subject satisfaction with the outcome of the treatment will be 
assessed 
with GAIS 
and the patient-reported outcome 
questionnaires measuring experience and outcomes of aesthetic 
facial procedures (FACE-Q) questionnaires. 
Pain assessment will be performed after initial and repeat-
treatment (15 min after last injection and at 15 min-intervals for 
60 min post-treatment). 
In order to evaluate any potential vision changes, visual 
examinations (including Snellen visual acuity, confrontational 
visual fields and ocular motility) will be additionally performed 
(prior to- and 30 min after any treatment) at Baseline (Visit 2) and 
at Week 4 (Visit 3b). Subjects receiving touch-up treatment 
(Week 2/Visit 3a) and subjects receiving repeat-treatment 
(Week 36/Visit 6 or Week 48/Visit 7) will be examined the same 
way as they would be at the Baseline (prior to- and 30 min after 
the treatment) and an additional examination will be performed 
four weeks after the treatment (at Week 6/Visit 3c after touch-up 
treatment and at Week 40/Visit 8a or at Week 52/Visit 8b after 
repeat-treatment and at Week 48/Visit 9a or at Week 60/Visit 9b 
after repeat-treatment). Subjects with clinically significant 
changes in visual examinations considered to be related to a 
vascular injection of the dermal filler will be treated per standard 
of care for intravascular injection of dermal filler. The subject will 
be withdrawn from the study and the need for stopping the study 
will be reviewed.  

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During the conduct of the trial, some subjects were not evaluated 
for repeat-treatment at Week 36 (Visit 6) and/or Week 48 (Visit 7) 
due to a hold on repeat-treatment. Therefore, a post 
repeat-treatment hold follow-up visit (Visit 7c) has been added in 
Clinical Investigation Plan Version 7.0 to allow subjects to return 
for evaluation and repeat-treatment (if eligible) after the end of the 
hold on repeat-treatment. Subsequent follow-up visits (Visit 8c 
[4 weeks after repeat-treatment] and Visit 9c [12 weeks after 
repeat-treatment]) have also been added. For subjects who receive 
repeat-treatment at Visit 7c, Visit 9c will be their end of study 
visit. For subjects who do not qualify for repeat-treatment at 
Visit 7c, Visit 7c will be their end of study visit. 
Outcome Measures 
The outcome measures will be separately evaluated for the left and 
right side of the face. 
Responder is defined as having at least one grade improvement 
over Baseline, on the 5-point NLF-SRS. 
Primary outcome measure: 
The percentage of responders based on the independent blinded 
evaluating investigator live assessment at Week 24 after initial 
treatment and compared to Juvéderm® Ultra XC.NLF-SRS scores 
are ranked as 0 (None/minimal), 1 (Mild), 2 (Moderate), 
3 (Severe) and 4 (Extreme). 
Secondary outcome measures: 
Responder is defined as having at least one grade improvement 
over Baseline, on the 5-point NLF-SRS. 
 
1. Responder is defined as having at least one grade improvement 
over Baseline, on the 5-point NLF-SRS.The percentage of 
responders based on the independent blinded photographic 
reviewers assessments at Week 24 after initial treatment, 
compared to Juvéderm® Ultra XC and based on photographs  

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2. The percentage of responders based on the treating investigator 
live assessment at Week 24 after initial treatment and compared 
to Juvéderm® Ultra XC 
3. The percentage of subjects with an improvement over Baseline 
(subjects who have been rated as “very much improved” or 
“much improved” or “improved”), based on the independent 
blinded evaluating investigator assessment at Week 24 after 
initial treatment and using the 5-point GAIS 
4. The percentage of subjects with an improvement over Baseline 
(subjects who have been rated as “very much improved” or 
“much improved” or “improved”), based on subject assessment 
at Week 24 after initial treatment and using the 5-point GAIS 
Additional outcome measures: 
Responder is defined as having at least one grade improvement 
over Baseline, on the 5-point NLF-SRS. 
1. The percentage of responders based on the independent blinded 
evaluating investigator live assessment at Week 12, 36, 48 and 
Visit 7c after initial treatment and compared to Juvéderm® Ultra 
XC 
2. The percentage of responders based on the independent blinded 
photographic reviewers assessments at Week 12, 36, 48 and 
Visit 7c after initial treatment, compared to Juvéderm® Ultra 
XC and based on photographs  
3. The percentage of responders based on the treating investigator 
live assessment at Week 12, 36, 48 and Visit 7c after initial 
treatment and compared to Juvéderm® Ultra XC 
4. The percentage of subjects with an improvement over Baseline 
(subjects who have been rated as “very much improved” or 
“much improved” or “improved”), based on the independent 

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blinded evaluating investigator assessment at Week 12, 36, 48
and Visit 7c after initial treatment and using the 5-point GAIS 
5. The percentage of subjects with an improvement over Baseline 
(subjects who have been rated as “very much improved” or 
“much improved” or “improved”), based on subject assessment 
at Week 12, 36, 48 and Visit 7c after initial treatment and using 
the 5-point GAIS 
6. The extent of subject satisfaction with outcome of the treatment, 
as assessed by the Face-Q questionnaire “Satisfaction with 
Outcome” at Week 12, 24, 36, 48 and Visit 7c after initial 
treatment 
7. Subject appearance appraisal after treatment as assessed by the 
Face-Q questionnaire “Appraisal of Nasolabial Folds” at 
Week 12, 24, 36, 48 and Visit 7c after initial treatment, relative 
to Baseline 
8. Subject’s perception of pain after initial treatment with 
Princess® FILLER Lidocaine and with Juvéderm® Ultra XC, 
and Subject’s perception of pain after repeat-treatment with 
Princess® FILLER Lidocaine, using a scale adapted from the 
11-point Numeric Pain Rating Scale (NPRS), where 0 is no pain 
and 10 is the worst pain imaginable. 
9. Time from initial to repeat-treatment for each treatment group 
will be assessed by tabulating the following rates: 
 repeat-treatment at Week 36 
 repeat-treatment at Week 48 
 repeat-treatment at Visit 7c 
 no repeat-treatment 

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10. Recording of injection volume required to achieve optimal 
correction for Princess® FILLER Lidocaine and Juvéderm® 
Ultra XC at initial and touch-up treatments (separate 
assessments) and recording of injection volume required to 
achieve optimal correction for Princess® FILLER Lidocaine 
and Juvéderm® Ultra XC at repeat-treatments (separate 
assessments) 
Safety outcome measures: 
Frequency, severity, seriousness and causal relationship of AEs, 
ADEs, SAEs and SADEs during the entire clinical investigation 
period including subject complaints will be recorded in the subject 
diaries during four weeks after initial-, touch-up-treatments, in 
comparison with Juvéderm® Ultra XC. Frequency, severity, 
seriousness and causal relationship of AEs, ADEs, SAEs and 
SADEs during the entire clinical investigation period including 
subject complaints will be recorded in the subject diaries during 
four weeks after repeat-treatments, for Princess® FILLER 
Lidocaine  
SUBJECT SELECTION 
Targeted Accrual 
Approx. 300 subjects to be screened/ 270 randomized subjects 
/240 evaluable subjects (accounting for a screening failure rate of 
approx. 10% as well as approx. 10% of subjects to be excluded 
from the Per-Protocol Set due to major protocol deviations or 
subjects lost to follow-up) 
Approximately 10-12 United States (US) sites planned 
Number of 
Groups 
Two groups: 
 Group A: 
 Princess® FILLER Lidocaine on left NLF 
 Juvéderm® Ultra XC on right NLF 
 Group B:  
 Juvéderm® Ultra XC on left NLF 

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2. History of allergies or hypersensitivity to hyaluronic acid (HA)
preparations, lidocaine or anesthetics of any amide-based 
anesthetic 
3. Since Juvéderm® Ultra XC contains trace amounts of Gram-
positive bacterial proteins, subjects with history of allergies to 
such material can not be included in this clinical investigation 
4. Tendency to keloid formation, hypertrophic scars and/or 
pigmentation disorders 
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative cancerous 
or pre-cancerous lesions in the area to be treated 
7. Recurrent herpes simplex in the treatment area 
8. History or presence of any autoimmune or connective tissue 
disease, or current treatment with immunomodulating therapy 
9. Uncontrolled (or instable) diabetes mellitus or systemic 
diseases 
10. Facial plastic surgery, tissue augmentation with silicone, fat or 
another non-absorbable substance (permanent fillers) in the area 
of device application 
11. Implantation of facial dermal fillers in the treatment area in the 
preceding twelve months  
12. Skin of the nasolabial region affected by aesthetic treatments 
(e.g. laser therapy, absorbable and non-absorbable sutures 
(threads), microneedling and/or botulinum toxin within the last 
twelve months, dermabrasion and mesotherapy within the last 
six months, chemical peeling within the last three months) or 
planning to undergo such procedures during the clinical 
investigation 

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13. Facial lipolysis, including submental fat treatments, within last 
month prior to enrollment and during the clinical investigation 
14. Bariatric surgery within 12 months prior to enrollment and 
during the clinical investigation 
15. History of bleeding disorder and/or use of anticoagulant, 
antiplatelet or thrombolytic medication from ten days pre- to 
three days post injection 
16. Planned dental/oral surgery or modification (bridge-work, 
implants) within two weeks prior to injection and to a minimum 
of four weeks post injection 
17. Any medical condition prohibiting the inclusion in the clinical 
investigation according to the judgment of the treating 
investigator 
18. Previous enrollment in this clinical investigation 
19. Current participation in another clinical investigation, or 
treatment with any investigational drug/medical device within 
30 days prior to clinical investigation enrollment, or five half-
lives of the investigational drug, whichever is longer  
20. Any dependency of the subject to the treating investigator, the 
blinded independent evaluating investigator or clinical 
investigation site (e.g. employees of the sponsor), or subjects 
who are employees or relatives of the treating investigator 
and/or the independent blinded evaluating investigator 
21. Subjects who have one of the following assessments during the 
visual examinations at Baseline: Snellen visual acuity test 
worse than 20/40 (with corrective eyewear, if applicable), 
abnormal confrontational visual field test, or abnormal ocular 
motility test.  

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Inclusion Criteria –
Repeat-treatment  
Subjects who meet ALL the following criteria are eligible for a 
repeat-treatment: 
1. In the opinion of the treating investigator, the subject has 
returned to sufficient severity of both NLFs that would have 
qualified him for enrollment into the clinical investigation 
initially (note that the subject does not have to return to his 
Baseline severity to be permitted to receive a repeat treatment) 
2. Subjects with NLFs with severity scores of 2 or 3 on the 
5-point NLF-SRS for both NLFs as judged by the treating 
investigator in conjunction with the independent blinded 
evaluating investigator (note that it is not necessary for the 
treating and evaluating investigator to agree on the same 
rating) 
3. Females of childbearing age must have a negative urine 
pregnancy test at the repeat-treatment visit and must agree to 
continue to use an adequate method of contraception for the 
duration of the clinical investigation 
4. Healthy skin in the nasolabial area and free of diseases that 
could interfere in cutaneous aging evaluation and/or injection 
Exclusion Criteria 
– Repeat-treatment 
Subjects who meet ANY of the following criteria are NOT eligible 
for a repeat-treatment: 
1.  Occurrence of a serious adverse event or adverse event of 
special interest (i.e. changes in vision [loss of vision, 
blurriness, double vision, pain in or around the eye, blindness, 
blind spots, problems moving the eyes, changes in peripheral 
vision], skin changing color around the eyelids or around the 
site of injection) during or after the initial injection and/or 
touch-up injection 

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2. Subjects who experienced visual changes or other serious 
medical conditions during or after the initial/touch-up injection 
3. Subjects who have one of the following assessments during the 
visual examinations:  
 Snellen acuity test worse than 20/40 (with corrective 
eyewear, if applicable) 
 abnormal confrontational visual field test 
 abnormal ocular motility test 
4. Subjects who became pregnant since start of the study or are 
planning to become pregnant during the clinical investigation  
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative 
cancerous or pre-cancerous lesions in the area to be treated 
7. Development of recurrent herpes simplex in the treatment area 
since study start 
8. Development of any autoimmune or connective tissue disease 
since start of participation in the study, or current treatment 
with immunomodulating therapy 
9. Development of uncontrolled (or instable) diabetes mellitus or 
any other systemic disease since study start  
10. Development of a bleeding disorder since study start or use of 
anticoagulant, antiplatelet or thrombolytic medication from ten 
days pre- to three days post injection 
11. Planned dental/oral surgery or modification (bridge-work, 
implants) within 2 weeks prior to injection and to a minimum 
of four weeks post injection  

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12. Any medical condition prohibiting the inclusion for repeat 
treatment according to the judgement of the treating 
investigator  
STATISTICAL ANALYSIS 
Sample Size 
Calculation 
The primary effectiveness outcome measure will be evaluated by 
means of a one-sided 95% confidence interval for the difference 
in paired proportions pA-pB. At this, pA is the response rate for 
Princess® FILLER Lidocaine and pB is the response rate for 
Juvéderm® Ultra XC. Thus, a negative value for this difference 
means that the response rate of Princess® FILLER Lidocaine is 
lower than the response rate for Juvéderm® Ultra XC. Princess® 
FILLER Lidocaine will be considered non-inferior to Juvéderm® 
Ultra XC if the lower confidence limit exceeds the non-inferiority 
margin of -10%. 
Further assumptions for sample size calculation: 
 Response rate at Week 24 for Juvéderm® Ultra XC is 88% 
 Response rate at Week 24 for Princess® FILLER Lidocaine 
is 87% 
 Proportion of subjects with response only in one NLF: 
21.9% (88.0% * 13.0% + 87.0% * 12.0% = 21.9%) 
 Proportion of subjects with response in both NLFs: 76.5% 
(88.0% * 87.0% = 76.5%) 
The latter two proportions were calculated on the basis of the 
response rates for Princess® FILLER Lidocaine and Juvéderm® 
Ultra XC assuming that the two NLFs of one subject are 
independent. Since there should be a concordant correlation 
between the two NLFs of one subject, this assumption is 
considered to be conservative. 
Based on these assumptions, 222 subjects will be necessary in 
order to achieve a power of 90%. 

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Sample size calculation was done using nQuery Advisor® 7.0. The 
result is based on 1600 simulations using the Newcombe-Wilson 
score method to construct the confidence interval. 
Analysis Data Sets 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) consists of all randomized subjects 
who received at least one administration of Princess® FILLER 
Lidocaine and the control medical device at the same visit. 
Subjects who received only one treatment (only Princess® 
FILLER Lidocaine or only Juvéderm® Ultra XC) during initial 
treatment will be excluded from the FAS. 
Per-Protocol Set (PPS) 
The Per-Protocol Set (PPS) is defined as a subset of the subjects 
in the Full Analysis Set who had no major protocol deviations. 
Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) comprises all subjects who were 
randomized and received at least one treatment (i.e., any dose of 
Princess® FILLER Lidocaine or the control medical device). 
The PPS and FAS will be both considered equally important for 
the primary analysis; the primary analysis will be performed with 
the FAS; if Princess® FILLER Lidocaine can be considered non-
inferior to Juvéderm® Ultra XC according to this analysis, the 
sensitivity analysis based on the PPS can be considered 
confirmatory. Otherwise, this analysis has to be considered 
exploratory. Non-inferiority is demonstrated only if the results are 
consistent for both analysis data sets. 
All effectiveness analyses will be conducted for the FAS and 
subsequently for the PPS. Safety analyses will be based on the 
SAF. 
General Statistical 
Considerations 
The analysis of the primary effectiveness outcome measure using 
the FAS and the subsequent sensitivity analysis using the PPS, as 

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well as the analyses of the secondary outcome measures 1 and 2,
will be considered confirmatory within the bounds of the 
corresponding hierarchical testing procedure. All other analyses 
will be considered exploratory. 
Planned Statistical 
Analysis 
All effectiveness outcome measures will be tabulated by treatment 
group and visit. To calculate the primary outcome measure, the 
improvement over Baseline in the NLF-SRS grade assessed by the 
independent blinded evaluating investigator at Week 24 will be 
computed for each subject and treatment side by subtracting the 
NLF-SRS grade obtained at Week 24 from ipsilateral NLF-SRS 
grade obtained at Baseline. The response rate will then be 
calculated for each treatment group as the proportion of subjects 
with NLF-SRS improvement (i.e., reduction) 
oint. 
The primary effectiveness outcome measure will be evaluated by 
means of a one-sided 95% confidence interval for the difference 
in paired proportions pA-pB. At this, pA is the response rate for 
Princess® FILLER Lidocaine and pB is the response rate for 
Juvéderm® Ultra XC. Thus, a negative value for this difference 
means that the response rate of Princess® FILLER Lidocaine is 
lower than the response rate for Juvéderm® Ultra XC. Princess® 
FILLER Lidocaine will be considered non-inferior to Juvéderm® 
Ultra XC if the lower confidence limit exceeds the non-inferiority 
margin of -10% and thus if the null hypothesis H0: pA-pB 
-10% 
can be rejected. In addition to this, the response rates for both 
treatment groups will be tabulated.  
The statistical analysis of the secondary and additional outcome 
measures will be described in detail in the statistical analysis plan. 
A hierarchical testing procedure will be applied for the analysis of 
the primary outcome measure, as well as the secondary outcome 
measures 1 and 2, in order to control multiplicity. For qualitative 
variables, the frequencies (absolute and relative) will be calculated 

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and compared between the treatment groups. Quantitative 
parameters will be described by declaring the mean value, standard 
deviation, minimum, first quartile, median, third quartile, and 
maximum per treatment group. In addition to this, mean value, 
standard deviation, minimum, first quartile, median, third quartile, 
and maximum will also be provided for the difference in 
quantitative parameters between the two treatment sides of a 
subject. Secondary outcome measures 1 and 2 will be analyzed as 
described for the primary effectiveness outcome measure. 
Descriptive statistics will be used to summarize the remaining 
outcome measures. Adverse events will be summarized by 
treatment, preferred term and system organ class, and also by 
intensity, duration, causal relationship to the device or procedure, 
and seriousness. 

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3 
Investigators and administrative structure of the clinical 
investigation 
 
Treating investigators: 
This clinical investigation will be conducted at approximately 
ten to twelve clinical investigational sites in the United States 
(US). An updated list of investigators and investigation sites is 
kept separately from the Clinical Investigation Plan (CIP) and is 
available on request. 
Independent blinded 
evaluating investigators: 
An updated list of independent blinded evaluating investigators 
is kept separately from the CIP and is available on request 
Governing IRB(s): 
An updated list of governing Institutional Review Boards(s) 
(IRB[s]) is kept separately from the CIP and is available on 
request. 
Sponsor: 
Croma-Pharma GmbH 
Industriezeile 6, 2100 Leobendorf, Austria 
Tel: +43 2262 684 680 
Fax: +43 2262 6846 8165 
E-mail: office@croma.at 
Web: www.croma.at 
Sponsor’s CIP signatories: 
 
 
  
 
 
 
 

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4 
Background Information and Scientific Rationale 
4.1 
Background Information Regarding Dermal Fillers 
The facial signs of aging are characterized by the formation of wrinkles and folds, which result 
due to the loss of bone mass and soft tissue volume, the redistribution of fat, as well as decreased 
skin elasticity and thickness (Donofrio, 2000; John & Price, 2009; Lowe, Maxwell, & Patnaik, 
2005; Smith, 2008). With the natural process of aging, the endogenous hyaluronic acid (HA) is 
reduced, resulting in a less hydrated and consequently less elastic skin (Bogdan Allemann & 
Baumann, 2008). In the midface, furrowing and flattening of the central mid cheek occurs, with 
displacement medially exaggerating the depth of the nasolabial folds (NLFs) (Coleman & 
Grover, 2006; Mendelson & Jacobson, 2008; Raspaldo, 2008).   
Dermal fillers serve as one of the most common and useful treatments for wrinkles and folds 
and appeal to the growing population keen to reverse the signs of aging (Raspaldo, 2008). Over 
the past two decades, soft tissue augmentation using injectable fillers, has become a standard 
clinical approach for correcting age-related facial defects (Raspaldo, 2008). Among these, HA-
based fillers appear to be ideal, due to their low immunogenic potential and relatively long-
lasting effect. HA is a naturally occurring glycosaminoglycan which exhibits no species and no 
tissue specificity and is an essential component of the extracellular matrix in adult tissue 
(Carruthers, Glogau, Blitzer, & Facial Aesthetics Consensus Group, 2008; John & Price, 2009; 
Rao, Chi, & Goldman, 2005; Vedamurthy, 2004). In the skin, it is located among the collagen 
fibers. It has a hydrophilic capability (Bogdan Allemann & Baumann, 2008; John & Price, 
2009), promoting skin hydration and contributing to skin turgidity (John & Price, 2009). In 
dermal fillers, the HA molecules are chemically cross-linked in order to improve consistency 
and to increase the intradermal residence time of the filler (Landau, 2011). A wide range of 
HA-based dermal fillers are currently on the market differing in terms of source material, 
concentration, method and degree of cross-linking, viscosity, consistency, stiffness and 
injection force (Sundaram & Cassuto, 2013). Due to their favourable risk/benefit profile, HA 
products are the most widely used dermal fillers in Europe and the USA. HA fillers have also 
been used successfully to correct debilitating scars (Halachmi, Ben Amitai, & Lapidoth, 2013; 
Hasson & Romero, 2010; Khan, Richards, & Rashid, 2012; Richards & Rashid, 2011), facial 
lipoatrophy (Bugge, Negaard, Skeie, & Bergersen, 2007; Gooderham & Solish, 2005; Pavicic, 

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Ruzicka, Korting, & Gauglitz, 2010; Ross & Malhotra, 2010) and morphological facial 
asymmetry (Choi et al., 2011; Myung, Lee, & Chang, 2012). 
In order to improve the comfort of filler injections, the local anaesthetic lidocaine hydrochloride 
(the terms “lidocaine” and “lidocaine hydrochloride” are used interchangeably in this 
document) has been included in their formulation to reduce procedural pain and to bypass the 
need for additional anaesthesia (Weinkle et al., 2009). Clinical studies (F. Brandt, Bank, Cross, 
& Weiss, 2010; Few, Cox, Paradkar-Mitragotri, & Murphy, 2015; Glaser et al., 2015; Levy, De 
Boulle, & Raspaldo, 2009a, 2009b; Lupo, Smith, Thomas, Murphy, & Beddingfield, 2008; 
Philipp-Dormston et al., 2014; Prager & Micheels, 2015; Raspaldo, De Boulle, & Levy, 2010; 
Royo de la Torre et al., 2013; Wahl, 2008; Weinkle et al., 2009) have demonstrated that 
treatment with dermal fillers with lidocaine resulted in a statistically and clinically significant 
reduction in pain (p <0.0001). 
Princess® FILLER Lidocaine is a sterile, biodegradable, viscoelastic, clear, absorbable, isotonic 
and homogenized injectable HA gel implant produced by Croma-Pharma GmbH in Austria. 
Princess® FILLER Lidocaine contains HA at a concentration of 23 mg/mL in a physiologic 
buffer and is chemically cross-linked with 1,4-butanediol diglycidyl ether (BDDE) which 
covalently binds native HA molecules to each other with repeating bridges, creating a polymer 
‘network’, transforming the viscous liquid into a gel. Compared with native HA, the cross-
linked HA gel is considerably more resistant against enzymatic and free radical breakdown, so 
that its tissue residence time is dramatically increased. Native HA is added in order to adjust 
the rheological properties and injectability of the fillers (Kablik, Monheit, Yu, Chang, & 
Gershkovich, 2009; Tezel & Fredrickson, 2008). The cross-linking process is optimized so that 
the device is most suitable for injections into the mid to deep dermis. Lidocaine has been added 
to reduce procedural pain and to improve the comfort of filler injections.  
Princess® FILLER Lidocaine is intended to correct moderate to severe facial wrinkles and folds 
and to increase lip volume. The device was also conceived for medical purposes in the European 
Union (EU), consistent with the current Medical Device Directive and aims to address 
reconstructive purposes in the treatment, for instance, of facial lipoatrophy, debilitating scars 
or morphological asymmetry. It is indicated to be injected into the mid to deep dermis (EU 
Instructions for Use [IFU], see Section 22.2). 

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declared highly successful by investigators, patients and independent reviewer. There were no 
serious adverse events (SAEs) in the study, and only few adverse device effects (ADEs) were 
recorded; apart from two events of headache, all ADEs were limited to the injection site and 
have already been described in the literature as common adverse effects of crosslinked HA 
dermal fillers. 
Hence, the studies demonstrated the safety and effectiveness of Princess® FILLER in the 
treatment of NLFs and confirmed the favourable benefit/risk ratio evident from Post-Market 
Surveillance. 
The current clinical investigation will assess the safety and effectiveness of Princess® FILLER 
Lidocaine in the correction of moderate to severe NLFs.  
4.2 
Clinical Condition/Indication 
The indication for Princess® FILLER Lidocaine to be studied in this clinical investigation is 
correction of moderate to severe NLFs. 
The device is not yet approved in the US, while in Europe the label is stating the following: 
Princess® FILLER Lidocaine is intended to correct moderate to severe facial wrinkles and folds 
and to increase lip volume; the device was also conceived for medical purposes and aims to 
address reconstructive purposes in the treatment, for instance, of facial lipoatrophy, debilitating 
scars or morphological asymmetry; it is indicated to be injected into the mid to deep dermis 
(EU IFU, see Section 22.2).  
Juvéderm® Ultra XC is indicated for injection into the mid to deep dermis for correction of 
moderate to severe facial wrinkles and folds (such as NLFs) (see Section 22.3).  
In this clinical investigation, both investigational medical devices (IMDs) will only be used to 
treat NLFs. 
4.3 
Description of the Investigational Medical Devices  
4.3.1 
Princess  FILLER Lidocaine 
Princess  FILLER Lidocaine is a biodegradable HA filler for soft tissue augmentation. It is a 
sterile, viscoelastic, clear, transparent, isotonic and homogenized, injectable gel implant. 
Princess  FILLER Lidocaine consists of cross-linked HA, obtained from Streptococcus equi 

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bacteria, formulated to a concentration of 23 mg/mL in a physiologic buffer. The gel is 
produced with HA molecules of biofermentative origin which are cross-linked via BDDE. The 
formulation additionally contains 0.3% of the medicinal product lidocaine hydrochloride as an 
ancillary substance.  
The device is intended for single use, it is sterile, non-active, and without measuring function. 
No materials of human or animal origin are used during manufacture or as raw materials.  
The device is intended to correct moderate to severe facial wrinkles and folds and to increase 
lip volume. The device was also conceived for medical purposes and aims to address 
reconstructive purposes in the treatment, for instance, of facial lipoatrophy, debilitating scars 
or morphological asymmetry. It is indicated to be injected into the mid to deep dermis (EU IFU, 
see Section 22.2). 
Biodegradation of cross-linked HA occurs through different pathways (e.g. enzymatic, 
temperature, free radicals), and its longevity in vivo is thus limited. Degradation of BDDE 
cross-linked HA is isovolemic, i.e. it remains most of its initial filler volume throughout the 
degradation phase (F. S. Brandt & Cazzaniga, 2008). The benefit of the fillers is via a volume 
effect and by attracting and binding water. When fully degraded, it is absorbed without any 
fibrosis or remaining implant product (F. S. Brandt & Cazzaniga, 2008). Metabolism by-
products are water and carbon dioxide. 
Princess  FILLER Lidocaine is provided in steam sterilized syringes containing 1.0 mL of the 
injectable gel implant. The syringes are packed in boxes also containing two 27 G ½  
disposable sterile needles. Batch numbers, attached to the boxes, are used to ensure traceability.  
The maximal recommended dosage is up to 10 mL per treatment session and up to 20 mL per 
subject per year. 
For more information please refer to the Investigator’s Brochure. 
Manufacturer of Princess® FILLER Lidocaine:  Croma-Pharma GmbH, Industriezeile 6, 2100 
Leobendorf, Austria. 
Manufacturer of the needle: 
. 

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4.4.2 
 Clinical experience 
Over the past two decades, soft tissue augmentation using injectable fillers, has become a 
standard clinical approach for correcting age-related facial defects. Among these, HA-based 
fillers appear to be ideal due to their low immunogenic potential and relatively long-lasting 
effect. Moreover, due to their very favorable risk/benefit profile, HA products are the most 
widely used dermal fillers in Europe and the USA. 
Since their introduction, these devices have been proven to be safe, effective and easy to use 
(Beasley, Weiss, & Weiss, 2009). Princess® FILLER Lidocaine carries the European 
Conformity (CE) mark and has been on the European market since 2016. Princess® FILLER 
(without lidocaine) obtained the CE mark in 2008.    
4.4.3 
Clinical Summary 
Clinical data is not yet available for Princess® FILLER Lidocaine, however data is available 
for Princess® FILLER, which is virtually the same dermal filler without lidocaine. Clinical 
studies with Princess® FILLER, conducted in the course of post-marketing activities in Europe, 
confirmed that the device is safe and effective. 
Post-marketing study 1: “
 for the treatment of nasolabial folds”. 
This clinical investigation was performed in 30 subjects with NLFs, aged 30 to 60 years. At the 
start of the investigation, 76% of subjects had moderate and 24% of subjects had severe 
wrinkles. One year post-injection of HA, 8% of subjects presented with severe, 56% with 
moderate, and 36% mild wrinkles with changes being statistically significant. Other 
effectiveness outcome measures confirmed these positive results and most subjects (88%) were 
willing to repeat the treatment at the end of the clinical investigation. Collagen levels and elastic 
fibers were not significantly changed after the treatment. The AEs with positive causal nexus 
were: local erythema/edema, ecchymosis, hematoma and local pain. They presented mild to 
 
 
 
  

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moderate intensity, and short to medium duration. The AEs were rare and resolved completely, 
thus demonstrating the safety of the device (Arruda et al., 2013). 
Post-marketing study 2: “An open-label study of the safety and efficacy of Princess 
FILLER for the correction of moderate to severe wrinkles”. 
This clinical investigation was performed in 71 subjects with different indications (NLFs, 
marionette lines and glabellar lines). The evaluation of the wrinkle severity score showed a 
significant immediate improvement of the wrinkles as well as a long lasting effect after 
administration of Princess® FILLER. On a 4-point scale (from 1, mild, to 4, severe) average 
wrinkle severity was reduced from 2.17 before treatment to 1.16 and 1.7 one month and nine 
months post-injection, respectively. More than 70% of the subjects reported that their 
expectations had been reached at 240 days (end of follow-up period). Short term reactions were 
transient and related to the injection procedure (e.g. redness, swelling and pain). No long term 
adverse reactions were reported, confirming that the device was well tolerated (Landau, 2011).  
Therefore, both studies demonstrated the safety and effectiveness of Princess® FILLER in the 
treatment of NLFs. 
Post-marketing study 3: “Prospective, open label, non-comparative, multicentre, post-
market clinical follow-up study of the Princess® FILLER performance and safety for 
correction of facial lipoatrophy, morphological asymmetry of the face, or debilitating 
scars (CPH-410-201259, FLASH 1)” 
Princess® FILLER was evaluated in a post-market clinical follow-up study (FLASH 1, see 
Section 6.2.1), in order to evaluate its performance and safety for the correction of facial 
lipoatrophy, morphological asymmetry of the face, or debilitating scars. The study showed 
treatment with Princess® FILLER to be safe, well tolerated and efficacious in the treatment of 
facial lipoatrophy, morphological asymmetry and debilitating scars and confirmed the 
effectiveness of the investigational device over a six-month period. The treatment outcome was 
declared highly successful by investigators, patients and independent reviewer. There were no 
SAEs in the study, and only few ADEs were recorded; apart from two events of headache, all 
ADEs were limited to the injection site and have already been described in the literature as 
common adverse effects of crosslinked HA dermal fillers. 

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4.5 
Clinical investigation Rationale 
The current clinical investigation is designed to support regulatory approval in the US and to 
obtain clinical safety and effectiveness data for the dermal filler Princess® FILLER Lidocaine 
in the treatment of NLFs.  
A non-inferiority investigation to assess the safety and effectiveness of Princess® FILLER 
Lidocaine in comparison with Juvéderm® Ultra XC is considered appropriate and in line with 
current FDA guidance. Each subject will receive Princess® FILLER Lidocaine to correct one 
NLF and Juvéderm® Ultra XC to correct the contralateral NLF. NLFs severity will be assessed 
with the NLF-SRS, which is an new objective and validated measurement tool for NLFs 
severity assessments developed recently for Croma-Pharma GmbH by Canfield Scientific Inc. 
Since the effects of HA dermal fillers have been reported to last from four to twelve months 
(Downie, Grimes, & Callender, 2013; Goodman et al., 2011; Nast et al., 2011) the follow-up 
period for effectiveness will be 36 weeks, with an option for repeat-treatment at 36 or 48 weeks.  
The clinical investigation schedule includes a single treatment per subject, which is sufficient 
to provide optimal correction as determined by the treating investigator, with an option for 
touch-up treatment two weeks later to address any possible under-correction and a 
repeat-treatment at Week 36 or Week 48, if repeat-treatment is not needed at Week 36. The 
schedule includes visits at 2, 12, 24 and 36 and or 48 weeks after treatment for effectiveness 
and safety evaluation, as well as weeks 40 and/or 52 for safety evaluation.  
The marketed product Juvéderm® Ultra XC is used as comparator in this clinical investigation, 
since containing the same lidocaine hydrochloride concentrations as Croma-Pharma GmbH’s 
product and approved for the treatment of NLFs. Moreover, Juvéderm® Ultra XC is comparable 
to Princess® FILLER Lidocaine regarding its composition and intended use. 
A non-inferiority investigation to assess the safety and effectiveness of Princess® FILLER 
Lidocaine in comparison to Juvéderm® Ultra XC is considered appropriate and in line with 
current FDA guidance. 
 
 

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5 
Clinical Investigation Purpose and Objectives 
5.1 
Purpose 
To evaluate the effectiveness and safety of Princess® FILLER Lidocaine in the correction of 
moderate to severe NLFs compared to Juvederm® Ultra XC. 
5.2 
Primary Objective 
The primary objective is to assess the effectiveness of Princess® FILLER Lidocaine in reducing 
the severity of NLFs compared to Juvederm® Ultra XC, based on the independent blinded 
evaluating investigator live assessment using the NLF-SRS at Week 24 after initial treatment 
and relative to Baseline assessments. 
5.3 
Secondary Objectives 
1. To assess the effectiveness of Princess® FILLER Lidocaine in reducing the severity of 
NLFs compared to Juvederm® Ultra XC, based on the independent blinded 
photographic reviewers assessments of photographs from Baseline and Week 24 after 
initial treatment 
2. To assess the effectiveness of Princess® FILLER Lidocaine in reducing the severity of 
NLFs compared to Juvederm® Ultra XC, based on the treating investigator live 
assessments at Week 24 after initial treatment, relative to Baseline assessments 
3. To evaluate aesthetic improvement over Baseline after treatment using GAIS, based on 
the independent blinded evaluating investigator assessment at Week 24 after initial 
treatment 
4. To evaluate aesthetic improvement over Baseline after treatment using GAIS, based on 
the subject assessment at Week 24 after initial treatment 
5.4 
Additional Objectives 
1. To assess the effectiveness of Princess® FILLER Lidocaine in reducing the severity of 
NLFs compared to Juvederm® Ultra XC, based on the independent blinded evaluating 
investigator live assessments at Week 12, 36, 48 and the post repeat-treatment hold 
follow-up visit (Visit 7c) after initial treatment and relative to Baseline assessments 
2. To assess the effectiveness of Princess® FILLER Lidocaine in reducing the severity of 
NLFs compared to Juvederm® Ultra XC, based on the independent blinded 

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photographic reviewers assessments of photographs from Baseline and Week 12, 36, 48 
and Visit 7c after initial treatment 
3. To assess the effectiveness of Princess® FILLER Lidocaine in reducing the severity of 
NLFs compared to Juvederm® Ultra XC, based on the treating investigator live 
assessments at Week 12, 36, 48 and Visit 7c after initial treatment and relative to 
Baseline assessments 
4. To evaluate aesthetic improvement over Baseline after treatment using GAIS, based on 
the independent blinded evaluating investigator assessments at Week 12, 36, 48 and 
Visit 7c after initial treatment 
5. To evaluate aesthetic improvement over Baseline after treatment using GAIS, based on 
the subject assessments at Week 12, 36, 48 and Visit 7c after initial treatment 
6. To assess subject satisfaction with aesthetic outcome after treatment at Week 12, 24, 36, 
and/or 48 and Visit 7c after initial treatment 
7. To assess subject appearance appraisal of NLFs after treatment at Week 12, 24, 36, 
and/or 48 and Visit 7c after initial treatment compared to Baseline 
8. To evaluate subject’s perception of pain after initial and repeat-treatment with Princess® 
FILLER Lidocaine and Juvederm® Ultra XC  
9. To assess time from initial to repeat-treatment for each treatment group 
10. To assess injection volume (initial, touch-up and repeat-treatments, separate 
assessments) needed for optimal correction for Princess® FILLER Lidocaine and 
Juvederm® Ultra XC 
5.5 
Safety Objectives 
To assess frequency, severity, seriousness and causal relationship of AEs, ADEs, SAEs, and 
serious adverse device effects (SADEs) during the entire clinical investigation period including 
subjects complaints recorded in the subject diaries during the four weeks following initial-, 
touch-up- and repeat-treatments, as in comparison with Juvéderm® Ultra XC. 

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6 
Risks and Benefits of the Investigational Device and Clinical 
Investigation 
6.1 
Potential Risks 
In general HA fillers are the most frequently used dermal fillers and are considered the most 
predictable, having been shown to be safe and well-tolerated, with studies reporting mild 
adverse events which resolve quickly. Risks associated with the clinical investigation IMDs 
may include common, short-term events like discomfort, redness, swelling or bruising 
(DeLorenzi, 2013). 
Less likely and uncommon events may include short-term events like injection site necrosis or 
hypersensitivity or medium-term events like visibility of injectant (blanched, bluish or white 
papule or lumps) or nodule formation (DeLorenzi, 2013; Funt & Pavicic, 2013; Ibrahim, 
Overman, Arndt, & Dover, 2017). 
Rare but serious adverse events associated with the unintended intravascular injection of dermal 
fillers in the face have been reported and include temporary or permanent vision impairment, 
blindness, cerebral ischemia or cerebral hemorrhage, which are leading to stroke, skin necrosis, 
and damage to underlying facial structures (Beleznay et al., 2015). Possibly unrelated events 
like headache, sinusitis, respiratory symptoms, itching, acne and herpes simplex reactivation 
have been occasionally reported after treatment with dermal fillers (Bugge et al., 2007; 
DeLorenzi, 2013; Funt & Pavicic, 2013; Gazzola, Pasini, & Cavallini, 2012; Requena et al., 
2011). 
The risks will be mitigated by following strategies: 
 engagement of investigators who are experienced in use of dermal fillers for correction 
of NLFs to ensure correct application of the investigational device 
 regular follow-up assessments throughout the study duration, which will allow for 
timely recognition and management of potential AEs 
 evaluation of vision changes through visual examinations before and after treatment 
 protocols at each investigational site for immediate intervention in the event of 
unintended vascular injection 
 phone calls for safety follow-up: the subjects will be contacted by phone three days 
after initial, touch-up and repeat-treatments to check their health condition, and will be 

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established and no serious ADEs are expected if injected correctly by an adequately trained and 
experienced user with appropriate knowledge of facial anatomy. Please refer to the 
Investigator’s Brochure for a list of possible adverse events associated with the use of dermal 
fillers. 
From clinical investigations to date, effectiveness has been reported to be immediate and long-
lasting. The treatment is also expected to positively influence the emotional and social 
wellbeing of the subjects. Thus, the benefits for the subjects participating in this clinical 
investigation outweigh the possible risks.  
 
 

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7 
Design of the Clinical Investigation 
7.1 
Description of the Clinical Investigation Design  
This is a randomized, subject- and evaluating investigator-blinded, non-inferiority, multicenter, 
split-face comparison clinical investigation of Princess® FILLER Lidocaine compared to 
Juvederm® Ultra XC in the treatment of moderate to severe NLFs.  
Eligible subjects will undergo baseline assessments, where the baseline severity of NLFs (the 
left side and right side been separately evaluated) will be assessed live by the treating 
investigator in conjunction with the independent blinded evaluating investigator. Each subject 
will receive an injection of Princess® FILLER Lidocaine (Group A: left NLF; Group B: right 
NLF) and an injection of Juvederm® Ultra XC (Group A: right NLF; Group B: left NLF) at 
Visit 2 (Day 0, Baseline). A touch-up treatment may be performed at Visit 3a two weeks 
(± 3 days) after initial treatment, if optimal aesthetic correction was not achieved after the first 
injection at Baseline. Follow-up assessments for safety and effectiveness will be performed at 
Week 2 (optional touch-up), Week 12, 24, 36 and/or 48 (for details see Section 2.1). At Visit 6 
and/or Visit 7 and/or Visit 7c (see end of this section for details on this visit), an evaluation for 
repeat-treatment is scheduled, followed by repeat-treatment as well during these visits if 
needed. The repeat-treatment will be performed with Princess® FILLER Lidocaine on both 
NLFs. 
In that case safety visits are then scheduled four weeks after the repeat-treatment (at 
Week 40/Visit 8a or Week 52/Visit 8b or Visit 8c) and twelve weeks after the repeat-treatment 
(at Week 48/Visit 9a or Week 60/Visit 9b or Visit 9c) (see end of this section for details on 
Visit 8c and Visit 9c). Additional safety follow-up assessments will be performed on the phone 
three days (± 24 hours) after initial, touch-up and repeat-treatments, only for subjects who 
received this treatment. At the end of each treatment session, subjects will receive a diary to 
record the injection site reactions, as well as the incidence of AEs associated with unintended 
intravascular injection over the following four weeks after initial-, touch-up- and repeat-
treatments.  
NLFs severity will be evaluated (live assessment) by the treating investigator and by the 
independent blinded evaluating investigator, using the NLF-SRS. The aesthetic improvement 
will be assessed by the subject and by the independent blinded evaluating investigator 

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(separated assessments) using the GAIS. In addition, NLFs severity will be assessed from 
photographs by three independent blinded photographic reviewers. 
Subject satisfaction will be assessed by FACE-Q questionnaires on “Satisfaction with 
Outcome” and “Appraisal of Nasolabial Folds”. 
Pain assessment will be done after initial and repeat-treatment in 15 min increments (starting 
15 min after last injection and for 60 min post-treatment). 
In order to evaluate vision changes, visual examinations (including Snellen visual acuity, 
confrontational visual fields and ocular motility) will be performed at Baseline (Visit 2) and at 
Week 4 (Visit 3b); visual examinations will be done as well at Week 2 (Visit 3a) and at Week 6 
(Visit 3c) for subjects who received touch-up treatment, and also at Week 40 (Visit 8a) or at 
Week 52 (Visit 8b) or at Visit 8c for subjects having received repeat-treatment respectively at 
Week 36 (Visit 6) or at Week 48 (Visit 7) or at Visit 7c. These assessments will be done prior 
to- and 30 min after any treatment. Further details on visual examinations and the action to be 
taken in case of clinically significant changes are provided in Section 10.8. 
The effectiveness of the investigational device will be assessed according to changes in NLFs 
severity compared to Baseline using the 5-point NLF-SRS, as assessed by the independent 
blinded evaluating investigator, the treating investigator and three independent blinded 
photographic reviewers, and compared to the results obtained using Juvederm® XC. 
Note: During the conduct of the trial, some subjects were not evaluated for repeat-treatment at 
Week 36 (Visit 6) and/or Week 48 (Visit 7) due to a hold on repeat-treatment. Therefore, a post 
repeat-treatment hold follow-up visit (Visit 7c, no visit window) has been added in CIP Version 
7.0 to allow subjects to return for evaluation following the end of the hold on repeat-treatment. 
Subsequent follow up visits (Visit 8c [4 weeks after repeat-treatment] and Visit 9c [12 weeks 
after repeat-treatment]) have also been added. 
7.2 
Population to be Studied 
A total of approximately 300 subjects of either gender, over 22 years of age inclusive at 
Screening, who meet all the inclusion criteria and do not meet any exclusion criteria and who 
provide written informed consent, will be enrolled in the clinical investigation. 

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7.3 
Outcome Measures 
7.3.1 
Effectiveness Outcome Measures 
Responder is defined as having at least one grade improvement over Baseline, on the 5-point 
NLF-SRS. 
7.3.1.1 
Primary outcome measure: 
The percentage of responders based on the independent blinded evaluating investigator live 
assessment at Week 24 after initial treatment and compared to Juvederm® Ultra XC. NLF-SRS 
scores are ranked as 0 (None/minimal), 1 (Mild), 2 (Moderate), 3 (Severe) and 4 (Extreme) (see 
Table 1). 
7.3.1.2 
Secondary Outcome Measures: 
Responder is defined as having at least one grade improvement over Baseline, on the 5-point 
NLF-SRS. 
 
1. 
The percentage of responders based on the independent blinded photographic 
reviewers assessments at Week 24 after initial treatment, compared to Juvéderm® Ultra 
XC and based on photographs  
2. 
The percentage of responders based on the treating investigator live assessment at 
Week 24 after initial treatment and compared to Juvederm® Ultra XC 
3. 
The percentage of subjects with an improvement over Baseline (subjects who have 
been rated as “very much improved” or “much improved” or “improved”), based on 
the independent blinded evaluating investigator assessment at Week 24 after initial 
treatment and using the 5-point GAIS 
4. 
The percentage of subjects with an improvement over Baseline (subjects who have 
been rated as “very much improved” or “much improved” or “improved”), based on 
subject assessment at Week 24 after initial treatment and using the 5-point GAIS 
7.3.1.3 
Additional Outcome Measures: 
Responder is defined as having at least one grade improvement over Baseline, on the 5-point 
NLF-SRS. 
 

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1. The percentage of responders based on the independent blinded evaluating investigator 
live assessment at Week 12, 36, 48 and Visit 7c after initial treatment and compared to 
Juvederm® Ultra XC  
2. The percentage of responders based on the independent blinded photographic reviewers 
assessments at Week 12, 36, 48 and Visit 7c after initial treatment, compared to 
Juvéderm® Ultra XC and based on photographs  
3. The percentage of responders based on the treating investigator live assessments at 
Week 12, 36, 48 and Visit 7c after initial treatment and compared to Juvederm® Ultra 
XC 
4. The percentage of subjects with an improvement over Baseline (subjects who have been 
rated as “very much improved” or “much improved” or “improved”), based on the 
independent blinded evaluating investigator assessments at Week 12, 36, 48 and 
Visit 7c after initial treatment and using the 5-point GAIS 
5. The percentage of subjects with an improvement over Baseline (subjects who have been 
rated as “very much improved” or “much improved” or “improved”), based on subject 
assessments at Week 12, 36, 48 and Visit 7c after initial treatment and using the 5-point 
GAIS 
6. The extend of subject satisfaction with outcome of the treatment as assessed by the 
Face-Q questionnaire “Satisfaction with Outcome” at Week 12, 24, 36, 48 and Visit 7c 
after initial treatment 
7. Subject appearance appraisal after treatment as assessed by the Face-Q questionnaire 
“Appraisal of Nasolabial Folds” at Week 12, 24, 36, 48 and Visit 7c after initial 
treatment relative to Baseline 
8. Subject’s perception of pain after initial treatment with Princess® FILLER Lidocaine 
and with Juvéderm® Ultra XC, and Subject’s perception of pain after repeat-treatment 
with Princess® FILLER Lidocaine, using a scale adapted from the 11-point Numeric 
Pain Rating Scale (NPRS), where 0 is no pain and 10 is the worst pain imaginable.  
9. Time from initial to repeat-treatment for each treatment group will be assessed by 
tabulating the following rates: 
 Repeat-treatment at Week 36 
 Repeat-treatment at Week 48 
 Repeat-treatment at Visit 7c 

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 No repeat-treatment 
10. Recording of injection volume required to achieve optimal correction for Princess® 
FILLER Lidocaine and Juvéderm® Ultra XC at initial and touch-up treatments (separate 
assessments) and recording of injection volume required to achieve optimal correction 
for Princess® FILLER Lidocaine at repeat-treatments (separate assessments) 
 
7.3.2 
Safety Outcome Measures 
Frequency, severity, seriousness and causal relationship of AEs, ADEs, SAEs and SADEs 
during the entire clinical investigation period including subject complaints will be recorded in 
the subject diaries during four weeks after initial-, touch-up-treatments, in comparison with 
Juvéderm® Ultra XC. Frequency, severity, seriousness and causal relationship of AEs, ADEs, 
SAEs and SADEs during the entire clinical investigation period including subject complaints 
will be recorded in the subject diaries during four weeks after repeat-treatments, for Princess® 
FILLER Lidocaine 
All effectiveness and safety outcome measures are standard measurements. The 5-point 
NLF-SRS, used to assess the primary effectiveness outcome measure, is an objective and 
validated measurement tool for NLFs severity assessment (see Section 10.1).  
7.4 
Subject Identification 
Each site will be assigned a unique site identification code; additionally, at each site, the treating 
investigator will assign an unique subject identification number in ascending order e.g. 001, 
002, 003 etc. 
Subjects will be enrolled until the planned sample size is achieved. Drop-outs will not be 
replaced. 
7.5 
Screening Failures 
Data for screening failures (eligible subjects who did not receive investigational device for 
whatever reason) will be collected in source documentation at the site, documented in the 
Screening log and entered into the electronic case report form (eCRF), including the reason for 
the failure. 

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7.6 
Randomization and Blinding 
Randomization will be performed at Baseline (Visit 2) per clinical investigation site via 
interactive web response system (IWRS). Each participant will receive Princess® FILLER 
Lidocaine in one NLF and Juvéderm® Ultra XC in the contralateral NLF, with allocation of 
respective fillers to the sides randomized as followed: 
 Group A: 
 Princess® FILLER Lidocaine on left NLF  
 Juvéderm® Ultra XC on right NLF  
 Group B:  
 Juvéderm® Ultra XC on left NLF 
 Princess® FILLER Lidocaine on right NLF 
The treating investigator performing the treatment will be aware of the device injected 
(unblinded treating investigator).  
 
The independent blinded evaluating investigator will not be aware of the device injected. To 
check if the independent blinded evaluating investigator has been successfully blinded, the 
following questions will be asked after the initial treatment: 
- Can you guess which of the two fillers the subject has received into the left nasolabial fold? 
- If Yes, which one? 
- Why do you deem that the subject has received that filler into the left nasolabial fold? 
The subject will be blinded using a blindfold. To check if the subject has been successfully 
blinded, the following questions will be asked after the initial treatment: 
- Can you guess which of the two fillers you’ve received into the left nasolabial fold? 
- If Yes, which one? 
- Why do you deem that you’ve received that filler into the left nasolabial fold? 
Moreover, an evaluation of NLFs severity by three independent blinded photographic reviewers 
using the 5-point NLF-SRS and based on photographs will take place at the end of the clinical 
investigation. Each of the three independent blinded photographic reviewers will review all 
photographs. These independent blinded photographic reviewers, will not be aware of the 
treatment allocation. They will be dislocated from the clinical investigational sites, will have 

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no access to randomization schedule, and will not discuss any findings with the treating 
investigators or independent blinded evaluating investigators during the clinical investigation 
and until the final database lock.  
The repeat-treatment will be performed with Princess® FILLER Lidocaine on both NLFs. 
The randomization assignment should not be revealed before the database has been cleaned and 
closed. 
Emergency unblinding 
There will be no special procedure for emergency unblinding because the treating investigators 
will be aware of the treatment allocation, and the subjects will know that they have received a 
HA dermal filler with lidocaine, which is, in both cases, sufficient level of information needed 
in case of emergency. 
 
 

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8 
Investigational Medical Devices  
8.1 
Packaging and Labeling 
Princess® FILLER Lidocaine is provided in syringes containing 1.0 mL of the injectable gel 
implant, together with two 27 G ½  disposable sterile needles.  
Juvéderm® Ultra XC injectable gel is supplied in syringes containing 1.0 mL of the injectable 
gel implant with 30 G needles.  
Both devices will be labeled according to applicable guidelines and national legal requirements. 
8.2 
Storage and Handling 
Both Princess® FILLER Lidocaine and Juvéderm® Ultra XC must be stored at 2 to 25°C in a 
dry place in the original box, protected from light, heat and frost. There are incompatibilities 
between sodium hyaluronate and quaternary ammonium compounds such as benzalkonium 
chloride solutions. Therefore, Princess® FILLER Lidocaine or Juvéderm® Ultra XC should 
never be placed in contact with these substances, or with medical-surgical instruments that have 
been in contact with these substances. 
8.3 
Administration of the Device 
8.3.1 
Preparation of Administration 
The IMDs must not be used if the packaging is opened or damaged. Upon opening of the 
packaging, the devices should not be re-sterilized or reused. 
For more information please refer to the respective Instructions for Use (see Section 22.2). 
The skin to be treated should be thoroughly cleaned and disinfected prior to injection of the 
device and appropriate aseptic technique should be employed throughout the procedure.  
Prior to use the device, the luer-lock adapter should be held securely and the tip cap should be 
removed by twisting and pulling carefully, which should prevent formation of bubbles. The 
syringe should be held and the enclosed needle firmly attached. The needle should be secured 
tightly by twisting clockwise. The syringe is held correctly if the backstop opens at the back, 
toward the hand in which it is held.  

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8.3.2 
Injection Technique 
The injection technique used is essential for the success of treatment. Therefore, all 
participating treating investigators will receive, or must have previously received, specific 
training in injection techniques for filling NLFs; such specific training in the injection technique 
will be documented in the Trial Master File.  
The investigational device should be injected into the mid- to deep dermis. Superficial 
injections, near the interface of the epidermis and papillary dermis, can result in visible white, 
yellow, or blue nodules, which may be persistent. Deep injections into the subcutaneous fat 
may result in loss of the filler in the vast subcutaneous space, requiring larger volumes. 
On Day 0 (Visit 2), the Princess® FILLER Lidocaine will be injected to one nasolabial fold and 
the control Juvéderm® Ultra XC to the contralateral nasolabial fold of each subject, according 
to the randomization scheme; the left nasolabial fold will be treated first and the right nasolabial 
fold thereafter. 
After insertion of the needle, and just before injection, the plunger rod should be withdrawn 
slightly to aspirate and verify that the needle is not intravascular.  
After the first small amount of material has been injected into the subject, it is suggested to wait 
a full three seconds to allow the lidocaine to take effect before proceeding with the rest of the 
injection (Juvéderm® IFU, see Section 22.3).  
Different injection techniques can be employed based on investigator's preference and 
characteristics of the defect under correction. These include: 
Retrograde technique: introduction of the entire needle along the fold or skin depression and 
injecting while slowly withdrawing the needle. 
Fan technique: introduction of the entire needle along the fold or skin depression and injecting 
while slowly withdrawing the needle. The fan technique consists in introducing the needle as 
for the retrograde technique, and injecting the gel while withdrawing the needle, without 
removing its tip from the skin; then, changing the direction of the needle and injecting a new 
line. Repeating this process several times will achieve a fan pattern. This technique allows 
filling a large area and creating or restoring facial volume from a single injection point. 

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Lateral movements of the needle must be avoided since these may result in a fanlike dissection 
of the sub-epidermal plane, increasing the incidence of local AEs like bruising, swelling, 
redness, pain, or tenderness at the injection site. 
The device should only be used with the needle and syringe provided by the manufacturer. 
The device should be injected slowly with the least amount of possible pressure for the same 
reason. If the needle is blocked, the pressure on the plunger rod should not be increased, but the 
injection stopped and the needle replaced.  
If a larger volume of the filler is needed to achieve the correction, small volumes should be 
injected in two or more sessions, instead of high volumes in one session. 
The injection must be stopped just before the needle is pulled out of the skin to prevent leakage 
of the device or placement too superficially in the skin. 
The needle must not be manipulated or bent, if the needle is blocked, pressure on the plunger 
rod should not be increased, instead injection should be stopped and the needle replaced.  
After use the syringe, needle and remaining contents should be disposed appropriately and the 
device should never be re-used. 
8.3.3 
Touch-up treatment 
The decision to perform touch-up treatment is in the responsibility of the treating investigator 
and aim to obtain optimal aesthetic result, if not already achieved with the initial treatment. 
8.3.4 
Applied volume of the device 
The dosage (volume) of filler to be administered will depend on the depth of the NLF to be 
corrected, with the goal of optimal correction of the respective NLF with the respective HA 
filler during the first injection session, and will be decided in each case by the treating 
investigator. The severity of each NLF, as well as The total volume injected per treatment for 
each NLF and device, will be recorded in the eCRF. The devices should be injected according 
to the respective IFU (see Sections 22.2 and 22.3) and will not exceed 10 mL per treatment 
session. 
The maximal recommended Princess® FILLER Lidocaine dosage is up to 10 mL per treatment 
session and up to 20 mL per subject per year.  
Juvéderm® Ultra XC should be limited to 20 mL per 60 kg (130 lbs) body mass per year. 

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8.4 
Precautions and Warnings, Prohibited Medications/Treatments and 
Restrictions 
8.4.1 
Precautions and Warnings 
 The device must not be used if the expiry date has lapsed, if the packaging or contents are 
damaged, or if the gel in the syringe appears inhomogenous and/or cloudy 
 The device should not be injected into blood vessels, bones, tendons, ligaments, nerves, 
muscles or naevi 
 Immediately stop the injection if a subject exhibits any signs or symptoms associated with 
injection into a blood vessel, such as changes in vision, signs of a stroke (including sudden 
difficulty speaking, numbness or weakness in their face, arms or legs, difficulty walking, 
face drooping, severe headache, dizziness, or confusion), white appearance (or blanching) 
of the skin, or unusual pain during or shortly after the procedure 
 In case of a vascular event, emergency treatment must be sought, and high dose 
hyaluronidase (Alam et al., 2008), vigorous massage and heat (gauze with hot water) should 
be applied. In addition, topical 2% nitroglycerin paste may encourage vasodilatation 
(Belazay et al., 2015) 
 The device should never be placed in contact with quaternary ammonium compounds (such 
as benzalkonium chloride solutions) or with medical-surgical instruments that have been in 
contact with these substances 
Upon completion of device administration 
 After injection the investigator may apply a light massage for uniform distribution of the 
filler 
 Application of ice packs for 5-10 min. post injection is optional and may reduce redness 
and swelling; this have to be recorded in the clinical investigation eCRF(s) along with any 
other concomitant medication/treatment 
 
The subject should be requested to stay in the office for a period of at least 30 minutes after 
the injection to assess pain following injection and to detect possible blanching caused by 
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 The health care professionals must be familiar with the signs and symptoms associated with 
vascular occlusion, and have a plan detailing how to treat the subject in the event of vascular 
occlusion; this may include on-site treatment and/or immediate referral to another health 
care professional for treatment. For instance, in the event of blindness or any ophthalmic 
signs or symptoms, subjects have to undergo immediate evaluation by a ophthalmology 
specialist. Ophthalmology specialists (ideally a Retinal Specialist, if readily available) near 
each investigational site who are able to immediately examine subjects should be identified 
and informed about the clinical investigation procedure. Additionally, a specific treatment 
protocol in case of unintended intravascular injection that is consistent with those 
recognized by national, professional societies should be in place at each investigational site. 
 The following information will be recorded in the eCRF(s) for each of the treatments 
administered: date of application, the side of application, injection technique, exact start 
time and end time of injection, injected volume of the device (see Section 8.3.4) and device 
ID. 
8.4.2 
Prohibited Medications/Treatments 
The following medications/treatments will be prohibited: 
 From ten days before Day 0 (Baseline) until three days post-injection: use of anticoagulant, 
antiplatelet or thrombolytic medication 
 
Current treatment with immunomodulating therapy 
8.4.3 
Restrictions 
 Subjects must be advised not to apply any make-up for twelve hours after the injection  
 Subjects should avoid prolonged exposure to sunlight and ultraviolet (UV) for one week 
after injection 
 Subjects should abstain from use of saunas or Turkish baths for one week after the injection 
 Subjects should abstain from frequent solarium visits  
 Subjects should abstain from consuming alcohol, nicotine –containing products one hour 
before and after injection 

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 Subjects should not massage the treatment site or apply pressure to the area for one week 
following the injection, to avoid the possible risk of device mobility 
 Subjects should avoid strenuous exercise within 24 hours after injection 
8.5 
Rescue Medication 
In case of overcorrection, commercially available hyaluronidase should be used at the discretion 
of the treating investigator, in accordance with the American Society for Dermatologic Surgery 
guidelines (Alam et al., 2008). 
If the subject complains of ocular pain or vision changes, they should be immediatey refered to 
an ophthamolgy specialist.  
8.6 
Medical Device Accountability 
The assumed average volume of such device to be administred for this indication is 2.0 mL per 
fold for the initial treatment, 1.0 mL per fold for potential additional touch-up treatment and 
2.0 mL per fold for potential repeat treatment. Considering the number of subjects to be enrolled 
(270 subjects), it is anticipated that maximum of 1,860 units of Princess® FILLER Lidocaine, 
as well as the 900 units of the control device, will be used during this clinical investigation. 
The clinical investigation material must not be used outside the context of this CIP. 
Documentation of receipt, dispensing and return of all IMDs must be performed by the principal 
investigator or his/her designee. It is the principal investigator’s responsibility to ensure that all 
clinical investigation materials are kept in a secure location, with access limited to individuals 
authorized by the principal investigator. At the end of the investigation, all remaining clinical 
investigation material should be destroyed on site, following the site-specific destruction 
procedure after a monitor has verified all accountability documentation. If the site does not have 
an appropriate destruction process, the material must be returned to the sponsor designee . 
Records on investigational device delivery to the center, the inventory at the site, the use by 
each subject, and return to the sponsor must be maintained by the principal investigator or 
designee. Forms will be provided to enhance device accountability. 
As the preparations are for use of the treating investigator only, compliance will be controlled 
by the drug accountability log and empty packages only. Empty or used syringes will not be 
returned to the sponsor, but will be destroyed as per investigational sites’s procedures. 

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9 
Subject Selection, Withdrawal and Discontinuation 
9.1 
Inclusion and Exclusion Criteria – Screening/Baseline 
9.1.1 
Inclusion Criteria 
Subjects who meet ALL the following criteria are eligible for this clinical investigation: 
1. Male or female subjects, 22 years of age or older, at the Screening visit  
2. Subjects with two fully visible, approximately symmetrical moderate to severe NLFs (same 
severity) with severity scores of 2 or 3 on the 5- point NLF-SRS for both NLF as judged by the 
treating investigator in conjunction with the independent blinded evaluating investigator.  
3. Females of childbearing potential must have a negative urine pregnancy test at injection visits 
and must agree to use an adequate method of contraception for the duration of the clinical 
investigation 
4. Healthy skin in the nasolabial area and free of diseases that could interfere in cutaneous aging 
evaluation 
5. Willingness to abstain from any aesthetic or surgical procedures in the treatment area for the 
duration of the clinical investigation, including botulinum toxin injections (except glabellar 
or forehead botulinum toxin treatment) 
6. Subjects having understood the purpose and conduct of the clinical investigation and having 
given written informed consent 
9.1.2 
Exclusion Criteria 
Subjects who meet ANY of the following criteria are NOT eligible for this clinical 
investigation: 
1. For females: pregnant and/or lactating or planning to become pregnant during the clinical 
investigation 
2. History of allergies or hypersensitivity to HA preparations, lidocaine or anesthetics of any 
amide-based anesthetic  

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3. Since Juvéderm® Ultra XC contains trace amounts of Gram-positive bacterial proteins, subjects 
with history of allergies to such material can not be included in this clinical investigation 
4. Tendency to keloid formation, hypertrophic scars and/or pigmentation disorders 
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in the 
area to be treated 
7. Re-current herpes simplex in the treatment area 
8. History or presence of any autoimmune or connective tissue disease, or current treatment with 
immunomodulating therapy 
9. Uncontrolled (or instable) diabetes mellitus or systemic diseases 
10. Facial plastic surgery, tissue augmentation with silicone, fat or another non-absorbable 
substance (permanent fillers) area of device application 
11. Implantation of facial dermal fillers in the treatment area in the preceding twelve months  
12. Skin of the nasolabial region affected by aesthetic treatments (e.g. laser therapy, absorbable and 
non-absorbable sutures (threads), microneedling and/or botulinum toxin within the last twelve 
months, dermabrasion and mesotherapy within the last six months, chemical peeling within the 
last three months) or planning to undergo such procedures during the clinical investigation 
13. Facial lypolysis, including submental fat treatments, within last month prior to enrollment and 
during the clinical investigation 
14. Bariatric surgery within 12 months prior to enrollement and during the clinical investigation 
15. History of bleeding disorders and/or use of anticoagulant, antiplatelet or thrombolytic 
medication from ten days pre- to three days post injection 
16. Planned dental/oral surgery or modification (bridge-work, implants) within two weeks prior 
injection and to a minimum of four weeks post injection 
17. Any medical condition prohibiting the inclusion in the clinical investigation according to the 
judgment of the treating investigator 
18. Previous enrollment in this clinical investigation 

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19. Current participation in another clinical investigation, or treatment with any investigational 
drug/medical device within 30 days prior to clinical investigation enrollment 
20. Any dependency of the subject to the treating investigator, the blinded independent evaluating 
investigator or clinical investigation site (e.g. employees of the sponsor), or subjects who are 
employees or relatives of the treating investigator and/or the independent blinded evaluating 
investigator 
21. Subjects who have one of the following assessments during the visual examinations at Baseline: 
Snellen visual acuity test worse than 20/40 (with corrective eyewear, if applicable), abnormal 
confrontational visual field test, or abnormal ocular motility test. 
9.2 
Inclusion and Exclusion Criteria – Repeat-treatment 
9.2.1 
Inclusion Criteria 
Subjects who meet ALL the following criteria are eligible for a repeat-treatment: 
1. In the opinion of the treating investigator, the subject has returned to sufficient severity of 
both NLFs that would have qualified him for enrollment into the clinical investigation 
initially (note that the subject does not have to return to his Baseline severity to be permitted 
to receive a repeat treatment) 
2. Subjects with NLFs with severity scores of 2 or 3 on the 5-point NLF-SRS for both NLFs as 
judged by the treating investigator in conjunction with the independent blinded evaluating 
investigator (note that it is not necessary for the treating and evaluating investigator to agree 
on the same rating) 
3. Females of childbearing age must have a negative urine pregnancy test at the 
repeat-treatment visit and must agree to continue to use an adequate method of contraception 
for the duration of the clinical investigation 
4. Healthy skin in the nasolabial area and free of diseases that could interfere in cutaneous aging 
evaluation and/or injection 
9.2.2 
Exclusion Criteria 
Subjects who meet ANY of the following criteria are NOT eligible for a repeat-treatment: 

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1. Occurrence of an SAE or adverse event of special interest (AESI; i.e., changes in vision [loss 
of vision, blurriness, double vision, pain in or around the eye, blindness, blind spots, 
problems moving the eyes, change in peripheral vision], skin changing color around the 
eyelids or around the site of injection) during or after the initial injection and/or touch-up 
injection 
2. Subjects who experienced visual changes or other serious medical conditions during or after 
the initial/touch-up injection 
3.  Subjects who have one of the following assessments during the visual examinations:  
 Snellen acuity test worse than 20/40 (with corrective eyewear, if applicable) 
 abnormal confrontational visual field test 
 abnormal ocular motility test 
4. Subjects who became pregnant since start of the study or are planning to become pregnant 
during the clinical investigation 
5. Known human immune deficiency virus-positive individuals 
6. Presence of infectious, inflammatory or proliferative cancerous or pre-cancerous lesions in 
the area to be treated 
7. Development of recurrent herpes simplex in the treatment area since study start 
8. Development of any autoimmune or connective tissue disease since start of participation in 
the study, or current treatment with immunomodulating therapy 
9. Development of uncontrolled (or instable) diabetes mellitus or any other systemic disease 
since study start 
10. Development of a bleeding disorder since study start or use of anticoagulant, antiplatelet or 
thrombolytic medication from ten days pre- to three days post injection 
11. Planned dental/oral surgery or modification (bridge-work, implants) within 2 weeks prior to 
injection and to a minimum of four weeks post injection 
12. Any medical condition prohibiting the inclusion for repeat treatment according to the 
judgement of the treating investigator 

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9.3 
Subject Withdrawal and Discontinuation 
Each subject has the right to withdraw his/her consent to participate in the clinical investigation 
at any time and without giving reasons. 
Subjects may be discontinued for the following reasons: 
 Lost to Follow-Up 
 Consent withdrawal (the treating investigator must try to find out and document the reasons 
for withdrawal of consent) 
 Safety reasons including abnormal and clinically significant changes in visual examinations 
(see Section 10.8.4) 
 Treating investigator’s decision 
 Poor compliance and/or disregard of the treating investigator’s instructions 
 Major CIP violation 
In case of early withdrawal, reasons, circumstances and findings should be described as 
completely as possible on the "Early Termination" page in the CRF respecting the subject’s 
privacy. Subjects who are withdrawn prematurely should undergo an early termination visit 
with the assessments that are scheduled for Week 40 (Visit 8a) or Week 52 (Visit 8b) or Visit 8c. 
In accordance with similar studies in this indication, the expected lost to follow-up rate is 
estimated to reach approximately 5% and repeat treatments will be offered in this clinical 
investigation to further decrease the amount of lost to follow-up subjects. Due to the split face 
design, minimal attrition bias is expected. 
9.4 
Subject Enrollment, Number and Duration of Subject’s Participation 
Subjects who have signed the informed consent form (ICF) and comply with all inclusion and 
exclusion criteria will be enrolled, and undergo treatment at Visit 2 on Day 0. Screening and 
Baseline may be combined in one visit. If full correction is not achieved after the initial 
treatment, subjects may receive a touch up treatment 2 weeks later and can receive repeat-
treatment (with Princess® Filler Lidocaine only) at Week 36 (Visit 6) or Week 48 (Visit 7) or 
Visit 7c. Each subject is expected to be in the clinical investigation for a maximum of 104 weeks 
including the temporary hold on repeat-treatment. 

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Approximately 300 subjects will be screened in the USA; the enrollment of a total of 
approximately 270 subjects is planned in order to obtain at least 240 evaluable subjects 
randomized in an 1:1 ratio to each clinical investigation group (accounting for a screening 
failure rate of approximately 10%, as well as approximately 10% of subjects to be excluded 
from the Per-Protocol Set due to major protocol deviations or subjects lost to follow-up). 
The clinical investigation is planned to be conducted at approximately 10-12 US sites with 
enrolment target of 23-27 subjects per site. Competitive recruitment may be allowed to 
stimulate enrollment, but no site will be allowed to enroll more than 54 subjects (20%) unless 
prior approval of the sponsor is given; in this case, the maximum number of subjects per site is 
capped at 68 (25%). This will maintain adequate balance between the investigational sites. 
 
 

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10 
Clinical investigation Procedures and Assessments 
10.1 
Nasolabial Folds-Severity Rating Scale (NLF-SRS) 
The Baseline severity of NLFs will be assessed by the treating investigator in conjunction with 
the independent blinded evaluating investigator at Screening using the NLF-SRS. Subjects can 
be included with two fully visible, approximately symmetrical moderate to severe NLFs (same 
severity) with severity scores of 2 or 3 on the 5- point NLF-SRS for both NLF as judged by the 
treating investigator in conjunction with the independent blinded evaluating investigator.  It is 
essential that the subject qualifies on both evaluator assessment as having a rating of 2 or 3 on 
the 5-point NLF-SRS, both investigators do not need to be full agreement as long as they agree 
that the subject has at rating of 2 or 3. The NLF-SRS is a validated 5-point rating scale ranging 
from Grade 0 (none) to Grade 4 (extreme) as outlined in Table 1; this scale have been developed 
and validated by Canfield Scientific Inc. for Croma-Pharma GmbH. Additional information on 
how NLFs severity should be evaluated for the standardized treating investigator’s live 
assessment and for the standardized live assessment by the independent blinded evaluating 
investigator will be outlined in the manual.  
After enrollment, live assessments, using the NLF-SRS, will be performed by the treating 
investigator and the independent blinded evaluating investigator (separate assessments) at 
Week 12 (Visit 4), at Week 24 (Visit 5), at Week 36 (Visit 6) and/or at Week 48 (Visit 7) and/or 
at Visit 7c.  
Photographic assessments using the NLF-SRS will be performed at the end of the clinical 
investigation by three blinded independent photographic reviewers. 
The treating investigator and the independent blinded evaluating investigator will be trained on 
the 5-point NLF-SRS prior to the study start, during the investigator meeting, a live WebEx 
with a sponsor medical consultant, or through review of a recording of the WebEx. Additional 
open questions will be answered during the pre-study visits; further training on the scale will 
be also performed during site pre-study visits, if needed. The independent blinded photographic 
reviewers will be trained on the 5-point NLF-SRS prior to their assessments of the photographs. 
 

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Week 48 (Visit 7) and/or at Visit 7c. At Week 36 (Visit 6), Week 48 (Visit 7), and/or Visit 7c, 
GAIS assessments will be performed prior to repeat-treatment. 
Separate assessments will be performed for the left and the right side of the face.  
Table 2: 
Global Aesthetic Improvement Scale 
Grade 
 
Definition 
1 
Very much 
improved 
Optimal aesthetic results for the implant in this subject 
2 
Much improved 
Marked improvement in appearance from initial 
condition, but not completely optimal for this subject. A 
touch-up would slightly improve the result 
3 
Improved 
Obvious improvement in appearance from the clinical 
condition, but a touch-up or retreatment is indicated 
4 
No change 
The appearance is essentially the same as the original 
condition 
5 
Worse 
The appearance is worse than the original condition 
Cited from (Narins et al., 2003). 
10.3 
Subject Satisfaction using Face-Q Questionnaires  
FACE-Q, User’s Manual, version 1.0, January 2015 (see Section 22.1). 
10.3.1 
Satisfaction with Outcome 
In the section of the User’s manual, “Process of Care Scales”, the questionnaire about the 
“Satisfaction with Outcome” will be used: This scale measures a subject’s satisfaction with the 
result of their most recent procedure. 
“Satisfaction with Outcome” assessments will be performed by the subject at Week 12 (Visit 4), 
at Week 24 (Visit 5), at Week 36 (Visit 6) and/or at Week 48 (Visit 7) and/or Visit 7c. 
Separate assessments will be performed for the left and the right side of the face.  
10.3.2 
Appraisal of Nasolabial Folds 
In the section of the User’s manual, “Appearance Appraisal Scales”, the questionnaire about 
the “Appraisal of Nasolabial Folds” will be used. 
“Appraisal of Nasolabial Folds” assessments will be performed by the subject at Week 12 
(Visit 4), at Week 24 (Visit 5), at Week 36 (Visit 6) and/or at Week 48 (Visit 7) and/or Visit 7c. 

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Separate assessments will be performed for the left and the right side of the face. 
10.4
Subject's Evaluation of Pain
The subject’s perception of pain will be evaluated for treatments with Princess® FILLER
Lidocaine and Juvéderm® Ultra XC.
This evaluation will be assessed using a scale adapted from the 11-point NPRS, where "0" 
indicates "no pain" and "10" indicates "the worst pain imaginable". 
The evaluation of subject’s pain will be done starting 15 min (+/- 3 min) after last injection and 
at 15 min-intervals (+/- 3 min) for 60 min (+/- 3 min) post-treatment (initial and repeat-
treatments) using the adapted NPRS. 
10.5
Injection Volume
For each subject, the total volume injected will be recorded separately for each treatment 
(initial, touch-up and repeat-treatments). 
10.6
Time to Repeat-Treatment
For each subject, the time from initial treatment to repeat-treatment will be recorded for each 
investigational group and assessed by tabulating the following rates: 
Repeat-treatment at Week 36
Repeat-treatment at Week 48
Repeat-treatment at Visit 7c
No repeat-treatment

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10.7 
Clinical Photography 
Clinical photography of the subject's face will be taken at Screening (Visit 1), on Day 0 
(Baseline) and at Week 12, 24, 36 and/or 48 and/or Visit 7c after initial treatment (at Visit 2, 4, 
5, 6 and/or 7 and/or Visit 7c, respectively) under standardized conditions in accordance with 
the manual. On treatment days (initial- and/or repeat-treaments), the clinical photography will 
be performed prior to the treatment. 
10.8 
Visual Examinations 
Visual examinations (including Snellen visual acuity, confrontational visual fields and ocular 
motility) will be performed at the study site by the examiner (i.e. treating investigator or 
authorized designee) prior to- and 30 min after any treatment (after all other assessments have 
been performed) at: 
o Baseline (Visit 2) 
o Week 2 (Visit 3a) (only in case of touch-up treatment) 
o Week 4 (Visit 3b) 
o Week 6 (Visit 3c) (only in case touch-up treatment was performed at Week 2 [Visit 3a]) 
o Week 36 (Visit 6) or Week 48 (Visit 7) or Visit 7c (only in case of repeat-treatment) 
o Week 40 (Visit 8a) or Week 52 (Visit 8b) or Visit 8c (only in case repeat-treatment was 
performed respectively at Week 36 [Visit 6] or Week 48 [Visit 7] or Visit 7c) 
o Week 48 (Visit 9a) or Week 60 (Visit 9b) or Visit 9c (only in case repeat-treatment was 
performed respectively at Week 36 [Visit 6] or Week 48 [Visit 7] or Visit 7c) 
All visual examination results and the use of corrective eyewear (i.e., glasses/contact lenses) 
will be recorded on the eCRF. 
10.8.1 
Snellen Visual Acuity 
Visual acuity for each eye will be assessed using the standard Snellen hanging wall chart 
(Figure 1).  

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Figure 1: Standard Snellen Hanging Wall Chart
The assessment will be carried out as follows:
The standard Snellen hanging wall chart will be read with the subject standing at a 
distance of 20 feet (6 meters). 
Each eye will be tested independently (i.e. one eye will be covered while the other eye 
will be used to read). 
If applicable, the subject should wear the same corrective eye wear 
(i.e. glasses/contact lenses) at each assessment. 
The ability to read every line on the chart does not need to be assessed. It is acceptable 
to move directly to the smaller characters, where appropriate. 
The numbers at the end of the line indicate the subject's visual acuity compared with a 
subject with normal visual acuity:
o
Normal limits are 20/25 or better, with no acuity difference between the eyes
o
The larger the denominator, the worse the acuity 
o
20/200 = subject sees at 20 ft (6 meters) what an individual with normal visual 
acuity sees at 200 ft (60 meters)
o
Results will be recorded in the eCRF as normal or abnormal alongside the 
actual Snellen results in numerical form for both eyes 
10.8.2
Confrontational Visual Fields
The confrontational visual fields will be used to assess peripheral vision for each eye. The 
assessments will be made as follows: 

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Correct positioning 
 The examiner should be eye level with the subject, separated by approximately 8 to 
12 inches (20 to 30 cm). 
 The subject should remove corrective eyewear (i.e. glasses/contact lenses). 
 The examiner will cover one eye and the subject will cover the one opposite. The open 
eyes should then be staring directly at one another. 
Technique 
 The examiner will present finger(s) in each of 4 quadrants, taking care not to position 
fingers in overlapping quadrates. 
 With head stationary the subject will be asked to correctly identify the number of 
fingers. 
 All 4 quadrants (upper and lower, temporal and nasal) must be tested. 
 The test will be repeated with the opposite eye open. 
10.8.3 
Ocular Motility 
The movements and alignment of eyes will be tested for each eye by evaluation of ocular 
motility as follows: 
 The examiner will stand in front of the subject. 
 The subject should remove corrective eyewear (i.e. glasses/contact lenses).  
 The subject will be asked follow examiner’s finger with their eyes while keeping their 
head in one position. 
 The examiner will trace an imaginary "H" or rectangular shape in front of them, 
making sure that the finger moves far enough out and up/down so that all appropriate 
eye movements can be seen (lateral up, lateral down, medial down, medial up). 
 Then the finger will be brought directly in towards the subject's nose. This will cause 
the subject to look cross-eyed and the pupils should constrict (accommodation). 
 The eyes should be able to easily and smoothly follow the examiner’s finger. 
 The results of the test will be documented for both the left and the right eye. 
10.8.4 
Abnormal Visual Examinations 
The following results from visual examinations at Baseline will be considered abnormal and 
will exclude the subject from participation in the study: 
 Snellen acuity test: any result worse than 20/40 (with corrections, if applicable) 
 Confrontational visual field test: abnormal is defined as the inability of the subject 
to correctly identify/count the examiner’s fingers in one or more quadrants in one or 
both eyes. 

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 Ocular motility: abnormal is defined as the inability of the subject to follow the 
finger of the tester smoothly; inability to focus on the finger as it points to the nose; 
any unexpected and/or uncontrolled eye movements such as nystagmus or divergent or 
unilateral strabismus 
Should any of the vision assessments (Snellen visual acuity, confrontational visual test field, or 
ocular motility) suddenly worsen after the injection of the filler, the treating investigator must 
examine the subject to exclude vascular injection and contact an eye specialist if necessary. 
In addition, any one of the following changes in visual examinations after Baseline will be 
considered abnormal and clinically significant: 
 Snellen acuity test: any change of 1 line or more 
 Confrontational visual field test: change to the peripheral vision 
 Ocular motility: change to ocular motility 
If any of the above changes occur at any assessment, the change should be reported as an AE 
and the subject must be referred to an ophthalmologist to evaluate if the resulting change is 
related to a vascular injection of the dermal filler. If the ophthalmologist confirms that the the 
result is related to a vascular injection of the dermal filler, the subject should be treated per 
standard of care for intravascular injection of dermal filler. The subject will be withdrawn from 
the study and the need for stopping the study will be reviewed. 
10.9 
Other Assessments 
Each of the following information have to be listed in the subject’s medical record and recorded 
on the eCRF: 
 Demography: includes date of birth, sex, race and ethnicity collected at Screening (Visit 1); 
every effort will be made to enroll male subjects in sufficient numbers.  
 Medical/aesthetic procedures history: collected from both subject interview and medical 
records at Screening (Visit 1). 
Particular attention should be paid to: 
o Diseases and medical conditions addressed in exclusion criteria 
o Previous aesthetic and surgical procedures in the treatment area 

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o All medications taken by the subject in the previous ten days (regularly or 
occasionally), including over-the-counter and herbal medicines, and with special 
attention to immune therapies, anticoagulant drugs, antiplatelet drugs, and analgesics 
All co-morbidities, major surgeries, aesthetic dermatology procedures in the previous year 
(e.g. skin resurfacing procedures, needling, mesotherapy, or similar), all medications taken 
within the previous ten days, and, in females, the date of the last period will be recorded in 
the eCRF. 
 Prior and concomitant medications/treatments: Prior medications/treatments are 
defined as all medications/treatments taken/received within ten days (whether continuing 
or not) prior to Day 0. Particular attention should be made to identify the use of anti-
coagulation 
or 
anti-platelet 
agents 
(e.g. acetylsalicylic 
acid). 
Concomitant 
medications/treatments is defined as all medication taken/received from Day 0 (including 
medication taken immediately pre-injection and post-injection) until the last visit.  
At each visit or phone call, the subject must be asked about any new medication taken or 
changes in current medication, as well as any aesthetic procedure applied in the area treated 
with the investigational devices. 
On treatment days (Visit 2, 3a, 6 or 7 or 7c), information on concomitant 
medications/treatments will be collected before the dermal filler injection procedure. 
All prior and concomitant medications/treatments will be recorded in the eCRF 
 Fitzpatrick skin types: to be documented at Screening (Visit 1); every effort will be made 
to include individuals with all Fitzpatrick skin types, included types V and VI. 
 Randomization: will only occurr via IVRS/IWRS once eligibility has been confirmed by 
the site.  
Treatment: Initial, touch-up with the assigned device following randomization scheme will be 
applied according to this CIP. The repeat-treatment will be performed with Princess® FILLER 
Lidocaine on both NLFs. 
 

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 Adverse events: Occurrence of adverse events will be collected at each visit after the initial 
treatment at Baseline (Visit 2), from Visit 2 to Visit 9a, 9b or 9c included (for more 
information, see Section 12). 
 Urine pregnancy test: Required in women of childbearing potential only, including those 
who are postmenopausal for less than twelve months. An urine pregnancy test (dip stick) 
will be performed at Screening (Visit 1), prior to initial treatment (Day 0/Visit 2), prior to 
touch-up treatment (Week 2/Visit 3a) and prior to repeat-treatment (Week 36/Visit 6, Week 
48/Visit 7 or Visit 7c).  
 Weight measurement: at Baseline (Day 0/Visit 2), at Visit 3a, 3b, 3c, 4 and 5, as well as 
at Visit 6, Visit 7 or Visit 7c upon evaluation for repeat-treatment; as well as Visit 8a/8b/8c 
or Visit 9a/9b/9c; weight measurement should be done to the nearest 0.1 kg and with the 
subjects standing barefoot and wearing light indoor clothing. 
 Subjects’ daily safety diary: to be dispensed to each subject at the end of each treatment 
session (and additionally at Week 4/Visit 3b for subjects having received touch-up treatment 
at Week 2/Visit 3a) in order to record injection site reactions, as well as the incidence of 
adverse events and AEs associated with the unintended intravascular injection; to be 
collected and reviewed two and four weeks after initial-/touch-up treatment (and 
additionally at Week 6/Visit 3c), and four weeks after repeat-treatment. 
 
The diary will include the following adverse events: 
o Changes in vision (i.e. loss of vision, blurriness, double vision, pain in or around 
your eye, blindness, blind spots, problems moving the eyes) 
o Skin changing color around the eyelids 
o Crusty or scabby skin around the eyelids 
o Headache 
o Fever 
o Dizziness 
o Confusion 
o Weakness or numbness in the arms or legs 
o Changes to consciousness or alertness 
o Difficulty speaking/speech impairment 

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o Face droop 
o Changes to chewing and drinking 
o Discomfort and discomfort with palpation 
o Sensitivity to hot/cold liquids and foods 
Furthermore, the subject diary will include specific instructions to seek immediate medical 
attention if any of the above symptoms or signs is observed. 
10.10 
Factors that may Compromise the Outcome 
There are no anticipated factors that may compromise the outcome. Substantial body weight 
changes (more than 10% change from Baseline), UV and sunlight exposure, as well as acne 
may affect the results. Subjects with unhealthy skin will not be included (see Section 9.1). 
Subjects will be advised to abstain from prolonged UV exposure for one week after the 
treatment (see Section 8.4.3) or from excess body weight gain or loss. 
10.11 
Schedule of the Clinical Investigation 
An overview of the schedule of the investigation is provided in Section 2.1. Subjects who have 
signed the ICF will be considered enrolled. 
10.11.1 
Screening (Visit 1) 
After written informed consent is obtained, the following procedures and/or assessments will 
be performed at Screening (Visit 1), Day -14 to -3: 
 Evaluation of inclusion and exclusion criteria (eligibility assessment) 
 Urine pregnancy test in women of childbearing potential only, including those who are 
postmenopausal for less than twelve months 
 Demography (date of birth, sex, race and ethnicity) 
 Fitzpatrick skin type 
 Medical history (including information on prior facial aesthetic or surgical procedures) 
 Live evaluation of nasolabial fold severity by treating investigator in conjunction with the 
independent blinded evaluating investigator using the 5-point NLF-SRS 
 Photography 

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10.11.2 
Baseline (Visit 2) 
The following procedures and/or assessments will be performed at Baseline (Visit 2), Day 0: 
 Body weight measurement 
 Visual examinations (including Snellen visual acuity, confrontational visual fields and 
ocular motility) prior to- and 30 min after the treatment (see Section 10.8) 
 Evaluation of eligibility criterion based on visual examinations 
 Urine pregnancy test in women of childbearing potential only, including those who are 
postmenopausal for less than twelve months (prior to treatment) 
 Randomization (prior to treatment) 
 Treatment (initial treatment) 
 Live assessment of nasolabial fold severity by treating investigator using NLF-SRS (prior 
to treatment) 
 Live assessment of nasolabial fold severity by the independent blinded evaluating 
investigator using NLF-SRS (prior to treatment) 
 Photography (prior to treatment) 
 Evaluation of pain assessment by the subject using the adapted NPRS 
 FACE-Q subject appearance appraisal questionnaire (“appraisal of nasolabial folds”) (prior 
to treatment) 
 Dispense of subject diary 
 Assessment of injection volume 
 AEs (prior to treatment) 
 Concomitant medications/procedures (prior to treatment) 
10.11.3 
Phone Contact after Visit 2 
The following assessments will be performed at Day 3 (±24 hours) after Visit 2: 

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 AEs including if subjects are experiencing or have experienced any signs/symptoms of 
vision changes or stroke since the injection 
 Concomitant medications/procedures 
10.11.4 
Week 2 (Visit 3a) 
The following assessments will be performed at Week 2 (± 3 days) after initial treatment: 
 Urine pregnancy test in women of childbearing potential only, including those who are 
postmenopausal for less than twelve months (in case of touch-up only and then prior to 
treatment) 
 Body weight measurement 
 In case of touch-up treatment, visual examinations (including Snellen visual acuity, 
confrontational visual fields and ocular motility). prior to- and 30 min after treatment. For 
action to be taken in case of abnormal findings, see Section 10.8.4.  
 Treatment (touch-up) if needed 
 Collect and review of subject diary dispensed at Baseline (Visit 2) 
 Dispense of new subject diary  
 Assessment of injection volume (in case of touch-up) 
 AEs (prior to treatment) 
 Concomitant medications/procedures (prior to treatment) 
10.11.5 
Phone Contact after Visit 3a 
The following assessments will be performed at Day 3 (±24 hours) after Visit 3a: 
 AEs including if subjects are experiencing or have experienced any signs/symptoms of 
vision changes or stroke since the injection 
 Concomitant medications/procedures 
10.11.6 
Week 4 (Visit 3b) 
The following assessments will be performed at Week 4 (± 5 days) after initial treatment: 

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 Body weight measurement 
 Visual examinations (including Snellen visual acuity, confrontational visual fields and 
ocular motility). For action to be taken in case of abnormal findings, see Section 10.8.4.  
 Collect and review of subject diary dispensed at Week 2 (Visit 3a)  
 Dispense of new subject diary (only in case touch-up treatment occurred at Week 2/Visit 3a) 
 AEs  
 Concomitant medications/procedures 
10.11.7 
Week 6 (Visit 3c) 
The following assessments will be performed at Week 6 (± 5 days) after initial treatment: 
 Body weight measurement 
 In case touch-up was performed at Week 2 (Visit 3a), visual examinations (including 
Snellen visual acuity, confrontational visual fields and ocular motility). For action to be 
taken in case of abnormal findings, see Section 10.8.4.  
 Collect and review of subject diary dispensed at Week 4 (Visit 3b) 
 AEs  
 Concomitant medications/procedures 
10.11.8 
Week 12 (Visit 4) and Week 24 (Visit 5)  
The following assessments will be performed at Week 12 (± 5 days) and Week 24 (± 5 days) 
after initial treatment: 
 Body weight measurement 
 Live assessment of nasolabial fold severity by treating investigator using NLF-SRS 
 Live assessment of nasolabial fold severity by the independent blinded evaluating 
investigator using NLF-SRS 
 Assessment of GAIS over Baseline by the evaluating investigator and the subject 
 Face-Q subject appearance appraisal questionnaire (“appraisal with nasolabial folds”)  

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 Face-Q subject satisfaction (“Satisfaction with Outcome”) 
 Photography 
 AEs  
 Concomitant medications/procedures 
10.11.9 
Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or Visit 7c - Evaluation 
A repeat-treatment will be performed, if the subject meets the criteria specified in Section 9.2. 
The following assessments will be performed at evaluation for repeat-treatment at Week 36 
(± 5 days) and/or Week 48 (± 5 days) after initial treatment and/or Visit 7c (no visit window): 
 Body weight measurement 
 Eligibility for repeat-treatment (see Section 9.2) 
 Urine pregnancy test in women of childbearing potential only, including those who are 
postmenopausal for less than twelve months 
 Live assessment of nasolabial fold severity by treating investigator using NLF-SRS 
 Live assessment of nasolabial fold severity by the independent blinded evaluating 
investigator using NLF-SRS 
 Assessment of GAIS over Baseline by the independent blinded evaluating investigator and 
the subject 
 Face-Q subject satisfaction (“Satisfaction with Outcome”) 
 FACE-Q subject appearance appraisal questionnaire (“Appraisal with Nasolabial Folds”) 
 Photography 
 AEs  
 Concomitant medications/procedures 
Some subjects were not assessed for repeat-treatment at Week 36 and/or Week 48 due to the 
hold on repeat-treatment. In this case, a subject can attend Visit 7c (no visit window) for 
evaluation and repeat-treatment as described above (if eligible).  

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10.11.10 
Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or Visit 7c - Repeat-
Treatment 
The following assessments will be performed at Week 36 (± 5 days) and/or Week 48 (± 5 days) 
after initial treatment and/or at Visit 7c (no visit window): 
 In case of repeat-treatment at Week 36 (Visit 6), Week 48 (Visit 7) or Visit 7c, visual 
examinations (including Snellen visual acuity, confrontational visual fields and ocular 
motility) prior to- and 30 min after the treatment. For action to be taken in case of abnormal 
findings, see Section 10.8.4. 
 Treatment  
 Evaluation of pain assessment by the subject using the adapted NPRS 
 Dispense of subject diary 
 Assessment of injection volume 
If the subject is being retreated at Week 36, subject qualifies for 4 Weeks Follow up after repeat-
treatment at Week 40. If the subject is being retreated at Week 48, subject qualifies for 4 Weeks 
Follow up after repeat-treatment at Week 52. If the subject is being retreated at Visit 7c, subject 
qualifies for 4 Weeks Follow up after repeat-treatment at Visit 8c.  
10.11.11 
Phone Contact after Visit 6, Visit 7 or Visit 7c 
The following assessments will be performed at Day 3 (± 24 hours) after Visit 6, Visit 7 or 
Visit 7c, if the subject received a repeat-treatment: 
 AEs including if subjects are experiencing or have experienced any signs/symptoms of 
vision changes or stroke since the injection 
 Concomitant medications/procedures 
10.11.12 
Week 40 (Visit 8a), Week 52 (Visit 8b) or Visit 8c 
The following assessments will be performed at the end of clinical investigation visit at 
Week 40 (± 5 days), Week 52 (± 5 days) or Visit 8c (± 5 days), which are four weeks after 
repeat-treatment: 

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 In case repeat-treatment was performed at Week 36 (Visit 6) or Week 48 (Visit 7) or 
Visit 7c, visual examinations (including Snellen visual acuity, confrontational visual fields 
and ocular motility). For action to be taken in case of abnormal findings, see Section 10.8.4. 
 Body weight measurement 
 Collect subject diary dispensed at repeat-treatment (Visit 6, Visit 7 or Visit 7c) 
 AEs  
 Concomitant medications/procedures 
If the subject is not being treated at Week 36, no Week 40 Visit is necessary.  
10.11.13 
Week 48 (Visit 9a), Week 60 (Visit 9b) or Visit 9c 
The following assessments will be performed at the end of clinical investigation visit at 
Week 48 (± 5 days), Week 60 (± 5 days) or Visit 9c (± 5 days), which are twelve weeks after 
repeat-treatment:  
 In case repeat-treatment was performed at Week 36 (Visit 6), Week 48 (Visit 7) or Visit 7c, 
visual examinations (including Snellen visual acuity, confrontational visual fields and 
ocular motility). For action to be taken in case of abnormal findings, see Section 10.8.4. 
 Body weight measurement 
 AEs  
 Concomitant medications/procedures 
For subjects who are not retreated at Week 36 (Visit 6) or Week 48 (Visit 7), the Week 48 Visit 
will be their end of study visit unless the subject returns for Visit 7c. For subjects who are not 
retreated at Visit 7c, Visit 7c will be their end of study visit. For subjects who are retreated at 
Week 36, the Week 48 Visit will be their end of study visit. For subjects who are retreated at 
Week 48, the Week 60 Visit will be their end of study visit. For subjects who are retreated at 
Visit 7c, Visit 9c (12 weeks after Visit 7c) will be their end of study visit.  
10.12 
Early Termination 
In case a subject prematurely discontinues the clinical investigation, the subject will be asked 
to complete an early termination visit, where as many assessments as possible (which would 
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will be completed. If an early termination visit can’t take place, the investigator or any member 
of the clinical investigation team should try to contact the subject, or his relatives, in order to 
collect adverse events and concomitant medications/treatments. 
In case of early withdrawal, reasons, as well as circumstances and findings, should be collected 
and fully described on the "Early Termination" page in the eCRF.  
10.13 
Time-Windows 
A time deviation of ± 5 days is allowed for each visit, except for phone contacts (+/- 24 hours) 
and for the touch-up visit at Week 2 (+/- 3 days). Clinical investigational sites must adhere to 
the Schedule of Clinical investigation Procedures and Assessments (see Section 2.1) and visit 
windows, and subjects must ensure they are available for those visits. However, if for practical 
reasons, e.g. bank holidays, a visit window cannot be met, a visit can be scheduled as close as 
possible to that visit window. However, any deviation from the visit schedule and its associated 
time windows will still be documented as a protocol deviation. 
10.14 
Medical Care upon Termination of the Clinical Investigation 
Clinical investigation subjects will not receive any clinical investigation-specific treatment after 
the final visit. Any further treatment, if needed, will be proposed to the subject by the 
investigator at their discretion. After the final visit, subjects will not receive any further clinical 
investigation-specific treatment. 
 
 

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11 
Monitoring Plan 
The extent of monitoring and source data verification will be specified in a monitoring plan. 
100% source data verification should be ensured in accordance to the monitoring plan. 
Before clinical investigation initiation at a center, a clinical research associate (CRA) from the 
sponsor or sponsor’s representative will discuss the CIP and eCRF with the treating 
investigators and their staff. The center must not enroll any subject before this initiation visit. 
During the clinical investigation, further monitoring visits will be performed according to 
ISO 14155:2011, the applicable standard operating procedures (SOP), and local regulations. 
The eCRFs will be reviewed against source data in accordance to the monitoring plan for 
adherence to the CIP, as well as for completeness, accuracy and consistency of data. 
Additionally, the CRA will check the progress of enrollment, and will ensure that the 
investigational device is stored, dispensed and accounted for according to respective 
specifications. Key clinical investigation personnel must be available to assist the CRA during 
these visits. The CRA informs the treating investigator or authorized designee of any eCRF 
entry error, omission, or illegibility. The CRA should ensure that appropriate corrections, 
additions, or deletions are made, dated, explained (if necessary), and initialed by the treating 
investigator or by an authorized designee. 
The treating investigators must permit the monitors access to those portions of the subject’s 
primary medical records, which directly concern this clinical investigation.  
It is the treating investigator’s obligation to assure documentation of all relevant data in the 
subject’s file, such as medical/aesthetic procedures history and concomitant diseases, date of 
enrollment into the clinical investigation, visit dates, results of examinations, application of 
medical device, and AEs and ADEs. 
 
 

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12 
Assessment of Safety  
12.1 
Definitions of Adverse Events and Adverse Device Effects 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs in subjects, users or other persons. This definition includes events 
whether or not related to the IMDs and those events related to the procedures involved.  
Adverse Device Effect (ADE) 
An ADE is defined as an AE that is related to the use of the IMDs. This includes any AE 
resulting from insufficiencies or inadequacies in the IFU, the deployment, the implantation, the 
installation, the operation, or any malfunction of the IMDs. In addition, this includes any event 
that is a result of a use error or intentional misuse of the IMDs. 
Those AEs occurring after provision of informed consent and prior to application of the IMDs 
will be recorded as part of the medical/aesthetic procedures history. Any medical condition that 
is present at the time that the subject is screened should be also considered as medical/aesthetic 
procedures history and not recorded as an AE (see Section 10.9). However, if the condition 
deteriorates at any time from date of administration of the IMDs during the clinical 
investigation, it should be recorded and reported as an AE. 
For a list of anticipated AEs and anticipated ADEs please refer to Section 6.1. In addition, the 
following events could specify as Adverse Events of Special Interest (AESI);  
 
Changes in vision (i.e. loss of vision, blurriness, double vision, pain in or around your 
eye, blindness, blind spots, problems moving the eyes, change in peripheral vision) 
 
Skin changing color around the eyelids or around the site of injection 
Serious Adverse Event (SAE) 
An SAE is defined as an AE meeting one or more of the following conditions: 
 led to death 
 led to serious deterioration in health of the subject that either resulted in: 
o a life-threatening illness or injury, or 

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o a permanent impairment of a body structure or a body function, or 
o in subject hospitalization or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
 led to fetal distress, fetal death, or a congenital abnormality or birth defect 
 is an important medical event  
Note: Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or require hospitalization, but may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed in the 
definitions above. Examples of such events are: invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependence or drug 
abuse. Hospitalization is defined as at least one overnight stay. Pre-planned hospitalizations 
(known already prior to signing the ICF) will not be considered an SAE, unless any of the above 
criteria are fulfilled over the course of the hospitalization due to unplanned complications.  
A planned hospitalization for pre-existing condition, or a procedure required by the CIP, 
without a serious deterioration in health, is not considered to be an SAE. 
Serious Adverse Device Effect (SADE) 
A serious adverse device effect (SADE) is defined as an ADE that has resulted in any of the 
consequences characteristic of an SAE.  
Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect (UADE) is defined as “any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, 
if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects” (21 Code of Federal Regulations [CFR] 812.3[s]).  

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Investigators should report UADEs to the sponsor and to the IRB as follows: Investigators are 
required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the event (21 
CFR 812.150[a]). 
Sponsors must immediately conduct an evaluation of a UADE and must report the results of 
the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working 
days after the sponsor first receives notice of the effect (21 CFR 812.46[b], 21 CFR 
812.150[b]). 
12.2 
Documentation of Adverse Events 
For each AE, the following must be reported: the date of onset, description of event (event 
term), event status or date of resolution, severity, action taken (none, medical and/or surgical), 
relationship to investigational device, relationship to procedure, and seriousness criteria. Each 
AE must be reported separately. The treating investigator must record all AEs on the ”AE” page 
of the CRF. For SAEs, the Serious Adverse Event Form must also be completed. A complete 
description of all AEs must also be available in the source documents.  
AEs (or ADEs or SADEs) occurring after provision of informed consent and prior to application 
of the IMDs will be recorded as part of the medical /aesthetic procedures history. Any medical 
condition that is present at the time that the subject is screened should also be considered as 
medical/aesthetic procedures history (see Section 10.9) and not recorded as an AE (or ADE or 
SADE). However, if the condition deteriorates at any time during the clinical investigation from 
the date of administration of the IMDs, it should be recorded and reported as an AE. 
In case the severity or seriousness of an AE changes, the most severe intensity or seriousness 
of the AE will be recorded and included in the analysis. Separate AEs will not be recorded for 
each intensity level.  
Changes in the assessment of relationship to the IMDs or procedure should also be clearly 
documented. 
Any medication necessary for the treatment of an AE must be recorded on the “Concomitant 
Medication” page of the CRF.  

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12.3 
Assessment of Adverse Events 
All AEs will be assessed in terms of seriousness, severity, outcome, relationship to the IMDs 
and relationship to procedures.  
12.3.1 
Assessment of Causality 
Investigator is obligated to estimate the relationship between each AE/SAE and the IMD or 
clinical investigation procedure. Clinical judgment should be used and the relevant documents 
(e.g., IFU) consulted. The presence of confounding factors, such as concomitant 
medications/treatments, the natural history of the underlying disease and/or other concurrent 
illness or risk factors, shall also be considered. This has to be documented within the source 
data accordingly. The type of relationship should be determined using one of the following 
causality levels: 
 Definitely related: 
The AE/SAE is associated with the investigational device or with procedures beyond reasonable 
doubt when: 
o the AE/SAE is a known side effect of the product category the device belongs to, or 
of similar devices and procedures 
o the AE/SAE has a temporal relationship with investigational device use/application 
or procedures 
o the AE/SAE involves a body-site or organ that the investigational device or 
procedures are applied to or have an effect on 
o the AE/SAE follows a known response pattern to the medical device (if the response 
pattern is previously known) 
o the discontinuation of medical device application (or reduction of the level of 
exposure), when clinically feasible, and reintroduction of its use (or increase of the 
level of exposure) impact on the event 
o other possible causes (e.g. an underlying or concurrent illness/clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out 
o harm to the subject is due to error in use 

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 Probably related: 
The relationship with the use of the investigational device seems relevant and/or the event 
cannot reasonably be explained by another cause, but additional information may be obtained. 
 Possibly related: 
The relationship with the use of the investigational device is weak, but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases where 
relatedness cannot be assessed, or no information has been obtained, should also be classified 
as possible. 
 Unlikely related: 
The relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
 Not related: 
Relationship to the device or procedures can be excluded when: 
o the AE/SAE is not a known side effect of the product category the device belongs 
to or of similar devices and procedures 
o the AE/SAE has no temporal relationship with the use of the investigational device 
or the procedures 
o the AE/SAE does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible 
o the discontinuation of medical device application or the reduction of the level of 
exposure (when clinically feasible) and reintroduction of its use (or increase of the 
level of exposure) do not impact on the event 
o the AE/SAE involves a body-site or an organ not expected to be affected by the 
device or procedure 
o the AE/SAE can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors) 

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o harm to the subject are not clearly due to use error 
The treating investigator will use his/her clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the IMD administration will be 
considered and investigated. The treating investigator will also consult the IFU in the 
determination of his/her assessment. 
If there is a disagreement between Sponsor and Investigator, queries will be sent in an attempt 
to reach a resolution. The queries will include a statement providing the rationale for the 
Sponsor assessment causality. Consequentely, a request for the rationale for the Investigator 
causality will be requested and a confirmation of their causality assessment. 
In instances where there is a discrepancy in causality between the Investigator and the reviewing 
medic, for the causality of the event to the study device. The event will be considered as being 
related to the study device for the purposes of reporting. 
 
12.3.2 
Assessment of Severity 
The following definitions for rating severity will be used: 
 Mild: The AE is easily tolerated and does not interfere with daily activity 
 Moderate: The AE interferes with daily activity but the subject is still able to function 
 Severe: The AE is incapacitating and/or requires medical intervention 
12.3.3 
Adverse Event Outcome 
The outcome of an AE will be assessed as follows: 
 Ongoing: the event is ongoing at the time of reporting and the subject has still not 
recovered 
 Resolved: the subject has fully recovered from the event, or the condition has returned 
to the level observed at Baseline 
 Resolved with Sequelae: as a result of the AE, the subject suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf or paralyzed) 

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 Death: the subject died due to the event 
 Unknown: if outcome is not known or not reported 
12.4 
Adverse Event Monitoring and Assessment  
Subjects will be monitored for AEs throughout the clinical investigation from signing the ICF 
until the final visit. Should an SAE occur after the final visit, which is considered at least 
possibly related to the IMD or procedure, such events should always be reported to Croma-
Pharma GmbH or its representative, even after the end of the clinical investigation.  
Subjects will be questioned concerning their well-being at all visits from screening through to 
the final visit. Furthermore, subject diaries will be provided to the subjects, and they will be 
instructed to note Injection site reactions, AEs and AESI. In addition, subjects will be 
encouraged to spontaneously report any AEs, ADEs or SAEs. Any subject with an AE, SAE or 
clinically significant abnormal test result will be evaluated by the treating investigator and will 
be treated and/or followed up as per local clinical practice. A physician, either at the 
investigative site or at a nearby hospital emergency room, will administer treatment for any 
SAEs. Where appropriate, medical tests and examinations may be performed to ensure that an 
AE has fully resolved.  
If an Injection site reaction is not resolved at the time the by the time the diary is returned after 
4 weeks (after treatment, touch-up treatment, retreatment), the injection site reaction might be 
classified as an AE s per investigator discretion. 
By default, AEs ongoing at the termination visit will not be followed-up. However, SAEs which 
are ongoing at the End of Clinical investigation visit will be followed-up until recovery or 
normalization of changed laboratory parameters, or until the treating investigator determines 
that the subject’s condition is stable or a plausible explanation has been provided, whichever 
occurs first.  
All subjects excluded from repeat-treatment should continue to be followed until the resolution 
of all ongoing AEs, regardless of device relatedness. 
Adverse events will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Whenever possible, a specific disease or syndrome, rather than 

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individual associated signs and symptoms, should be identified by the treating investigator and 
recorded on the CRF. However, if an observed or reported sign or symptom is not considered 
a component of a specific disease or syndrome by the treating investigator, it should be recorded 
as a separate AE on the CRF 
When documenting AEs, standard medical terminology should be used in order to avoid the 
use of vague, ambiguous, or colloquial expressions. Each AE will be evaluated by the treating 
investigator for: 
 Seriousness, as defined in Section 12.1. 
 Severity, as defined in Section 12.3.2. 
 Causal relationship to IMD or procedure, as defined in Section 12.3.1. 
 Outcome, as defined in Section 12.3.3. 
If the severity rating for an ongoing AE changes before the event resolves, the AE will be 
reported in an additional row in the AE log (or additional AE page) with complete information 
(i.e. start and stop date, severity, relationship, outcome etc.). 
Reporting Serious Adverse Events All SAEs for all subjects occurring from the time of 
informed consent until the End of Clinical investigation visit must be reported to Croma-
Pharma GmbH or their representative within 24 hours of knowledge of the occurrence. If 
considered at least possibly related to clinical investigation treatment, SAEs observed after the 
End of Clinical investigation must also be reported. 
SAE Report Forms must be completed and faxed to the Safety department 
 
within 24 hours of awareness of the event.  
 
 
 
  
 will inform the sponsor about all SAEs without undue delay after receipt of the 
respective report from the treating investigator. 

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Reporting to IRBs and regulatory authorities will follow pertinent national legislation. 
Any details about AE reporting and casuality assessement are described in the current valid 
version of device safety management plan. 
12.4.1 
Unanticipated Adverse Device Effects Reporting 
A UADE is “any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects” 
(21 CFR 812.3[s]). 
Investigators should report UADEs to the sponsor and to the IRB as follows: Investigators are 
required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the event 
(21 CFR812.150[a][1]). 
Sponsors must immediately conduct an evaluation of a UADE and must report the results of 
the evaluation to FDA, all reviewing IRBs, and participating investigators within 10 working 
days after the sponsor first receives notice of the effect (21 CFR 812.46[b], 21 CFR 
812.150[b][1]). 
 
Clinical investigation stopping rules in case of vascular occlusion: 
Special care will be taken in case of vascular occlusion which is a rare, but serious, adverse 
event; this encompasses vascular embolic events which may lead to skin necrosis, vision loss 
or stroke.  
In the event that such a complication occurs, the enrollment and treatment at the investigational 
site will be suspended and a root cause investigation has to be conducted to determine the cause 
of the event. If the investigator didn’t properly follow the treatment procedure, he/she will be 
re-trained before being allowed to recruit further subjects. 
In case this event was unanticipated and the investigator did follow the treatment procedure 
correctly, the entire clinical investigation has to be immediately suspended and no subjects 

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should be enrolled until the event can be properly characterized and an appropriate treatment 
strategy to avoid this unanticipated event can be devised. 
For received reports containing any event relating to incidences of visual distrubances, in the 
form of a site query (‘Device Safety Query for Additional Information’ form, see SMP 9.5.4), 
the following information must be urgently requested: 
 
Depth of injection (i.e. subcutaneous or supraperiosteal)  
 
The injection volume 
 
The symptoms that were observed 
 
The time to event onset, and resolution 
 
Any interventions that were implemented 
 
The symptoms that were observed 
 
The time to event onset, and resolution 
 
Any interventions that were implemented 
If a response to the aforementioned queries is not received within 24 hours, a follow up reminder 
will be sent, and the queries escalated to the Clinical Monitor and Project Manager. 
 
12.5 
Adverse Events/Serious Adverse Events Follow-up 
The investigator will take all appropriate and necessary measures required for resolution of the 
AE. Should this include prohibited medication, the investigator will contact the Medical 
Monitor in order to seek advice. 
All AEs must be followed-up by the investigator until recovery, or until the investigator 
determines that the subject’s condition is stable, or until the last day of the clinical investigation 
at the site, whichever occurs first. 
Any pregnancy must be followed-up until the pregnancy outcome on the pregnancy report form. 
If it is still on-going at the end of the clinical investigation, follow-up will be continued outside 
of the context of clinical investigation and pregnancy outcome (including pregnancy duration 

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and health status of a newborn or cause of premature termination, as applicable) will be reported 
to the Sponsor. 
All SAEs judged to be related to the IMDs (SADEs) must be followed by the investigator until 
the subject has recovered, recovered with sequelae, died, or until the investigator determines 
that the subject’s condition is stable, whichever occurs first. In case the clinical investigation 
ends before an SAE is resolved, the last status should be recorded. Every possibly effort should 
be made in order to follow up on SAEs until their resolution. 
12.6 
Visual Examinations 
For details of visual examinations, see Section 10.8. 
12.7 
Device Deficiencies 
12.7.1 
Definition of a Device Deficiency 
A device deficiency is defined as an inadequacy of an IMD with respect to its identity, quality, 
durability, reliability, safety or effectiveness. Deficiencies include malfunctions, use errors and 
inadequate labeling.  
12.7.2 
Recording and Reporting of Device Deficiencies 
Device deficiencies should be reported to the Safety Department of
 
will forward the deficiency report to the sponsor within 24 hours after receipt of the 
respective report from the treating investigator.  
Device deficiencies will be recorded as per relevant SOPs from the CRO. In case a device 
deficiency is associated with an AE, additionally, the corresponding AE documentation 
procedures must be adhered to (see Section 12.2). 
12.7.3 
Handling of Deficient Medical Devices 
Any medical device alleged to be deficient must not be used by the treating investigator and 
must be returned to Croma-Pharma GmbH or its representative or destroyed according to the 
site’s procedures, after device accountability has been performed.  
 
 

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13 
Assessment of Effectiveness 
Effectiveness will be determined using a well defined, valid and reliable scale, the NLF-SRS 
(outlined in Section 10.1). The scale and the proposed instructions for its use by treating 
investigators is outlined in the manual.  
Response is defined as having at least one grade improvement over Baseline on the 5-point 
NLF-SRS . 
Scores are assessed as 1 (None/minimal), 2 (Mild), 3 (Moderate), 4 (Severe), 5 (Extreme). 
 
 

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14 
Statistical Considerations 
The statistical analyses will be described in detail in a statistical analysis plan. 
14.1 
Analysis Sets 
The statistical analyses will be based on the following data sets: 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) consists of all randomized subjects who received at least one 
administration of Princess® FILLER Lidocaine and the control medical device at the same visit; 
subjects who receive only one treatment (only Princess® FILLER Lidocaine or only Juvéderm® 
Ultra XC) during initial treatment will be excluded from the FAS. The analyses based on the 
FAS will use the randomized treatment groups. 
Per-Protocol Analysis Set (PPS)  
The Per-Protocol Set (PPS) is defined as a subset of the subjects in the FAS who had no major 
protocol deviations. A possible per protocol analysis population bias will not be influenced by 
the exclusion criteria due to the split face design. The excluded subjects due to protocol 
deviations will be discussed in detail while the statistical analysis plan is being prepared and 
definitively ahead of the database lock in order to identify any possibly bias. 
Safety Analysis Set (SAF) 
The Safety Analysis Set (SAF) comprises all subjects who were randomized and received at 
least one treatment (i.e., any dose of Princess® FILLER Lidocaine or the control medical 
device). The analyses based on the SAF will use the actual treatment groups. 
14.2 
Statistical Analyses  
The PPS and the FAS will be both considered equally important for the primary analysis; the 
primary analysis will be performed with the FAS; if Princess® FILLER Lidocaine can be 
considered non-inferior to Juvéderm® Ultra XC according to this analysis, the sensitivity 
analysis based on the PPS can be considered confirmatory. Otherwise, this analysis has to be 
considered exploratory. Non-inferiority is demonstrated only if the results are consistent for 
both analysis data sets. 

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All effectiveness analyses will be conducted for the FAS and subsequently for the PPS . Safety 
analyses will be based on the SAF. 
Effectiveness 
The primary effectiveness outcome measure will be evaluated by means of a one-sided 95%  
confidence interval for the difference in paired proportions pA-pB. At this, pA is the response 
rate for Princess® FILLER Lidocaine and pB is the response rate for Juvederm® Ultra XC. Thus, 
a negative value for this difference means that the response rate of Princess® FILLER Lidocaine 
is lower than the response rate for Juvederm® Ultra XC. Princess® FILLER Lidocaine will be 
considered non-inferior to Juvederm® Ultra XC if the lower confidence limit exceeds the non-
inferiority margin of -10% and thus if the null hypothesis H0: pA-pB
-10% can be rejected. In 
addition to this, the response rates for both treatment groups will be tabulated. 
In order to assess the homogeneity of the primary effectiveness outcome measure and of the 
treatment effect among the clinical investigational sites, a mixed logistic regression model with 
treatment, site, and treatment-by-site interaction as fixed effects and random subject effects will 
be fitted. Small clinical investigational sites with less than ten subjects will be pooled and a 
two-sided alpha level of 15% will be used to test for a treatment-by-site interaction. In case that 
the treatment-by-site interaction is not statistically significant (at the alpha level mentioned 
above), the treatment-by-site interaction will be removed from the mixed model and the 
confidence interval for the difference in proportions will be derived from this mixed model 
adjusted for site effects. If the treatment-by-site interaction effect is statistically significant (at 
the alpha level mentioned above), the treatment difference is not interpretable in the model. In 
this case, the treatment difference in the main effect model without adding the interaction effect 
is tested and in addition, the treatment difference by site will be presented and observed 
heterogeneities will be evaluated.  
Subjects with missing NLF-SRS grades at Baseline and/or at Week 24 will be considered as 
non-responders for the primary analysis. Since it is very unlikely that the assessment of only 
one NLF will be missing, presumably either no or both assessments will be available for one 
subject at a certain time point. Therefore, this imputation method will probably decrease the 
response rate in both treatment groups simultaneously. Due to the fact that the sample size 
calculation was based on rather high response rates (88% for Juvederm® Ultra XC and 87% for 
Princess® FILLER Lidocaine), lower response rates will make it more difficult to demonstrate 

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non-inferiority of Princess® FILLER Lidocaine and thus this approach is considered to be 
conservative. In addition to this approach, a complete case analysis (using the available data 
without any imputation), a best-case analysis (missing values for Princess® FILLER Lidocaine 
will be considered as a response, missing values for Juvéderm® Ultra XC will be considered as 
a non-response), a worst-case analysis (missing values for Princess® FILLER Lidocaine will be 
considered as a non-response, missing values for Juvéderm® Ultra XC will be considered as a 
response), and a tipping point analysis will be conducted as sensitivity analyses.  
The statistical analysis of the secondary and additional outcome measures will be described in 
detail in the statistical analysis plan. A hierarchical testing procedure will be applied for the 
analysis of the primary outcome measure, as well as the secondary outcome measures 1 and 2, 
in order to control multiplicity. At this, the following order will be used: 
1. Analysis of primary outcome measure based on FAS 
2. Analysis of primary outcome measure based on PPS 
3. Analysis of secondary outcome measure 1 based on FAS 
4. Analysis of secondary outcome measure 1 based on PPS 
5. Analysis of secondary outcome measure 2 based on FAS 
6. Analysis of secondary outcome measure 2 based on PPS 
For qualitative variables the frequencies (absolute and relative) will be calculated and compared 
between the treatment groups. Quantitative parameters will be described by declaring the mean 
value, standard deviation, minimum, first quartile, median, third quartile, and maximum per 
treatment group. In addition to this, mean value (incl. two-sided 95% confidence interval), 
standard deviation, minimum, first quartile, median, third quartile, and maximum will also be 
provided for the difference in quantitative parameters between the two treatment sides of a 
subject. The secondary outcome measures 1 and 2 will be analyzed as described for the primary 
effectiveness outcome measure. Descriptive statistics will be used to summarize the remaining 
outcome measures. Kappa statistics will be calculated in order to assess inter-rater consistency 
among the three independent blinded photographic reviewers. 
Safety 
Safety variables will be analyzed based on the SAF. Adverse events will be coded by the 
MedDRA. Incidence of AEs will be summarised by preferred term (PT) and system organ class 

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(SOC). AEs (SOC and PTs) will be summarised also by intensity, relationship to the IMDs or 
procedure and seriousness. All AEs will be properly listed (by subject, type, date, treatment and 
time since last treatment [first injection or touch-up]).  
14.3 
Sample Size Calculation 
The primary effectiveness outcome measure will be evaluated by means of a one-sided 95% 
confidence interval for the difference in paired proportions pA-pB. At this, pA is the response 
rate for Princess® FILLER Lidocaine and pB is the response rate for Juvederm® Ultra XC. Thus, 
a negative value for this difference means that the response rate of Princess® FILLER Lidocaine 
is lower than the response rate for Juvederm® Ultra XC. Princess® FILLER Lidocaine will be 
considered non-inferior to Juvederm® Ultra XC if the lower confidence limit exceeds the non-
inferiority margin of -10%. 
Further assumptions for sample size calculation: 
 Response rate at week 24 for Juvederm® Ultra XC is 88% 
 Response rate at week 24 for Princess® FILLER Lidocaine is 87% 
 Proportion of subjects with response only in one nasolabial fold: 21.9% (88.0% * 
13.0% + 87.0% * 12.0% = 21.9%) 
 Proportion of subjects with response in both NLFs: 76.5% (88.0% * 87.0% = 76.5%) 
The latter two proportions were calculated on the basis of the response rates for Princess® 
FILLER Lidocaine and Juvederm® Ultra XC assuming that the two NLFs of one subject are 
independent. Since there should be a concordant correlation between the two NLFs of one 
subject, this assumption is considered to be conservative. 
Based on these assumptions, 222 subjects will be necessary in order to achieve a power of 90%. 
Sample size calculation was done using nQuery Advisor® 7.0. The result is based on 
1600 simulations using the Newcombe-Wilson score method to construct the confidence 
interval. 
15 
Data Handling and Record Keeping 
15.1 
Electronic Case Report Forms 
An eCRF will be completed for each subject screened and included. Data generated after the 
subject has given informed consent must be recorded in the eCRF. The treating investigator is 

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responsible for ensuring accurate and proper completion of the eCRF according to the 
instructions in the eCRF. Data for all subjects screened for inclusion in the clinical investigation 
must be documented in the respective form provided by the sponsor.  
Only treating investigators and authorized designees are allowed to make entries in the eCRF. 
The eCRF data should be entered within five days after obtaining it. The investigator or 
designee has to carefully answer queries issued by Data Management in the eCRF. Answered 
queries and changed data due to queries will be reviewed by Data Management and the monitor; 
required data will be required or verified accordingly. 
Any source data corrections should be made in a way which does not obliterate the original 
entry. Treating investigators or designees must initial and date all corrections. 
The treating investigator or designee must carefully answer queries issued by Data 
Management. Queries issued by Data Management must be carefully answered.  
15.2 
Data Management Procedures  
All data management activities will be conducted by the sponsor's representative following their 
SOPs. The database will be built by the sponsor's representative. 
Details on data handling will be described in the Data Management Plan. Computerized 
validation check programs on completeness, correctness, plausibility (such as range checks, 
cross-checks) will verify the data according to the Data Validation Plan. All identified 
discrepancies will be queried and addressed to the treating investigator.  
Regarding self-evident corrections (such as spelling and header corrections) if applicable, 
treating investigator’s agreement will be obtained, that these will be made by the Data Manager 
and documented in the audit trail. 
The sponsor’s representative will handle the data cleaning process, including logical check, 
medical checks, and query processes.  
All changes will be tracked (audit trail). Sponsor approval prior to database lock is mandatory. 
15.3 
Data Retention 
The treating investigator shall retain all clinical investigation records during the clinical 
investigation and for at least 15 years after the formal discontinuation, premature termination 

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or completion of clinical investigation. However, the treating investigator must contact the 
sponsor prior to destruction of any records or reports pertaining to the clinical investigation, in 
order to ensure they no longer need to be retained. In addition, the sponsor should be contacted 
if the treating investigator plans to leave the site so that arrangements can be made for transfer 
of records. 
The medical files of clinical investigation subjects must be retained in accordance with local 
legislation and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
15.4 
Clinical Investigation Report 
Following completion of clinical investigation, the results will be evaluated and a clinical 
investigation report will be generated, including a summary of all available data, statistical 
measures, tabulated results, graphical results, and interpretations. This report will be submitted 
to regulatory authorities and ethics committees, as appropriate, within the timeframes defined 
per national regulation or by the IRB. 
 
 

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16 
Regulatory and Ethical Considerations 
16.1 
Ethical Conduct of the Investigation  
The treating investigator will ensure that this clinical investigation is conducted in full 
conformity with the current revision of the Declaration of Helsinki and in compliance with IRB 
informed consent regulations and ISO guideline 14155:2011 (Clinical investigation of medical 
devices for human subjects - Good Clinical Practice [GCP]). In addition, all local regulatory 
requirements will be followed.  
16.2 
Institutional Review Board (IRB) 
Before the initiation of the clinical investigation, the final CIP, any amendments if applicable, 
the subject information sheet and ICF, as well as any additional documents which are required 
by national regulations and the IRB will be submitted to the competent IRB for review. A 
favorable opinion for the clinical investigation must be obtained from the IRB before any 
subject is enrolled at a center.  
If appropriate, any additional requirements imposed by the IRB will be followed. Amendments 
to the clinical investigation documents will be notified to, or approved by, the IRB before 
implementation, if applicable.  
16.3 
Insurance 
Insurance coverage for damages emerging from the clinical investigation will be provided 
according to applicable legal requirements. During the informed consent procedure, the treating 
investigator must inform the subject accordingly. Insurance details will be provided to the 
subject within the subject information sheet.  
16.4 
Informed Consent Process 
Written informed consent must be obtained from each subject prior to initiation of any of the 
investigation-specific procedures, including collection of data for the study.  
Before any clinical clinical investigation-related activities are performed, the treating 
investigator (or authorized designee) must review the ICF and explain the clinical investigation 
to potential clinical investigation subjects. The treating investigator must ensure that the subject 

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is fully informed about the aims, procedures, potential risks (including precautions and 
restrictions), any discomforts and expected benefits of the clinical investigation. 
Before consenting, the subject must be left with ample time to consider and ask questions. It 
must be emphasized that participation is voluntary and that the subject has the right to withdraw 
from the clinical investigation at any time without prejudice. The subject must then sign and 
date the ICF prior to the conduct of any clinical investigation procedures. The treating 
investigator must sign and date the ICF as well. 
A copy of the subject information sheet and ICF will be given to the subjects for their records. 
The rights and welfare of the clinical investigation subjects will be protected by emphasizing 
that the quality of their medical care will not be adversely affected if they decline to participate 
in this clinical investigation. 
If amendments to the final CIP affect the subject’s participation in the clinical investigation 
(e.g. a change in any procedure), the subject information and ICF must be updated to 
incorporate modifications, and subjects must agree to sign the amended form indicating that 
they re-consent to participate in the clinical investigation. 
16.5 
Subject Confidentiality 
The clinical investigation CIP, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the clinical investigation or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
The treating investigator must receive written permission from the subject for direct access to 
the subject’s data (including photographs taken) as part of the informed consent procedure. Any 
party (e.g. domestic and foreign regulatory authorities, monitors and auditors) with direct access 
must take all reasonable precautions within the constraints of the applicable regulatory 
requirements, to maintain the confidentiality of the subject’s identity and the sponsor’s 
proprietary information. The data collected during the clinical investigation must be transferred 
to the sponsor only in pseudonymous form. The treating investigator will keep the original 
Subject Identification Log (including complete name and date of birth of each subject) in his/her 
file. The treating investigator must maintain these documents in strictest confidence. 
Personal subject data will be kept confidential in compliance with Health Insurance Portability 
and Accountability Act (HIPAA) and other applicable international and national requirements. 

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Personal subject data transferred to Croma-Pharma GmbH in Austria should be in compliance 
with the European Data Protection Directive. 
On CRFs, compensation documentation, or any other documents submitted to the sponsor or 
sponsor's representative, subjects must be identified only by their identification codes; use of 
subjects’ names, addresses, telephone numbers, or similar information is prohibited. For GCP 
compliance, all subjects will be asked for consent regarding access to their personal clinical 
clinical investigation-related data for monitoring, audits, and inspections as well as regarding 
transmission and storage of their anonymous data; a respective statement will be part of the 
ICF. Professionals receiving access to source data for monitoring, audits and inspections must 
preserve strict confidentiality. 
 
 

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17 
Amendments to and deviations from the CIP 
17.1 
Amendments 
Any change to the CIP concerning the purpose of the clinical investigation, the clinical 
investigation design or the subject’s eligibility must be made in the form of a written 
amendment to the CIP. Such amendments must be discussed and signed by the sponsor, the 
coordinating investigator, and the principal investigator(s) before implementation Amendments 
that might have an impact on subject-related clinical investigation procedures and/or the well-
being of the subject require an additional ICF that must be signed by all subjects enrolled in the 
clinical investigation who are affected by the amendment. 
17.2 
Deviations 
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the 
CIP. As required by national regulation or guidelines, requests for deviations and reports of 
deviations will be provided to the IRB if the deviation affects subject’s rights, safety and well-
being, or the scientific integrity of the clinical investigation. 
Under emergency circumstances, deviations from the CIP may proceed without prior approval 
by the sponsor and favorable opinion of the IRB if the rights, safety and well-being of human 
subjects need to be protected. Such deviations will be documented and reported to the sponsor 
and the IRB as soon as possible in accordance with national regulations. 
The investigator must maintain accurate, complete and current records of any deviation from 
the CIP, including the date and reason for each deviation. 
The investigator shall notify the Sponsor and the reviewing IRB of any deviation from the CIP 
made to protect the life or physical well-being of a subject in emergency as soon as possible, 
but in no event later than five working days after the emergency occurred.  
All CIP deviations will be listed and (if evaluable for analysis) will be discussed in a blind data 
review meeting prior to the statistical analysis. 
No waivers to the CIP will be granted by the Sponsor. 

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18 
Suspension or Premature Termination of the Clinical 
Investigation 
The sponsor reserves the right to terminate the clinical investigation for any reason. The sponsor 
will provide instructions if assessments beyond the regular per protocol procedures should be 
necessary. 
The sponsor may suspend enrollment or terminate the clinical investigation at a specific site for 
reasons including, but not limited to, inadequate data collection, low subject enrollment rate, 
achievement of the total enrollment, or non-compliance with the protocol or other clinical 
research requirements. 
A principal investigator, IRB, or FDA may also suspend or prematurely terminate the clinical 
investigation at the investigational sites for which they are responsible.  
If the clinical investigation is prematurely terminated, the sponsor or the sponsor’s 
representative will promptly inform the FDA of the termination and its reason(s); the treating 
investigator or the sponsor (or representative) will promptly inform the IRB as specified in 
applicable regulations. 
In case of vascular occlusion, clinical investigation stopping rules are described in the 
Section 12.4.1.  
 
 

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19 
Publication Policy 
The clinical investigation will be posted on the “clinicaltrials.gov” site.  
Moreover, the results of the clinical investigation may be published and/or presented at 
scientific meetings. However, results should not be published without prior written consent by 
the sponsor and such consent will not be unreasonably withheld. All manuscripts and abstracts, 
which refer to data originating from the clinical investigation, must be submitted to the sponsor 
for comments at least 90 days prior to submission for publication. 
If the proposed publication contains any invention related to the clinical investigation, the 
sponsor is entitled to file respective patent applications and - on this ground - to delay the 
submission for publication or presentation of medical results. 
 
 

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20 
References 
Alam, M., Gladstone, H., Kramer, E. M., Murphy, J. P., Nouri, K., Neuhaus, I. M., Ceilley, R. 
I. (2008). ASDS guidelines of care: injectable fillers. Dermatologic Surgery, 34(s1).  
Arruda, L., Costa, A., Pereira, E., de Oliveira Pereira, M., & Assumpção, E. (2013). Evaluation 
of Clinical Safety and Effectiveness of Hyaluronic Acid-based Temporary Dermal Filler 
Used in Nasolabial Folds. J Clin Exp Dermatol Res, 4, 196.  
Beasley, K. L., Weiss, M. A., & Weiss, R. A. (2009). Hyaluronic acid fillers: a comprehensive 
review. Facial Plast Surg, 25(2), 86-94. doi:10.1055/s-0029-1220647 
Beleznay, K., FRCPC, FAAD, Carruthers, J., FRCSC, FRC (OPTH), FASOPRS, Humprey, S., 
FRCPC, FAAD, & Jones, D. (2015). Avoiding and treating blindness from filles: a 
review of the literature world. Am Soc Derm Sur, 41: 1097-1117. 
Bogdan Allemann, I., & Baumann, L. (2008). Hyaluronic acid gel (Juvederm) preparations in 
the treatment of facial wrinkles and folds. Clin Interv Aging, 3(4), 629-634.  
Brandt, F., Bank, D., Cross, S. L., & Weiss, R. (2010). A lidocaine-containing formulation of 
large-gel particle hyaluronic acid alleviates pain. Dermatol Surg, 36 Suppl 3, 1876-
1885. doi:10.1111/j.1524-4725.2010.01777.x 
Brandt, F. S., & Cazzaniga, A. (2008). Hyaluronic acid gel fillers in the management of facial 
aging. Clin Interv Aging, 3(1), 153-159.  
Bugge, H., Negaard, A., Skeie, L., & Bergersen, B. (2007). Hyaluronic acid treatment of facial 
fat atrophy in HIV-positive patients. HIV Med, 8(8), 475-482. doi:10.1111/j.1468-
1293.2007.00494.x 
Carruthers, J. D., Glogau, R. G., Blitzer, A., & Facial Aesthetics Consensus Group, F. (2008). 
Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, 
and combination therapies--consensus recommendations. Plast Reconstr Surg, 121(5 
Suppl), 5S-30S; quiz 31S-36S. doi:10.1097/PRS.0b013e31816de8d0 
Choi, H. S., Whipple, K. M., Oh, S. R., Priel, A., Looi, A., Korn, B. S., & Kikkawa, D. O. 
(2011). Modifying the upper eyelid crease in Asian patients with hyaluronic acid fillers. 
Plast Reconstr Surg, 127(2), 844-849. doi:10.1097/PRS.0b013e3181fed6cb 
Coleman, S. R., & Grover, R. (2006). The anatomy of the aging face: volume loss and changes 
in 
3-dimensional 
topography. 
Aesthet 
Surg 
J, 
26(1S), 
S4-9. 
doi:10.1016/j.asj.2005.09.012 
DeLorenzi, C. (2013). Complications of injectable fillers, part I. Aesthet Surg J, 33(4), 561-
575. doi:10.1177/1090820X13484492 
Donofrio, L. M. (2000). Fat distribution: a morphologic study of the aging face. Dermatol Surg, 
26(12), 1107-1112.  
Downie, J. B., Grimes, P. E., & Callender, V. D. (2013). A Multicenter Study of the Safety and 
Effectiveness of Hyaluronic Acid with a Cohesive Polydensified Matrix for Treatment 
of Nasolabial Folds in Subjects with Fitzpatrick Skin Types IV, V, and VI. Plast 
Reconstr Surg, 132(4S-2), 41S-47S 10.1097/PRS.1090b1013e318299ff318253.  
Few, J., Cox, S. E., Paradkar-Mitragotri, D., & Murphy, D. K. (2015). A Multicenter, Single-
Blind Randomized, Controlled Study of a Volumizing Hyaluronic Acid Filler for 
Midface Volume Deficit: Patient-Reported Outcomes at 2 Years. Aesthet Surg J, 35(5), 
589-599. doi:10.1093/asj/sjv050 
Funt, D., & Pavicic, T. (2013). Dermal fillers in aesthetics: an overview of adverse events and 
treatment 
approaches. 
Clin 
Cosmet 
Investig 
Dermatol, 
6, 
295-316. 
doi:10.2147/CCID.S50546 

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Gazzola, R., Pasini, L., & Cavallini, M. (2012). Herpes virus outbreaks after dermal hyaluronic 
acid filler injections. Aesthet Surg J, 32(6), 770-772. doi:10.1177/1090820X12452293 
Glaser, D. A., Kenkel, J. M., Paradkar-Mitragotri, D., Murphy, D. K., Romagnano, L., & 
Drinkwater, A. (2015). Duration of effect by injection volume and facial subregion for 
a volumizing hyaluronic acid filler in treating midface volume deficit. Dermatol Surg, 
41(8), 942-949. doi:10.1097/DSS.0000000000000416 
Gooderham, M., & Solish, N. (2005). Use of hyaluronic acid for soft tissue augmentation of 
HIV-associated facial lipodystrophy. Dermatol Surg, 31(1), 104-108.  
Goodman, G. J., Bekhor, P., Rich, M., Rosen, R. H., Halstead, M. B., & Rogers, J. D. (2011). 
A comparison of the efficacy, safety, and longevity of two different hyaluronic acid 
dermal fillers in the treatment of severe nasolabial folds: a multicenter, prospective, 
randomized, controlled, single-blind, within-subject study. Clin Cosmet Investig 
Dermatol, 4, 197-205. doi:10.2147/CCID.S26055 
Halachmi, S., Ben Amitai, D., & Lapidoth, M. (2013). Treatment of acne scars with hyaluronic 
acid: an improved approach. J Drugs Dermatol, 12(7), e121-123.  
Hasson, A., & Romero, W. A. (2010). Treatment of facial atrophic scars with Esthelis, a 
hyaluronic acid filler with polydense cohesive matrix (CPM). J Drugs Dermatol, 9(12), 
1507-1509.  
Ibrahim, O., Overman, J., Arndt, K. A., & Dover, J. S. (2017). Filler Nodules: Inflammatory or 
Infectious? A Review of Biofilms and Their Implications on Clinical Practice. 
Dermatologic Surgery.  
John, H. E., & Price, R. D. (2009). Perspectives in the selection of hyaluronic acid fillers for 
facial wrinkles and aging skin. Patient Prefer Adherence, 3, 225-230.  
Kablik, J., Monheit, G. D., Yu, L., Chang, G., & Gershkovich, J. (2009). Comparative physical 
properties of hyaluronic acid dermal fillers. Dermatol Surg, 35 Suppl 1, 302-312. 
doi:10.1111/j.1524-4725.2008.01046.x 
Khan, F., Richards, K., & Rashid, R. M. (2012). Hyaluronic acid filler for a depressed scar. 
Dermatol Online J, 18(5), 15.  
Landau, M. (2011). Examining the safety and efficacy of a non-animal cross-linked hyaluronic 
acid. prime, 2011(November/December), 42-48.  
Levy, P. M., De Boulle, K., & Raspaldo, H. (2009a). A split-face comparison of a new 
hyaluronic acid facial filler containing pre-incorporated lidocaine versus a standard 
hyaluronic acid facial filler in the treatment of naso-labial folds. J Cosmet Laser Ther, 
11(3), 169-173. doi:10.1080/14764170902833142 
Levy, P. M., De Boulle, K., & Raspaldo, H. (2009b). Comparison of injection comfort of a new 
category of cohesive hyaluronic acid filler with preincorporated lidocaine and a 
hyaluronic acid filler alone. Dermatol Surg, 35 Suppl 1, 332-336; discussion 337. 
doi:10.1111/j.1524-4725.2008.01045.x 
Lowe, N. J., Maxwell, C. A., & Patnaik, R. (2005). Adverse reactions to dermal fillers: review. 
Dermatol Surg, 31(11 Pt 2), 1616-1625.  
Lupo, M. P., Smith, S. R., Thomas, J. A., Murphy, D. K., & Beddingfield, F. C., 3rd. (2008). 
Effectiveness of Juvederm Ultra Plus dermal filler in the treatment of severe nasolabial 
folds. Plast Reconstr Surg, 121(1), 289-297. doi:10.1097/01.prs.0000294968.76862.83 
Mendelson, B. C., & Jacobson, S. R. (2008). Surgical anatomy of the midcheek: facial layers, 
spaces, and the midcheek segments. Clin Plast Surg, 35(3), 395-404; discussion 393. 
doi:10.1016/j.cps.2008.02.003 

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Myung, Y., Lee, Y. H., & Chang, H. (2012). Surgical correction of progressive hemifacial 
atrophy with onlay bone graft combined with soft tissue augmentation. J Craniofac 
Surg, 23(6), 1841-1844. doi:10.1097/SCS.0b013e318264b0ab 
Narins, R. S., Brandt, F., Leyden, J., Lorenc, Z. P., Rubin, M., & Smith, S. (2003). A 
randomized, double-blind, multicenter comparison of the efficacy and tolerability of 
Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg, 29(6), 
588-595.  
Nast, A., Reytan, N., Hartmann, V., Pathirana, D., Bachmann, F., Erdmann, R., & Rzany, B. 
(2011). Efficacy and Durability of Two Hyaluronic Acid-Based Fillers in the Correction 
of Nasolabial Folds: Results of a Prospective, Randomized, Double-Blind, Actively 
Controlled Clinical Pilot Study. Dermatol Surg. doi:10.1111/j.1524-4725.2011.01993.x 
Pavicic, T., Ruzicka, T., Korting, H. C., & Gauglitz, G. (2010). Monophasic, cohesive-
polydensified-matrix crosslinking-technology-based hyaluronic acid filler for the 
treatment of facial lipoatrophy in HIV-infected patients. J Drugs Dermatol, 9(6), 690-
695.  
Philipp-Dormston, W. G., Eccleston, D., De Boulle, K., Hilton, S., van den Elzen, H., & Nathan, 
M. (2014). A Prospective, Observational Study of the Volumizing Effect of Open-Label 
Aesthetic Use of Juvederm(R) VOLUMA(R) with Lidocaine in Mid-Face Area. J 
Cosmet Laser Ther. doi:10.3109/14764172.2014.910079 
Prager, W., & Micheels, P. (2015). A prospective, comparative survey to investigate 
practitioners' satisfaction with a cohesive, polydensified-matrix((R)) , hyaluronic acid-
based filler gel with and without lidocaine for the treatment of facial wrinkles. J Cosmet 
Dermatol, 14(2), 124-129. doi:10.1111/jocd.12136 
Rao, J., Chi, G. C., & Goldman, M. P. (2005). Clinical comparison between two hyaluronic 
acid-derived fillers in the treatment of nasolabial folds: hylaform versus restylane. 
Dermatol Surg, 31(11 Pt 2), 1587-1590.  
Raspaldo, H. (2008). Volumizing effect of a new hyaluronic acid sub-dermal facial filler: a 
retrospective analysis based on 102 cases. J Cosmet Laser Ther, 10(3), 134-142. 
doi:10.1080/14764170802154607 
Raspaldo, H., De Boulle, K., & Levy, P. M. (2010). Longevity of effects of hyaluronic acid 
plus lidocaine facial filler. J Cosmet Dermatol, 9(1), 11-15. doi:10.1111/j.1473-
2165.2010.00481.x 
Requena, L., Requena, C., Christensen, L., Zimmermann, U. S., Kutzner, H., & Cerroni, L. 
(2011). Adverse reactions to injectable soft tissue fillers. J Am Acad Dermatol, 64(1), 
1-34; quiz 35-36. doi:10.1016/j.jaad.2010.02.064 
Richards, K. N., & Rashid, R. M. (2011). Twenty-four-month persistence of hyaluronic acid 
filler for an atrophic scar. J Cosmet Dermatol, 10(4), 311-312. doi:10.1111/j.1473-
2165.2011.00589.x 
Ross, J. J., & Malhotra, R. (2010). Orbitofacial rejuvenation of temple hollowing with Perlane 
injectable filler. Aesthet Surg J, 30(3), 428-433. doi:10.1177/1090820X10374099 
Royo de la Torre, J., Moreno-Moraga, J., Isarria, M. J., Munoz, E., Cruz, I., Perez, G., & 
Cornejo, P. (2013). The evaluation of hyaluronic acid, with and without lidocaine, in 
the filling of nasolabial folds as measured by ultrastructural changes and pain 
management. J Drugs Dermatol, 12(3), e46-52.  
Smith, K. C. (2008). Reversible vs. nonreversible fillers in facial aesthetics: concerns and 
considerations. Dermatol Online J, 14(8), 3.  

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Sundaram, H., & Cassuto, D. (2013). Biophysical characteristics of hyaluronic acid soft-tissue 
fillers and their relevance to aesthetic applications. Plast Reconstr Surg, 132(4 Suppl 
2), 5S-21S. doi:10.1097/PRS.0b013e31829d1d40 
Tezel, A., & Fredrickson, G. H. (2008). The science of hyaluronic acid dermal fillers. J Cosmet 
Laser Ther, 10(1), 35-42. doi:10.1080/14764170701774901 
Vedamurthy, M. (2004). Soft tissue augmentation--use of hyaluronic acid as dermal filler. 
Indian J Dermatol Venereol Leprol, 70(6), 383-387.  
Wahl, G. (2008). European evaluation of a new hyaluronic acid filler incorporating lidocaine. 
J Cosmet Dermatol, 7(4), 298-303. doi:10.1111/j.1473-2165.2008.00409.x 
Weinkle, S. H., Bank, D. E., Boyd, C. M., Gold, M. H., Thomas, J. A., & Murphy, D. K. (2009). 
A multi-center, double-blind, randomized controlled study of the safety and 
effectiveness of Juvederm injectable gel with and without lidocaine. J Cosmet 
Dermatol, 8(3), 205-210. doi:10.1111/j.1473-2165.2009.00451.x 
 
 
 

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21 
Revision History 

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Version 
Date 
Reason for Revision 
7.0 
15.03.2021 
Updates to the following sections to account for the extension to the 
study duration because of the temporary hold on repeat-treatment: 
2 Synopsis - planned clinical investigation period 
9.4 Subject Enrollment, Number and Duration of Subject’s 
Participation 
 
Updates to the following sections to include the additional visit for 
evaluation for repeat treatment (and receipt of repeat treatment if 
eligible) and the two follow-up visits if repeat treatment was 
received: 
2 Synopsis - additional objectives, design and additional outcome 
measures 
2.1 Schedule of Clinical Investigation Procedures and 
Assessments 
5.4 Additional Objectives 
7.1 Description of Clinical Investigation Design 
7.3.1.3 Additional Outcome Measures 
9.3 Subject Withdrawal and Discontinuation 
9.4 Subject Enrollment, Number and Duration of Subject’s 
Participation 
10.1 Nasolabial Folds-Severity Rating Scale (NLF-SRS) 
10.2 Global Aesthetic Improvement Scale (GAIS) 
10.3 Subject Satisfaction using Face-Q Questionnaires 
10.6 Time to Repeat-Treatment 
10.7 Clinical Photography 
10.8 Visual Examinations 
10.9 Other Assessments 
10.11.9 Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or 
Visit 7c – Evaluation 
10.11.10 Week 36 (Visit 6) and/or Week 48 (Visit 7) and/or 
Visit 7c – Repeat-Treatment 
10.11.11 Phone Contact after Visit 6, Visit 7 or Visit 7c 

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10.11.12 Week 40 (Visit 8a), Week 52 (Visit 8b) or Visit 8c 
10.11.13 Week 48 (Visit 9a), Week 60 (Visit 9b) or Visit 9c 
10.12 Early Termination 
In addition, minor formatting changes were made throughout. 
6.0 
(not 
finalized)a 
04.11.2020 
Update of the following sections as per FDA requests: 
Addition of Section 9.2 – Inclusion and Exclusion Criteria for 
repeat treatment eligibility of subjects; existing criteria were 
formally summarized and additional exclusion criteria based on 
visual assessments were introduced 
Addition of Section 10.8 as a separate section for description of 
Visual Assessments 
Updates throughout the entire protocol with a special emphasis on 
evaluation of potential changes to vision during or after device 
application: this includes updates to the Synopsis (Section 2), the 
Schedule of Events (Section 2.1), detailed description of study 
visits (Schedule of Clinical Investigation, Section 10.11) 
Section 12.1 and Section 12.4.1: updated to clarify the definition 
of UADEs and to specify investigator and sponsor responsibilities 
for reporting UADEs 
Sponsor related contact details 
Update of Croma-Pharma Clinical Project Manager 
Update of Croma-Pharma Global Director Clinical Development  
5.0 
10.12.2019 
 
 
 
 
 
 
 
 
 
In the synopsis under Outcome measures (Secondary outcome 
measures and additional outcome measure and in 7.3.1.2 and 7.3.1.3 
the following has been added: 
“Responder is defined as having at least one grade improvement over 
Baseline, on the 5-point NLF-SRS”  
Section 12.3.1: Correction in first sentence: medical device 
(instead of medicinal device) 
 
Addition in Section 12.3.1 Clarification of process in case of 
disagreement between Investigator and Sponsor was added 
Addition in 12.4 Any details about AE reporting and casuality 
assessement are described in the current valid version of device 
safety management plan. 

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Section 12.4.1: deletion of ‘working’ in the sentence: For the 
purpose of submission, any incidence of visual disturbance will be 
considered a reportable event within 10 working days. 
Required reporting details of visual disturbances are specified 
Sponsor related contact details 
Update of Croma-Pharma Clinical Project Manager 
 
4.0 
03.10.2019 
The retreatment procedure has been changed in a way that 
subjects are offered Princess Filler Lidocaine in both nasolabial 
folds at week 36/week 48, and no comparator product is used 
for retreatment. The visit schedule for subjects being retreated 
at week 36/48, and for subjects without retreatment has been 
explained in more detail. Throughout the document, slight 
modifications for clarification purposes have been 
implemented.  
The following Sections have been changed:  
2. Clinical Investigation Synopsis 
7.1 Description of the Clinical Investigation 
7.3 Outcome measures 
7.6 Randomization and Blinding 
8.6 Medical Device Accountability 
9.4 Subject Enrollment, Number and Duration of Subject’s 
participation 
10.1 Nasolabial Folds Severity Rating Scale (NLF-SRS) 
10.8 Other Assessments 
10.10 Schedule of the Clinical Investigation 
12.4 Adverse Event Monitoring and Assessment 
12.6. Device Deficiencies 

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3.0 
04.01.2019 
As per FDA request, the CIP has been updated: the follow up visit 
after optional repeat treatment has been increased from one to three 
months to allow for the collection of valuable safety and efficacy 
data following repeat-treatment. In addition, CIP was updated to 
eliminate smaller, but important errors. The Schedule of Clinical 
Investigation Procedures and Assessments as well as the Clinical 
Investigation Procedures and Assessments-Section have been 
updated to eliminate inconsistencies. Description of the Medical 
Device-Section has been updated to add the possibility to use 
cannulas. The Safety section has been updated in order to clarify 
Adverse events of special interest and the SAE/Device deficiency 
reporting procedure has been updated 
The following Sections have been updated:  
2. Clinical Investigation Synopsis 
2.1 Schedule of Investigation procedures and Assessments 
4.3 Description of the IMD 
7. Design description revised 
10. Clinical Investigation Procedures and Assessments 
12. Assessment of Safety 
2.0 
24.09.2018 
As per FDA request, the CIP has been updated: visual examinations
have been added in order to ensure that adverse events related to 
vision changes are fully evaluated. Additionally, clinical 
investigation stopping rules for vascular occlusion have been 
introduced. Moreover, the content of the subject diary has been 
extended to reflect the above changes, as well as the “Precautions 
for use” and “Warnings” sections. 
Following sections have been therefore updated: 
2. Clinical Investigation Synopsis 
5. Clinical Investigation Purpose and Objectives 
6. Risks and Benefits of the Investigational Device and Clinical 
Investigation 
7. Outcome Measures 
8. IMDs 
10. Clinical Investigation Procedures and Assessments 
12. Assessment of Safety: 

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18. Suspension or Premature Termination of the Clinical 
Investigation: 
20. References 
21. Revision History 
1.8 
13.07.2018 
CIP updated to accurately reflect wrinkle severity scores for the 
inclusion criteria. 
1.7 
22.06.2018 
Deletion of investigational sites located in Europe, and therefore 
deletion of any mention to European Ethics committees or 
competent authorities. 
Updated timelines in the “Planned Clinical Investigation Period” 
part of the synopsis. 
Clarification of indication wording to distinguish between the 
study and the indications as placed on the current EU label of the 
device. 
1.6 
09.04.2018 
As per FDA request and because of the availability of new 
information, additional changes were performed and are resulting 
in the update of the following sections: 
2. Clinical Investigation Synopsis: inclusion of European clinical 
investigational site(s) within the twelve planned sites 
3. Investigators and Administrative Structure of the Clinical 
Investigation: inclusion of European clinical investigation site(s) 
within the twelve planned sites and change of CRO name (only 
name but no organization change) 
4. Background Information Regarding Dermal Fillers:  
 intended use definition completed with medical indications 
 addition of pyrogenicity testing results 
 addition of results of one clinical investigation with Princess® 
FILLER (CPH-401-201259, medical indications) 
 update of state-of-the-art literature 
 update of Post-Market Surveillance data 
6. Risks and Benefits of the Investigational Device and Clinical 
Investigation: update of Post-Market Surveillance data 
7. Outcome Measures: same definition of responders used for all 
outcome measures (primary, secondary and additional). Detailed 
definition of the “improvement” term added 
9. Subject Enrolment, Number and Duration of Subject’s 
Participation: addition of European clinical investigational site(s) 

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a. Version 6.0 (Draft) of the Clinical Investigation Plan was submitted to the FDA; further changes were required following 
FDA review, and the additional changes were made under Clinical Investigation Plan Version 7.0 
 
 
procedure for secondary outcome measures 2; removing timing of 
analysis 
1.1 
30.03.2017 
Update of the following sections as per FDA recommendations: 
1. Abbreviations and definition of terms: missing abbreviations 
added 
2. Clinical investigational synopsis: updated according to the 
changes performed in CIP (described below) 
4. Background Information and Scientific Rationale: data 
updated accordingly to Post Market Surveillance report 2016; 
justification of comparator choice 
5. Clinical Investigation Purpose and Objectives: the hierarchy 
of the objectives has been changed in secondary and additional 
objectives 
6. Risks and Benefits of the Investigational Device and Clinical 
Investigation: addition of risk mitigation strategies 
7. Design of the Clinical Investigation: the hierarchy of the 
outcome measures has been changed in secondary and additional 
outcome measures; better description of the subject allocation to 
both randomization groups; description of emergency blinding 
8. Investigational Medical Devices: additional description of 
touch-up treatment and of the applied volume of the device; 
Section “Precautions, Prohibited Medications/Treatments and 
Restrictions” has been moved from Section 7 to Section 8; Section 
“Medical Device Accountability” has been moved from Section 7 
to Section 8 
9. Subject Selection, Withdrawal and Discontinuation: update 
of exclusion criteria; additional enrolment cap per study site 
10.Clinical investigation Procedures and Assessments: better 
description of the procedures and assessments 
12. Assessment of Safety: better description of assessment of 
causality and adverse event outcome 
14. Statistical considerations: additional poolability analysis; 
additional analysis of missing data; additional hierarchical testing 
procedure of the primary outcome measure, as well as the 
secondary outcome measures; additional timing of analysis 
15. Data Handling and Record Keeping: additional description 
of data cleaning process 
20. References: addition of missing references 

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22 
Appendices 
22.1 
Appendix 1: 
 
FACE-Q Questionnaires 

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22.2 
Appendix 2: 
 
Princess® FILLER Lidocaine Instructions for Use 

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22.3 
Appendix 3: 
 
Juvéderm® Ultra XC Instructions for Use