A Prospective, Open Label, Multicenter, Post Market Study Evaluating Princess® FILLER Lidocaine for the Correction of Nasolabial Folds
Phase: NA
Conditions: Correction of Nasolabial Folds
Sponsor: Croma-Pharma GmbH

 
CIP CPH-401-201324 (V1.0, 14-MAR-2017) 
 
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CLINICAL INVESTIGATION PLAN (CIP) 
Title of the clinical 
investigation/CIP: 
A prospective, open label, multicenter, post market study evaluating 
Princess® FILLER Lidocaine for the correction of nasolabial folds 
Short title: 
FINO (Filler LIdocaine in Nasolabial FOlds) 
Investigation ID: 
CPH-401-201324 
CIP version: 
1.0 
CIP version date: 
14 MARCH 2017 
Sponsor: 
CROMA-PHARMA GmbH 
Industriezeile 6, 2100 Leobendorf, Austria 
Phone: +43 2262 684 680; Fax: +43 2262 6846 8165 
E-mail: office@croma.at; Web: www.croma.at 
 
 
 
Investigation site(s): 
At least two sites located in Austria (an updated list of the sites, including 
names, addresses and positions of the corresponding Principal investigators, 
is kept separately from the CIP) 
Medical monitor: 
 
  
 
  
 
 
 
 
Other institutions 
involved: 
An updated list of institutions that are involved in project management, 
monitoring, data management and statistics is kept separately from the CIP 
 
CONFIDENTIAL 
 
This clinical investigation plan is the property of CROMA-PHARMA GmbH 
and must be kept strictly confidential. Any unauthorized disclosure, copy or 
use of this document, or information contained herein, is prohibited. 
... . 
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Approval and signature pages 
 
Clinical investigation plan agreed to by the Sponsor 
 
 
 
 
 
 
 
 
 
__________________________________ 
 
 
__________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________ 
 
 
__________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Approval and signature pages 
 
Clinical investigation plan agreed to by the Coordinating investigator 
 
 
 
 
 
 
 
 
 
 
 
N.A 
__________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Approval and signature pages 
 
Principal investigator agreement 
I agree: 
 
To assume responsibility for the proper conduct of the clinical investigation at the site specified 
above, and to conduct the investigation in compliance with this clinical investigational plan (CIP), 
including any amendments thereof, any other study conduct procedures provided by the Sponsor 
or their authorized representatives, the principles of good clinical practice, and applicable 
regulatory requirements. 
 
Not to implement any deviations from, or changes to, the CIP (including CIP amendments) without 
agreement from the Sponsor, prior review and favourable 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 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. 
 
To ensure that all persons providing assistance during the clinical investigation are adequately 
informed about the investigational medical device and of their study-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 study product, and 
more generally about his/her financial ties with the Sponsor. The Sponsor will use and disclose 
this information solely for the purpose of complying with regulatory requirements. 
 
Investigator's name: 
__________________________________ 
 
Investigator's address: 
__________________________________ 
 
Investigator's signature: 
__________________________________ 
 
 
Date: 
__________________________________ 
 
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Synopsis 
 
Investigation title 
A prospective, open label, multicenter, post-market study evaluating 
Princess® FILLER Lidocaine for the correction of nasolabial folds 
Short title 
FINO (Filler LIdocaine in Nasolabial FOlds) 
Investigation ID 
CPH-401-201324 
Investigation sites 
2 sites located in Austria 
Phase of 
development 
Post-market clinical follow-up 
Indication 
Moderate to severe nasolabial folds 
Planned duration 
The duration of the clinical investigation will be nine months for each 
participating subject. The total expected duration of the clinical investigation 
is about twelve months with an expected recruitment period of about 3 
months  
Objectives 
 To evaluate the performance of Princess® FILLER Lidocaine for the 
correction of nasolabial folds 
 To evaluate the safety of Princess® FILLER Lidocaine when used for 
correction of nasolabial folds 
Study design 
A prospective, open label, multicenter, post-market investigation. 
Following informed consent and screening, eligible subjects with moderate to 
severe nasolabial folds will be treated with Princess® FILLER Lidocaine, and 
will return for follow-up assessments 2, 4, 24 and 36 weeks after the initial 
treatment. A Touch-up treatment may be done at Week 2 after initial 
treatment, if deemed appropriate by the investigator. The performance of the 
investigational device will be evaluated by the investigator by assessing 
severity of nasolabial folds using the Nasolabial Folds Severity Rating Scale 
(NLF-SRS) (4, 24 and 36 weeks after the initial treatment and in comparison 
to Day 0) and global aesthetic improvement (4, 24 and 36 weeks after the 
initial treatment). The subject will evaluate pain intensity associated with the 
treatment (at Day 0 and at Week 2 after initial treatment (if Touch-up 
treatment occurred)), and satisfaction with the treatment 4, 24 and 36 weeks 
after the initial treatment. 
The safety will be evaluated based on occurrence of adverse events, which 
will be collected throughout the investigation. 
Number of subjects 
Up to 60 subjects will be included, to obtain the Week 24 performance data in 
at least 40 subjects. 
Eligibility criteria 
Inclusion criteria: 
1. Male or female 18 years of age or older 
2. Presence of two fully visible, approximately symmetrical nasolabial folds, 
with each of the folds scored 2-3 according to the 5-grade Nasolabial 
Folds Severity Rating Scale (NLF-SRS) as assessed by the investigator 
3. Healthy skin in the facial area and free of diseases that could interfere in 
cutaneous aging evaluation 
4. Willingness to abstain from any aesthetic or surgical procedures in the 
treatment area for the duration of the clinical investigation 
5. Written signed and dated informed consent 
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Exclusion criteria: 
1. Pregnancy, lactation, planned pregnancy or unwillingness to use 
contraception at any time during the study (for women of child-bearing 
potential only) 
2. History of mental disorders or emotional instability 
3. History of allergic reaction or hypersensitivity to hyaluronic acid, 
lidocaine, or any amide-based anaesthetic  
4. Presence of silicone implant or another non-absorbable substance 
(permanent fillers) in the nasolabial region 
5. Facial surgery or implantation of dermal fillers, absorbable and non-
absorbable sutures, laser therapy, dermoabrasion, or botulinum toxin 
application in the nasolabial region within previous twelve months, or 
chemical peeling within previous three months, or planning to undergo 
such procedures in the treatment area during the study 
6. Presence of infectious, inflammatory, or proliferative lesions in the 
nasolabial region 
7. Cutaneous lesions in the treatment area 
8. Known human immune deficiency virus-positive individuals 
9. History of allergies against aesthetic filling products and recurrent herpes 
simplex 
10. Tendency to hypertrophic scars, keloid formation and/or pigmentation 
disorders 
11. History or presence of any autoimmune or connective tissue disease, or 
current treatment with immune therapy 
12. Diabetes mellitus or uncontrolled systemic diseases 
13. Use of anticoagulant, antiplatelet or thrombolytic medication from 10 days 
pre- to three days post injection 
14. Any medical condition which, in the investigator’s opinion, prohibits the 
inclusion in the study 
15. Current or previous (within 30 days of enrolment) treatment with another 
investigational drug and/or medical device or participation in another 
clinical study 
16. Previous enrolment in this clinical investigation 
17. Subjects whose participation in clinical trials is prohibited by the Austrian 
Medical Devices Act (e.g., persons with a legal custodian appointed due 
to mental disability, prisoners, soldiers and other members of the armed 
forces, civil servants) 
Investigational 
device and mode of 
administration 
Princess® FILLER Lidocaine is a sterile, biodegradable, viscoelastic, clear, 
transparent, isotonic and homogenized injectable gel implant formulated in a 
physiologic buffer to a concentration of 23 mg/mL, with addition of 0.3% 
lidocaine hydrochloride. 
Princess® FILLER Lidocaine is administered by injection into mid to deep 
dermis. The volume applied depends on the size of the area which requires 
correction and will be selected by the investigator, but will not exceed 10 mL 
in total per treatment. 
Treatment duration 
A single application, with optional Touch-up treatment after two weeks, if the 
desired level of correction has not been achieved with the initial application  
Primary 
performance 
endpoints 
 The average change versus Baseline (Day 0) in the NLF-SRS grade of 
nasolabial folds at Week 24 after initial treatment as evaluated by the 
investigator 
 The proportion of subjects with the NLF-SRS grade reduced by ≥1 point 
versus Baseline at Week 24 after initial treatment 
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Secondary 
performance 
endpoints 
 The average change versus Baseline in the NLF-SRS grade at Week 4 and 
Week 36 after initial treatment as evaluated by the investigator 
 The proportion of subjects with the NLF-SRS grade reduced by ≥1 point 
versus Baseline at Week 4 and Week 36 after initial treatment 
 The proportion of subjects with aesthetic improvement at Week 4, Week 24 
and Week 36 after initial treatment, as evaluated by the investigator using 
the Global Aesthetic Improvement Scale (GAIS) 
 Subjects’ satisfaction with aesthetic outcome of the treatment at Week 4, 
Week 24 and Week 36 after initial treatment, as evaluated by the subject 
 The average pain intensity during and after the treatment, as evaluated by 
the subject using an 11-point Numeric Pain Rating Scale (NPRS) 
immediately after the last injection and 15 min. thereafter, respectively 
 The proportion of subjects with the NLF-SRS grade reduced by ≥1 point 
versus Baseline at Week 24 after initial treatment as evaluated by the 
independent reviewer of photographs. 
Safety endpoints 
Occurrence and frequency of adverse events 
Statistical methods 
All analyses will be done in the Intent-to-treat population, defined as all 
subjects who received the investigational device and have at least one post-
treatment assessment. Individual NLF-SRS grades per visit will be calculated 
as the mean of grades assigned to the left and the right nasolabial fold, 
respectively. The absolute NLF-SRS change versus Baseline will be 
computed by subtracting the value obtained on Day 0, and summarized by 
the visit using descriptive statistics. Additionally, the 95% confidence intervals 
of the mean will be given and proportions of the NLF-SRS change values ≥1 
or ≥2, respectively, will be calculated. Adverse events will be summarised by 
preferred term and system organ class, and also by intensity, relationship to 
the investigational medical device or procedure, and seriousness.  
 
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Schedule of procedures and events 
 
Table 1. Schedule of procedures and events 
 
VISIT 1 
Baseline Visit* 
VISIT 2 
Week 2 Visit 
VISIT 3 
Week 4 Visit 
VISIT 4 
Week 24 Visit 
VISIT 5 
Week 36 Visit 
Visit window 
Day 0 
Week 2 
(± 2 days) 
Week 4 
(± 4 days) 
Week 24 
(± 7 days) 
Week 36 
(± 7 days) 
Informed consent 
  x** 
 
 
 
 
Demographic dataa 
  x** 
 
 
 
 
Medical history 
  x** 
 
 
 
 
Prior medicationb 
  x** 
 
 
 
 
NLF-SRS grading of 
nasolabial foldsc 
  x** 
 
x 
x 
x 
Urine pregnancy testd 
  x** 
 
 
 
 
Eligibility assessment 
  x** 
 
 
 
 
Treatment 
x 
x§ 
 
 
 
Photography 
x** 
x§ 
x 
x 
x 
Pain assessmente 
x 
xΩ 
 
 
 
GAIS assessmentf 
 
 
x 
x 
x 
Subject satisfactiong 
 
 
x 
x 
x 
Adverse eventsh 
   x*** 
x 
x 
x 
x 
Concomitant medicationh 
   x*** 
x 
x 
x 
x 
* 
Includes screening and treatment.  
** Prior to application of the investigational device 
*** From beginning of the treatment onwards 
§ 
Optional, to be done at investigator’s discretion  
Ω 
To be performed only if Touch-up treatment occurred 
a 
Includes date of birth, sex, and race 
b 
All medication taken by the subject within the previous 10 days 
c 
Performed by the investigator using the Nasolabial Folds Severity Rating Scale (NLF-SRS); the severity of the left and 
the right fold will be separately graded 
d 
In females of child-bearing potential only, including women who are postmenopausal for less than 12 months 
e 
Evaluated by the subject immediately after injection and approximately 15 min. thereafter using an 11-point Numeric Pain 
Rating Scale 
f 
Evaluated by the investigator using the Global Aesthetic Improvement Scale (GAIS) 
g 
Evaluated by the subject 
h 
To be collected throughout the investigation, from beginning of the treatment until the last visit 
 
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List of abbreviations 
 
ADE 
Adverse device effect 
AE 
Adverse event 
BDDE 
1,4-butanediol diglycidyl ether 
CIP 
Clinical investigation plan 
CRF 
Case report form 
DCF 
Data clarification form 
EC 
Ethics Committee 
eCRF 
Electronic Case report form 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good clinical practice  
HA 
Hyaluronic acid 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
IFU 
Instructions for use 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIU 
Milli-international unit 
NLF 
Nasolabial fold 
NLF-SRS 
Nasolabial Folds Severity Rating Scale 
NPRS 
Numeric Pain Rating Scale 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TMF 
Trial master file 
USADE 
Unanticipated serious adverse device effect 
UV 
Ultraviolet 
w/w 
Weight/weight 
 
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Table of contents 
 
Approval and signature pages ................................................................................................................. 2 
Synopsis .................................................................................................................................................. 5 
Schedule of procedures and events ........................................................................................................ 8 
List of abbreviations ................................................................................................................................. 9 
1 
Background .................................................................................................................................... 13 
2 
Identification and description of the investigational device ............................................................ 13 
2.1 
Device description..................................................................................................................... 13 
2.2 
Manufacturer ............................................................................................................................. 14 
2.3 
Intended use and mode of administration ................................................................................ 14 
2.4 
Traceability ................................................................................................................................ 14 
3 
Justification for the design of the clinical investigation .................................................................. 14 
3.1 
Non-clinical data and biocompatibility ...................................................................................... 14 
3.2 
Clinical data .............................................................................................................................. 15 
3.3 
Justification for the clinical investigation ................................................................................... 16 
4 
Risks and benefits of the investigational device and clinical investigation .................................... 16 
4.1 
Anticipated clinical benefits ....................................................................................................... 16 
4.2 
Anticipated adverse device effects ........................................................................................... 16 
4.3 
Possible interactions with concomitant medical treatments ..................................................... 18 
4.4 
Risk mitigation strategy ............................................................................................................. 18 
4.5 
Risk-to-benefit rationale ............................................................................................................ 18 
5 
Objectives and hypotheses of the clinical investigation ................................................................. 18 
5.1 
Objectives ................................................................................................................................. 18 
5.2 
Hypotheses ............................................................................................................................... 18 
5.3 
Claims and intended performance of the investigational that are to be verified ....................... 18 
5.4 
Risks and anticipated adverse device effects that are to be assessed .................................... 19 
6 
Design of the clinical investigation ................................................................................................. 19 
6.1 
Design description .................................................................................................................... 19 
6.1.1 
Primary performance endpoints .......................................................................................... 19 
6.1.2 
Secondary performance endpoints ...................................................................................... 19 
6.1.3 
Safety endpoints .................................................................................................................. 19 
6.1.4 
Schedule of procedures and events .................................................................................... 19 
6.1.5 
Replacement of subjects ..................................................................................................... 20 
6.2 
Investigational device ............................................................................................................... 20 
6.2.1 
Packaging, labelling and storage ......................................................................................... 20 
6.2.2 
Methods of use .................................................................................................................... 21 
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6.2.3 
Applied volume of the device ............................................................................................... 22 
6.2.4 
Touch-up treatment ............................................................................................................. 22 
6.2.5 
Precautions .......................................................................................................................... 22 
6.2.6 
Rescue medication .............................................................................................................. 22 
6.2.7 
Investigational device accountability ................................................................................... 23 
6.3 
Subjects .................................................................................................................................... 23 
6.3.1 
Number of subjects and duration of the clinical investigation ............................................. 23 
6.3.2 
Recruitment strategy............................................................................................................ 23 
6.3.3 
Subject identification ............................................................................................................ 23 
6.3.4 
Inclusion criteria ................................................................................................................... 23 
6.3.5 
Exclusion criteria .................................................................................................................. 24 
6.3.6 
Withdrawal criteria and procedures ..................................................................................... 24 
6.3.7 
Life-style and other restrictions ............................................................................................ 25 
6.3.8 
Medical care upon termination of the clinical investigation ................................................. 25 
6.3.9 
Screening/baseline failures ................................................................................................. 25 
6.3.10 
Subject confidentiality .......................................................................................................... 25 
6.4 
Assessments and procedures .................................................................................................. 26 
6.4.1 
Demographic data ............................................................................................................... 26 
6.4.2 
Medical history ..................................................................................................................... 26 
6.4.3 
Pregnancy test ..................................................................................................................... 26 
6.4.4 
Photography ........................................................................................................................ 26 
6.4.5 
NLF-SRS grading of nasolabial folds .................................................................................. 27 
6.4.6 
Aesthetic improvement/GAIS assessment .......................................................................... 28 
6.4.7 
Pain assessment ................................................................................................................. 28 
6.4.8 
Subject’s satisfaction assessment ....................................................................................... 28 
6.4.9 
Outcome evaluationby the independent reviewer of photographs ...................................... 28 
6.4.10 
Safety monitoring ................................................................................................................. 29 
6.4.11       Prior and concomitant medication and non-drug therapies..................................................28 
6.4.12       Factors that may compromise the outcome......................................................................... 28 
6.5 
Monitoring plan ......................................................................................................................... 29 
7 
Statistical considerations ............................................................................................................... 29 
7.1 
Sample size .............................................................................................................................. 29 
7.2 
Analysed data sets.................................................................................................................... 30 
7.3 
Missing data .............................................................................................................................. 30 
7.4 
Methods of analysis .................................................................................................................. 30 
7.4.1 
Performance endpoints ....................................................................................................... 30 
7.4.2 
Safety endpoints .................................................................................................................. 30 
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8 
Data management ......................................................................................................................... 30 
8.1 
Case report forms ..................................................................................................................... 30 
8.2 
Data management procedures ................................................................................................. 31 
8.3 
Data retention ........................................................................................................................... 31 
8.4 
Report of the clinical investigation ............................................................................................ 31 
9 
Amendments to the clinical investigation plan ............................................................................... 32 
10 Deviations from the clinical investigation plan ............................................................................... 32 
11 Device accountability ..................................................................................................................... 32 
12 Statements of compliance.............................................................................................................. 32 
13 Informed consent process.............................................................................................................. 32 
14 Adverse events, adverse device effects and device deficiencies .................................................. 33 
14.1 
Definitions ................................................................................................................................. 33 
14.2 
Method of detecting AEs ........................................................................................................... 34 
14.3 
AE/SAE documentation ............................................................................................................ 34 
14.4 
AE/SAE assessment ................................................................................................................. 34 
14.4.1 
Severity assessment............................................................................................................ 34 
14.4.2 
Causality assessment .......................................................................................................... 35 
14.4.3 
Outcome assessment .......................................................................................................... 35 
14.5 
AE/SAE reporting requirements and contact details ................................................................ 36 
14.6 
AE/SAE follow-up...................................................................................................................... 36 
14.7 
Foreseeable AEs and anticipated ADEs .................................................................................. 36 
14.8 
Device deficiency reporting requirements ................................................................................ 37 
14.8.1 
Handling of deficient medical devices ................................................................................. 37 
14.9 
Data monitoring committee ....................................................................................................... 37 
15 Vulnerable populations .................................................................................................................. 37 
16 Suspension or premature termination of the clinical investigation................................................. 37 
17 Publication policy ........................................................................................................................... 37 
18 Bibliography ................................................................................................................................... 38 
 
 
 
 
 
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1 Background 
Skin aging is a natural and progressive process, driven by intrinsic and extrinsic factors. In addition to 
the skin, it also involves the skin support systems including the bone, cartilage, and subcutaneous 
compartments. Within the skin, aging results in reduced collagen production, fragmentation of elastin 
network, and decreased turnover of skin cells. The loss of extracellular matrix and its major 
component, hyaluronic acid, which forms a viscoelastic surrounding for collagen and elastin fibres, 
results in reduced skin elasticity and turgor1. Due to reduced elasticity, the repeated muscle action 
produces prominent wrinkles and creases in the mimetic areas of facial skin, while concomitant 
involution of facial fat deposits and bone atrophy contribute to skin laxity and facial volume loss and 
redistribution, resulting in aged face2. 
Appearance of nasolabial folds is one of the typical clinical manifestations of facial aging, which also 
include flaccidity of the skin and subcutaneous tissue, wrinkle expression in the upper third of the face, 
tear through, drop of the angle of the mouth, loss of definition in the mandibular border, cervico-facial 
platysmal bands, and changes in skin pigmentation3.  
Perception of age and health is critical in the judgement of attractiveness. Young faces are generally 
perceived to be more attractive than old faces, and estimated age is negatively correlated with 
perceived attractiveness4,5. Attractiveness influences both the self-perception and behaviour toward 
others, and is related to traits such as self-confidence and social acceptance. It is not surprising, 
therefore, that aesthetic interventions can improve the psychological well-being and quality of life in 
people who elect to undergo such procedures due to aging. Common positive changes include 
increased satisfaction with self-appearance, reduced depression or anxiety, improved emotional well-
being and increased self-confidence6.  
Dermal fillers are widely used for facial rejuvenation and correction of deep wrinkles, including 
nasolabial folds. These treatments provide desirable aesthetic outcomes with minimal invasiveness 
and without the downtime associated with surgery. Hyaluronic acid dermal fillers are most popular 
because of their ease of administration, predictable effectiveness, good safety profile, and quick 
patient recovery. In order to improve the comfort of filler injections, a local anaesthetic (lidocaine 
hydrochloride) has been included in their formulation to reduce procedural pain and to bypass the 
need for additional anaesthesia7. 
2 Identification and description of the investigational device 
Please refer to the Princess® FILLER Lidocaine Investigator’s brochure (IB)8 for detailed information on 
the investigational device. 
2.1 
Device description 
Princess® FILLER Lidocaine is a sterile, biodegradable, viscoelastic, clear, transparent, isotonic and 
homogenized injectable gel implant. The implant consists of hyaluronic acid obtained from 
Streptococcus equi bacteria, which is cross-linked using 1,4-butanediol diglycidyl ether (BDDE) and 
formulated to a concentration of 23 mg/mL in a physiologic buffer (phosphate buffer pH 6.8-7.4, 
sodium chloride) with supplementation of 0.3% w/w lidocaine hydrochloride. 
The device packaging contains one prefilled syringe with 1.0 mL of the injectable gel implant, two 27G 
½″ disposable sterile needles and a product leaflet. A set of two labels showing the batch number is 
situated at the bottom of the box. 
Princess® FILLER Lidocaine is a class III medical device, which also contains an active pharmaceutical 
ingredient, a well-known local anaesthetic lidocaine hydrochloride, as an ancillary substance. It is an 
absorbable soft tissue filler for injection into mid to deep dermis, and remains in long term contact with 
human skin and connective tissues. Hyaluronic acid is a natural component of human skin, hence 
Princess® FILLER Lidocaine is naturally absorbed, with the lifetime of the device anticipated to last up 
to 6-8 months after treatment. The ancillary component, lidocaine hydrochloride, is rapidly released 
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from the device after injection, and due to short half-life of around 90 minutes is quickly eliminated 
from the body. 
The device is manufactured in compliance with EN ISO 13485:2003/AC:2009. No materials of human 
or animal origin are used during manufacture or as raw materials. 
Princess® FILLER Lidocaine is designed for single use and upon opening should not be re-sterilized or 
reused. 
2.2 
Manufacturer 
Princess® FILLER Lidocaine is manufactured by CROMA-PHARMA GmbH, Industriezeile 6, 2100 
Leobendorf, Austria. 
Enclosed needles are manufactured by 
 
. 
2.3 
Intended use and mode of administration 
Princess® FILLER Lidocaine is a soft tissue filler, approved for use in adults (18 years and older) for 
the correction of moderate to severe facial wrinkles and folds and to increase lip volume, and for 
medical reconstructive purposes in the treatment of, e.g., facial lipoatrophy, debilitating scars, or 
morphological asymmetry of the face. 
The device is designed to be injected into the mid to deep dermis. The amount injected depends on 
the size of the area to be corrected and the desired level of soft tissue augmentation, but should not 
exceed 10 mL per treatment session or 20 mL per year. 
In the present clinical investigation, Princess® FILLER Lidocaine will be used for correction of 
moderate to severe nasolabial folds. 
2.4 
Traceability 
Each carton of Princess® FILLER Lidocaine is identified and tracked by its batch number. A set of two 
labels showing the batch number is situated at the bottom of each box. One of these labels should be 
attached to the subject’s file and the other should be given to the subject to ensure traceability of the 
device. 
3 Justification for the design of the clinical investigation 
3.1 
Non-clinical data and biocompatibility 
Hyaluronic acid is a naturally occurring glycosaminoglycan that consists of repeating non-sulfated 
disaccharide units of glucuronic acid and N-acetylglucosamine. It is an essential component of the 
animal and human extracellular matrix, present in all tissues, most abundantly in the skin. Hyaluronic 
acid has a considerable water-binding capacity, and by this mechanism it increases dermal volume 
and compressibility9. Furthermore, it stimulates collagen synthesis and up-regulation of elastin, 
possibly by mechanical stretching of the skin, which in turn leads to stretching and activation of dermal 
fibroblasts10. Hyaluronic acid is degraded by enzymatic depolymerization via hyaluronidases and 
oxidation by free radicals. Native chains have a short half-life of 24-48 h, which may be significantly 
extended by cross-linking of the chains. The most commonly used cross-linking agent is BDDE. The 
cross-linked hyaluronic acid is degraded via the same mechanisms as native chains, but at a much 
slower rate, extending the clinical effect of BDDE-cross-linked hyaluronic acid for up to one year11. 
Lidocaine hydrochloride, an ancillary component of the device, is a well-known local anaesthetic. 
Lidocaine exerts its anaesthetic effects by blocking fast voltage-gated sodium channels in the cell 
membrane of postsynaptic neurons, which prevents depolarization and inhibits the generation and 
propagation of nerve impulses12. Rapid release of lidocaine from hyaluronic acid gel, allowing for fast 
onset of action after injection, has been demonstrated in vitro.8  
The device is manufactured in compliance with ISO 9001, ISO 13485 and Good Manufacturing 
Practice. The chemical, physical and biological properties of Princess® FILLER Lidocaine were 
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extensively characterized during development. Compliance with ISO 14630 "Non-active surgical 
implants - general requirements" was demonstrated. Princess® FILLER Lidocaine was classified as an 
implantable medical device in permanent contact with tissues or bones according to ISO 10993-1. 
Hence, cytotoxicity, acute and subchronic systemic toxicity, local effects after implantation, 
sensitization, intracutaneous reactivity and genotoxicity of Princess® FILLER Lidocaine were evaluated 
in vitro and in vivo in biocompatibility studies conducted under GLP regulations. 
Animal experiments with guinea pigs, rabbits, and mice conducted over a period of up to nine months 
showed that cross-linked HA is non-inflammatory, non-toxic, non-immunizing, non-mutagenic and non-
genotoxic, and therefore biocompatible. An irritation test has additionally been conducted and showed 
that Princess® FILLER Lidocaine is well tolerated when administered intradermally and is considered 
as non-irritant to the tissue as compared to the negative control material. 8 
3.2 
Clinical data 
Since the launch of the first BODE-cross-linked hyaluronic acid dermal filler for aesthetic use in 1996, 
over 50 clinical studies have been conducted with this type of medical device, which included more 
than 9,000 subjects 11 . Hyaluronic acid gels are currently considered as the gold standard for dermal 
fillers and are widely used in aesthetic dermatolog{o for facial rejuvenation and re-contouring, with a 
remarkable track record of performance and safety 0. Over time, their use was extended to medical 
reconstructive purposes in the treatment of pathologic conditions like facial lipoatrophy, morphologic 
asymmetry of the face, and depressed scars. In order to improve the comfort of filler injections, novel 
formulations containing a local anaesthetic, lidocaine hydrochloride, have been developed to reduce 
procedural pain and to bypass the need for additional anaesthesia. 
Lidocaine hydrochloride is a well-known local anaesthetic, which has been in clinical use for over 60 
years. It is currently one of the most widely used local anaesthetics. When used for infiltrative 
anaesthesia, lidocaine hydrochloride has fast onset of action and moderate duration of effect lasting 
1.5-2 h 13. Absorbed lidocaine is metabolized in the liver and eliminated via the kidneys with a half-life 
of around 90 minutes 14. Lidocaine is generally well tolerated and safe. Adverse reactions are rare and 
usually result from high plasma concentrations due to accidental intravascular injection, excessive 
dosage (>400 mg), or rapid absorption from highly vascular areas. Early symptoms of toxicity include a 
metallic taste, tinnitus, light-headedness and confusion, and may be followed by tremors, shivering, 
seizures and, ultimately, respiratory arrest. Cardiovascular toxicity may be manifested by hypotension, 
bradycardia, arrhythmia and cardiac arrest13•14 . 
The performance and safety of hyaluronic acid dermal fillers supplemented with lidocaine 
hydrochloride have been studied in several randomized clinical trials, which were mostly designed as 
split face trials, where the same dermal filler was administered with and without ancillary lidocaine. A 
detailed analysis of nine randomized clinical trials with the equivalent devices 
and 
r
·1as confirmed a statistically significant reduction in pain with formulations which 
contained lidocaine. The pain reduction was consistent across the studies, and present irrespective of 
the dermal filler tested. The frequency and severity of adverse events ~AEs) was not different for 
dermal fillers with or without lidocaine, indicating no incremental safety risk •8. 
Princess® FILLER Lidocaine obtained the CE mark in 2016, Princess® FILLER (without lidocaine) 
obtained the CE mark in 2008. Post-market surveillance data for Princess® FILLER (without lidocaine) 
from 2008 to 2015 confirm the safety and effectiveness of the device, with secondary adverse events 
reported in 24 subjects among 1,557,6291 units of Princess® FILLER sold, the majority of which were 
expected adverse events (swelling, oedema) which are commonly reported after use with dermal 
fillers. Furthermore, no "unknown" (i.e. not already recorded in published literature) and no serious 
device-related events were recorded. 
Moreover, two investigator-initiated clinical investigations have been performed evaluating the safety 
and effectiveness of Princess® FILLER for the treatment of nasolabial folds (NLFs). The studies 
confirmed a significant decrease (p<0.05 Wilcoxon signed rank test) in wrinkle severity after treatment 
1 Source PMS Report 2015. 
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with Princess® FILLER, which lasted up to one year after treatment. The treatment was safe and well 
tolerated, with minor AEs related to treatment (erythema/edema at the injection site, ecchymosis, 
hematoma and local pain), all of which were mild to moderate in intensity, of short to medium duration 
and had completely resolved by the end of the clinical investigation. Hence, the studies demonstrated 
the safety and effectiveness of Princess® FILLER in the treatment of nasolabial folds 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 nasolabial folds (NLFs). 
3.3 
Justification for the clinical investigation 
Princess® FILLER Lidocaine has recently been approved for use in adults (18 years and older) for the 
correction of moderate to severe facial wrinkles and folds and to increase lip volume, and for medical 
reconstructive purposes in the treatment of, e.g., facial lipoatrophy, debilitating scars, or morphological 
asymmetry of the face.  
The current clinical investigation is designed to support the approval by obtaining clinical data on the 
performance and safety of Princess® FILLER Lidocaine for the correction of nasolabial folds. 
A prospective, open label, non-comparative design was selected because it allows for the most 
efficient collection of clinical data on the investigational device, in a manner which is appropriate to 
address the purpose and objectives of the present investigation. In the absence of spontaneous 
improvement of nasolabial folds, it is reasonable to assume that the treatment effect can be 
adequately assessed by comparing the post-treatment observations versus baseline, eliminating the 
need for a control group. 
The primary performance endpoints is based on evaluation using a validated 5-point scale for 
assessment of severity of nasolabial folds, the Nasolabial Folds Severity Rating Scale (NLF-SRS), and 
is set at 6 months after administration of the device to address the minimum required durability of 
effect. Follow-up is, however, extended to eight months, to get additional information on long-term 
effects. Information on occurrence of pain will be primarily obtained by collection of AEs, with 
additional insight into pain intensity being obtained directly after the injection using a validated 11-point 
Numeric Pain Rating Scale (NRPS)15.  
Up to 60 subjects will be included in this investigation to obtain 6-month effectiveness data in at least 
40 subjects. This sample size is arbitrarily selected, based on usual size of post-market clinical 
investigations, and is considered sufficient to provide robust estimations on performance and safety 
parameters in the study population. 
4 Risks and benefits of the investigational device and clinical investigation 
4.1 
Anticipated clinical benefits 
The treatment with Princess® FILLER Lidocaine may remove or reduce a distressing aesthetic defect 
in subjects with moderate-to-severe nasolabial folds, thereby improving their psychological and social 
wellbeing. This is achieved by a minimally invasive procedure with a short downtime, which results in 
an immediate and long-lasting effect, persisting for 6-8 months. 
4.2 
Anticipated adverse device effects 
The safety profile of BDDE-cross-linked hyaluronic acid dermal fillers, with or without lidocaine, is well 
established. In general, these devices are well tolerated and safe, with a low frequency of side 
effects16. Adverse effects that have been observed with devices similar to Princess® FILLER Lidocaine 
are summarized in Table 2, on the following page. 
Princess® FILLER Lidocaine received the CE mark in 2016, Princess® FILLER, the essentially identical 
device but without lidocaine, received the CE mark in 2008 (and is also traded under other brand 
names). Since its first market entry in 2008 up to the end of 2015, more than 1,557,6292 units of 
                                                     
2  Source PMS report for 2015 
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Princess® FILLER (without lidocaine) have been sold (in the European Union and 29 additional 
countries including Taiwan, Russia, Israel, Indonesia, India, Brazil, Australia and Argentina), with 164 
complaints (complaint ratio 0.011 %) registered over this period. This data confirm the favourable 
benefit/risk ratio outlined in the Clinical Evaluation Report and demonstrated in the clinical 
investigations. The majority of the complaints related to technical failure of the luer lock and syringe, 
with only 24 complaints related to secondary reactions. Among these, twelve were cases of edema, 
redness, itching, swelling or pain, which are adverse events commonly reported after treatment with 
dermal fillers (DeLorenzi, 2013, Funt and Pavicic, 2013). The remaining twelve complaints comprised 
single cases of inflammation, burning, nodules (lumps), necrosis, hyperpigmentation and one report of 
an allergic reaction, (adverse events which are listed in the instructions for use) and which resolved 
shortly thereafter. 
Princess® FILLER Lidocaine differs only by the inclusion of lidocaine and a slightly altered buffer 
formulation; hence the same favourable safety profile and risk/benefit ratio can be expected. 
Table 2. Adverse effects of cross-linked hyaluronic acid dermal fillers (with or without lidocaine) 
Common 
• Redness, erythema 
• Swelling, oedema 
• Pain, itching, burning, discomfort 
• Tenderness 
• Bleeding 
• Bruising, hematoma 
Rare 
• Hypersensitivity, angioedema 
• Infection, abscess 
• Herpes reactivation 
• Irritation, inflammation, granuloma 
• Malar oedema 
• Implant visibility, nodules, beading, 
lumpiness, implant-site mass 
• Firmness, induration 
• Discoloration, dispigmentation, 
puncture marks 
• Paresthesia, numbness 
• Implant migration 
• Scar sarcoidosis 
• Scleromyxedema 
• T eleangiectasia (generalized) 
• Vasculitis cutaneous 
• Vasospasm 
• Vasovagal reaction during injection 
Very rare 
• Vascular compromise or arterial 
occlusion (typically presented as 
immediate skin blanching, followed 
by a Livedoid pattern, discoloration 
or necrosis) 
• Retinal artery occlusion, vision loss 
• Necrosis 
Common AEs like swelling, redness, tenderness, pain and bruising are typically mild in severity and 
usually resolve within 1-2 days after injection; resolution of bruising may take a little bit longer. 
Discomfort and pain may be reduced or prevented by application of ice before the injection or local 
anaesthesia. Redness, swelling and bruising may be prevented or alleviated by application of ice-
packs for 5-10 minutes after the injection. 
Additional information on AEs, especially serious events like arterial occlusion and necrosis is provided 
in the IB. 
In case impending tissue necrosis, which may occur with any dermal filler, a recent consensus 
statement on the treatment of hyaluronic acid filler-induced impending necrosis recommends 
immediate treatment with high doses of hyaluronidase (e.g., at least 200 units of 
p or 
equivalent), followed by warm compress, vigorous massage and topical nitroglycerin paste. If no 
improvement is seen within 60 minutes, additional quantities of hyaluronidase should be injected (3-4 
cycles in total). An oral aspirin regimen (e.g., 650 mg per day) should help prevent further clot 
formation. Daily follow-up is advised. If no improvement or progression of necrosis is observed, the 
above regimen of hyaluronidase, nitroglycerin paste and aspirin should be repeated daily, typically for 
2-3 days 17. 
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4.3 
Possible interactions with concomitant medical treatments 
No studies on drug interactions with Princess® FILLER Lidocaine have been conducted in humans. 
Anticoagulant and antiplatelet drugs may increase the risk of bleeding or bruising, so the subject 
should be asked about use of such medications, and the prescribing physician should be consulted to 
appropriately assess the risk level. 
Sodium hyaluronate is incompatible with quaternary ammonium compounds such as benzalkonium 
chloride solutions. The device should never be placed in contact with these substances or with 
medical-surgical instruments that have been in contact with these substances. 
4.4 
Risk mitigation strategy 
The risks will be mitigated by careful selection of the subjects and exclusion of those who may have an 
increased risk of developing certain types of AEs (see Section 6.3.5), proper injection technique 
(described in Section 6.2.2), appropriate training of the investigators to ensure correct application of 
the device, and regular follow-up visits over the following nine months, which will allow for timely 
recognition and management of potential AEs. Furthermore, the subjects will be instructed to 
immediately contact the investigator in case of occurrence of any AE between the scheduled visits. 
4.5 
Risk-to-benefit rationale 
Hyaluronic acid-based dermal fillers, such as Princess® FILLER Lidocaine, are generally considered 
very safe and effective, and have been widely used for soft tissue augmentation worldwide. There is 
also no scientific evidence demonstrating adverse events of fillers or hyaluronidase in pregnant 
women. Observed adverse effects are mainly related to the injection procedure, are transient and 
mostly mild. While few serious adverse effects have been reported, these are very rare and not 
expected to occur when the device is correctly applied. This is supported by a remarkable safety track 
record of Princess® FILLER (without lidocaine), with few ADEs reported among with more than 1.5 
million units sold since 2009, combined with favorable safety data from one clinical trial.  
The performance and safety of lidocaine-containing hyaluronic acid dermal fillers for correction of 
nasolabial folds have been well documented in medical literature, and Princess® FILLER Lidocaine 
has been approved for use in this indication. Considering the potential benefits of correction, in 
particular the immediate and long lasting improvement of distressing aesthetic defect, and the low risk 
of the treatment when used appropriately by an experienced user, the benefits clearly outweigh the 
potential risks. 
5 Objectives and hypotheses of the clinical investigation 
5.1 
Objectives 
The objectives of this post-market clinical follow-up investigation are: 
 
To evaluate the performance of Princess® FILLER Lidocaine for the correction of moderate to 
severe nasolabial folds. 
 
To evaluate the safety of Princess® FILLER Lidocaine when used for correction of moderate to 
severe nasolabial folds. 
5.2 
Hypotheses 
This is a non-comparative study and does not entail formal hypothesis testing. 
5.3 
Claims and intended performance of the investigational that are to be verified 
Princess® FILLER Lidocaine has recently been approved for the correction of moderate to severe 
facial wrinkles and folds and to increase lip volume. The approval was based on clinical experience 
with similar devices and the present investigation is undertaken to support these claims. 
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5.4 
Risks and anticipated adverse device effects that are to be assessed 
The safety profile of lidocaine-containing hyaluronic acid dermal fillers is well established. Based on 
the equivalence of Princess® FILLER Lidocaine with these products and available non-clinical safety 
data, it is anticipated that it will share the same safety profile, described in Section 4.2. All AEs and 
device deficiencies occurring during the investigation will be collected and reported. 
6 Design of the clinical investigation 
6.1 
Design description 
The present investigation is designed as a prospective, open label, multicenter, post-market study. As 
justified in Section 3.3, this type of design is considered appropriate in view of the purpose and 
objectives of the study. 
The investigation will consist of five visits: the Baseline (Day 0) visit, which will entail informed consent, 
screening assessments, the treatment, and early post-treatment assessments, and follow-up visits 2, 
4, 24 and 36 weeks after the initial treatment. Procedures to be performed at each visit are specified in 
Table 1. Schedule of procedures and events, which is located on page 8 and in section 6.1.4. 
6.1.1 
Primary performance endpoints 
The performance of the investigational device will be evaluated using the following primary endpoints 
(justification is provided in Section 3.3): 
 The average change versus Baseline (Day 0) in the NLF-SRS grade at Week 24 after initial 
treatment as evaluated by the investigator 
 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point versus Baseline at Week 
24 after initial treatment 
6.1.2 
Secondary performance endpoints 
    The average change versus Baseline in the NLF-SRS grade at Week 4 and Week 36 after initial 
treatment as evaluated by the investigator 
 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point versus Baseline at Week 
4 and Week 36 after initial treatment 
 
The proportion of subjects with aesthetic improvement at Week 4, Week 24 and Week 36 after 
initial treatment, as evaluated by the investigator using the Global Aesthetic Improvement Scale 
(GAIS) 
 
Subjects’ satisfaction with aesthetic outcome of the treatment at Week 4, Week 24 and Week 36 
after initial treatment, as evaluated by the subject 
 
The average pain intensity during and after the treatment, as evaluated by the subject using an 
11-point Numeric Pain Rating Scale (NPRS) immediately after the last injection and 15 min. 
thereafter, respectively 
 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point versus Baseline at Week 
24 after initial treatment as evaluated by the independent photographic reviewer  
6.1.3 
Safety endpoints 
The safety of the investigational device will be evaluated using the following endpoint: 
 
Occurrence and frequency of adverse events 
6.1.4 
Schedule of procedures and events 
6.1.4.1 
Baseline Visit (Visit 1) 
After written informed consent is obtained, the following assessments will be performed during 
Baseline Visit at Day 0: 
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 
Demographic data collection 
 
Medical history (including information on prior facial aesthetic or surgical procedures) 
 
Prior medication 
 
Urine pregnancy test (in women of child-bearing potential) 
 
Photography 
 
Evaluation of inclusion and exclusion criteria 
 
NLF-SRS grading of nasolabial folds 
 
Treatment 
 
Pain assessment 
 
Adverse events 
 
Concomitant medication  
 
6.1.4.2 
Week 2 Visit (Visit 2) 
The following assessments will be performed 2 weeks (± 2 days) after Visit 1: 
 
Photography (optional) 
 
Touch-up treatment (optional) 
 
Pain assessment (only if Touch-up treatment performed) 
 
Adverse events 
 
Concomitant medication  
 
6.1.4.3 
Week 4 (Visit 3), Week 24 (Visit 4) and Week 36 (Visit 5) Visits 
The following assessments will be performed respectively 4 weeks (± 4 days), 24 weeks (± 7 days) 
and 36 weeks (± 7 days) after Visit 1: 
 
Photography 
 
NLF-SRS grading of nasolabial folds 
 
GAIS assessment 
 
Subject satisfaction 
 
Adverse events 
 
Concomitant medication  
6.1.5 
Replacement of subjects 
Subjects withdrawn from the investigation or lost for follow-up will not be replaced. 
6.2 
Investigational device 
6.2.1 
Packaging, labelling and storage 
The investigational device will be obtained from the commercial manufacturing batch.  
Each device will be provided in a folding box containing one syringe prefilled with 1.0 mL of the 
injectable gel implant, two 27G ½″ disposable sterile needles and a product leaflet (IFU). A set of two 
labels showing the batch number is situated at the bottom of the box. One of these labels should be 
attached to the subject’s file and the other must be given to the subject to ensure traceability of the 
device. 
An additional label, indicating that the device is exclusively for use in a clinical investigation, will be 
placed on the outer commercial package of each investigational device, if required by national 
regulations. 
The investigational device must be stored in the original box, at 2-25°C in a dry place, protected from 
light, heat and frost. The investigator must ensure that upon receipt of the investigational device and 
other study supplies, these are kept in an appropriate and secure location, with access limited to 
authorized individuals. 
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6.2.2 
Methods of use 
The investigational device will be administered to eligible subjects on study Day 0. 
Preparation for administration 
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. Sensitive skin may be 
pre-treated with a local anesthetic patch or cream. If anesthetic is used, the type of anesthetic and 
exact time of application will be recorded on the case report form (CRF). 
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. These steps are illustrated in the Instructions for Use. 
Injection technique 
The investigational device should be injected into 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. 
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.  
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 wrinkle or skin depression and 
injecting while slowly withdrawing the needle. 
Fan technique: introduction of the entire needle along the wrinkle 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. 
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 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 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 remainder of the investigational device from the same syringe after application to one fold can be 
used for the application to the other fold of the same subject at the same visit but not for any other 
subject or any other visit of the same subject. 
In case of a vascular event, injection must be stopped immediately, and high dose hyaluronidase, 
massage and heat (gauze with hot water) should be applied. In addition, nitroglycerin paste may 
encourage vasodilatation. More details are provided in Section 4.2. 
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Completion of 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. 
The subject should be requested to stay in the office for several minutes after the injection, to detect 
possible blanching caused by arterial occlusions. 
Prior to discharge the subject should be advised to follow restrictions specified in Section 6.3.7: 
• 
To refrain from application of make-up for twelve hours after injection; 
• 
To avoid prolonged exposure to sunlight or ultraviolet (UV) radiation for 36 hours after injection; 
• 
Not to massage the treatment site for one week following the injection, to avoid the possible risk of 
product mobility; 
• 
To abstain from use of saunas or Turkish baths for one week after the injection. 
6.2.3 
Applied volume of the device 
The amount of the device injected will depend on the defect to be corrected and will be selected by the 
investigator. The actual volume injected will be estimated by the investigator and recorded in the CRF, 
together with information on injection technique, area of application, date, and exact start time and end 
time of injection. 
The maximum recommended dosage is up to 10 ml per treatment session and up to 20 ml per 
subject per year; these amounts include potential Touch-up treatments. 
6.2.4 
Touch-up treatment 
A Touch-up treatment may be performed at the Week 2 visit at the investigator's discretion, if 
correction is not deemed satisfactory after the first injection. It will be documented in the CRF with the 
same level of details as the initial treatment. 
6.2.5 
Precautions 
• 
The device must not be used if the expiry date has lapsed, or if the packaging or contents are 
damaged. 
• 
The device should only be used with the needle and syringe provided by the manufacturer. 
• 
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. 
• 
The device should not be injected into blood vessels, bones, tendons, ligaments, nerves, muscles 
or naevi. 
• 
Injections into the periorbital area (crow's feet, eye circle, eye lids), glabellar region and nasal alae 
are not recommended. 
• 
Overcorrection should be avoided. 
• 
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. 
6.2.6 
Rescue medication 
In case of overcorrection or occurrence of nodules or vascular compromise, a commercially available 
hyaluronidase injection 
or similar) may be used at the discretion of 
the investigator. 
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6.2.7 
Investigational device accountability 
The investigational device must not be used outside the context of this clinical investigation plan (CIP).  
Documentation of receipt, dispensing/use in individual subjects, and return of investigational device 
must be maintained by the investigator or his/her designee. Appropriate forms will be provided by the 
Sponsor or their representative to facilitate investigational device accountability.  
At the end of the clinical investigation, all remaining supplies, including empty boxes of investigational 
devices that have been used, must be returned to the Sponsor for accurate accounting of the 
investigational device. Empty or used syringes will not be returned to the Sponsor, but will be 
destroyed by the investigation site, in line with their routine procedure for medical waste disposal. 
Considering the number of subjects to be enrolled, the average volume of the device administered in 
the clinical investigation of Princess® FILLER Lidocaine (up to 2 mL per fold), and potential additional 
Touch-up treatment, it is anticipated that up to 360 units of the investigational device may be used 
during this clinical investigation. 
6.3 
Subjects 
6.3.1 
Number of subjects and duration of the clinical investigation 
Up to 60 subjects with moderate to severe nasolabial folds will be enrolled and treated with the 
investigational device in order to obtain the Week 24 performance data in at least 40 subjects. 
Each subject will participate in the study for nine months. Taking into account the anticipated 
recruitment period of 3-4 months, the total expected duration of the clinical investigation will be 13 
months. 
6.3.2 
Recruitment strategy 
The recruitment over the study will be competitive and will be stopped as soon as 60 subjects are 
enrolled in the study. The study subjects will be recruited by the investigator, among subjects who 
attend the investigation site seeking the corrective treatment for nasolabial folds. The investigator may 
also offer participation in the study to potential candidates identified in their subject database. In case 
of an unexpectedly low recruitment rate, the investigation may be advertised. In such case, the 
advertising strategy and materials will be submitted to the Ethics Committee (EC) for prior review and 
approval. 
6.3.3 
Subject identification 
The study participants will be assigned a unique 5-digit number, with the first two digits identifying the 
site and the last three digits identifying the subject, e.g. 01-001. At each site the investigator will assign 
numbers to subjects in ascending order e.g. 001, 002, 003 etc. See also Section 6.3.10 for subject’s 
confidentiality. 
6.3.4 
Inclusion criteria 
A subject must meet all of the following criteria to qualify for participation in this investigation 
1. Male or female 18 years of age or older 
2. Presence of two fully visible, approximately symmetrical nasolabial folds, with each of the folds 
scored 2-3 according to the 5-grade NLF-SRS as assessed by the investigator 
3. Healthy skin in the facial area and free of diseases that could interfere in cutaneous aging 
evaluation 
4. Willingness to abstain from any aesthetic or surgical procedures in the treatment area for the 
duration of the clinical investigation 
5. Written signed and dated informed consent 
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6.3.5 
Exclusion criteria 
Subjects meeting any of the following criteria should not be enrolled: 
1. Pregnancy, lactation, planned pregnancy or unwillingness to use contraception at any time during 
the study (for women of child-bearing potential only) 
2. History of mental disorders or emotional instability 
3. History of allergic reaction or hypersensitivity to hyaluronic acid, lidocaine, or any amide-based 
anaesthetic  
4. Presence of silicone implant or another non-absorbable substance (permanent fillers) in the 
nasolabial region 
5. Facial surgery or implantation of dermal fillers, absorbable and non-absorbable sutures, laser 
therapy, dermoabrasion, or botulinum toxin application in the nasolabial region within previous 
twelvemonths, or chemical peeling within previous three months, or planning to undergo such 
procedures in the treatment area during the study 
6. Presence of infectious, inflammatory, or proliferative lesions in the nasolabial region 
7. Cutaneous lesions in the treatment area 
8. Known human immune deficiency virus-positive individuals 
9. History of allergies against aesthetic filling products and recurrent herpes simplex 
10. Tendency to hypertrophic scars, keloid formation and/or pigmentation disorders 
11. History or presence of any autoimmune or connective tissue disease, or current treatment with 
immune therapy 
12. Diabetes mellitus or uncontrolled systemic diseases 
13. Use of anticoagulant, antiplatelet or thrombolytic medication from ten days pre- to three days post 
injection 
14. Any medical condition which, in the investigator’s opinion, prohibits the inclusion in the study 
15. Current or previous (within 30 days of enrolment) treatment with another investigational drug 
and/or medical device or participation in another clinical study 
16. Previous enrolment in this clinical investigation 
17. Subjects whose participation in clinical trials is prohibited by the Austrian Medical Devices Act 
(e.g., persons with a legal custodian appointed due to mental disability, prisoners, soldiers and 
other members of the armed forces, civil servants) 
6.3.6 
Withdrawal criteria and procedures 
The subject may be withdrawn from the investigation for any of the following reasons: 
1. Occurrence of an AE which requires a premature termination of the treatment or precludes follow-
up of the subject 
2. A major CIP deviation, which may interfere with evaluation of the treatment outcome (e.g., 
additional aesthetic correction of the defect during the course of the study, use of prohibited 
medication, or similar) 
3. Investigator’s decision, triggered by safety, behavioural or administrative reasons 
4. Informed consent withdrawal 
A subject is free to withdraw the consent and leave the investigation at any time with no obligation to 
specify the reason for withdrawal. Efforts should be made, however, to get in touch with subjects who 
did not attend the scheduled visit and clarify the reason for default. 
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Reasons, circumstances and findings related to early withdrawal should be fully described on the CRF 
respecting the subject’s rights. Attempts should be made to perform an early termination visit, which 
should consist of the assessments planned for the Week 24 visit. In the event that the withdrawal is 
caused by an AE, the procedures stated in Section 14.6 must be followed.5 
6.3.7 
Life-style and other restrictions 
Contraception 
The safety of Princess® FILLER Lidocaine for use during pregnancy has not been established, so 
females of childbearing potential should use contraception or avoid unprotected sexual intercourse 
throughout the clinical investigation. Any pregnancy occurring during the subject’s participation in the 
investigation will be reported as an AE and followed-up as described in Section 14.6. 
Other restrictions 
The following restrictions apply to all subjects: 
 
Make-up should not be applied for 12 hours after injection; 
 
Prolonged exposure to sunlight or UV radiation must be avoided for 36 hours after injection; day 
care with UV protection should be used daily throughout the entire clinical investigation; 
 
To minimise the risk of product mobility, the subject should be advised to avoid massaging the 
treatment site or applying pressure to this area for one week following the injection; 
 
Subjects should abstain from frequent solarium visits; 
 
Subjects should abstain from alcohol on injection days. 
 
Use of saunas or Turkish baths is prohibited for one week after the injection. 
 
6.3.8 
Medical care upon termination of the clinical investigation 
The study participants will not receive any study-specific treatment after the final visit. Any further 
treatment, if needed, will be proposed to the subject by the investigator at their discretion. 
6.3.9 
Screening/Baseline failures 
Data for screening/Baseline failures (eligible subjects who did not receive investigational device for 
whatever reason) will be collected in source documentation at the site and documented in the 
Screening log but will not be entered into the CRF. 
6.3.10 Subject confidentiality 
This CIP, other study 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. 
Personal subject data will be kept confidential in compliance with the European Data Protection 
Directive and other applicable international and national requirements.  
The investigator must ensure that anonymity of the study participants will be maintained and that their 
identities are protected from unauthorized parties. On the CRF or any other documents submitted to 
the Sponsor or Sponsor's representative, subjects must be identified only by their identification codes; 
use of names, initials, addresses, telephone numbers, electronic addresses or similar information is 
prohibited. The investigator will keep the original of the Subject Identification Log (including complete 
name and date of birth of each subject) in his/her file. The investigator must maintain these documents 
in strict confidence. 
To allow compliance with good clinical practice (GCP), all subjects will be asked for consent regarding 
the access to their personal clinical study-related data for monitoring, audits, and inspections as well 
as regarding transmission and storage of their anonymous data for the duration defined in the current 
GCP regulation; a respective statement will be part of the Informed consent form (ICF). Professionals 
with access to source data for monitoring, audits and inspections are bound to preserve strict 
confidentiality. 
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6.4 
Assessments and procedures 
Assessments and procedures that will be performed during the investigation are described below. The 
exact timing of each assessment is indicated in Table 1. Schedule of procedures and events and in 
section 6.1.4. 
It is the investigator’s obligation to assure documentation of all relevant data in the subject’s medical 
record, such as medical history and concomitant diseases, date of enrolment into the clinical 
investigation, visit dates, results of examinations, application of medical device, and AEs. 
6.4.1 
Demographic data 
The following demographic data will be collected: date of birth, gender and race. 
6.4.2 
Medical history 
Medical history will be collected at Day 0, from subject interview and medical records (if available), 
covering relevant past medical history with particular reference to facial aesthetic or surgical 
procedures.  
6.4.3 
Pregnancy test 
In females of childbearing potential, including women who are postmenopausal for less than twelve 
months, a urine pregnancy test will be performed using a dipstick test with sensitivity of ≤20 mLU of 
human chorionic gonadotropin per mL. The result will be recorded in the subject’s medical record and 
the CRF. 
6.4.4 
Photography 
Photographs of the subjects are taken as part of routine practice at the clinical site before the 
application of the medical device at the Baseline visit and after the intervention.  
6.4.5 
NLF-SRS grading of nasolabial folds 
NLF-SRS is a validated, 5-point rating scale ranging from Grade 0 (none) to Grade 4 (extreme) as 
outlined in  
Table 3 and Table 4. The severity of nasolabial folds will be evaluated by the investigator according to 
the NLF-SRS. The left and right nasolabial fold will be separately graded, and the assigned grades will 
be recorded in the subject’s record and the CRF. 
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Table 3. Nasolabial Folds Severity Rating Scale (NLF-SRS} 
Table 4 CROMA - NLF Severity Rating Scale (NLF-SRS) 
CROMANLF-
Description 
SRS grade 
0 
None/minimal No visible/minimal nasolabial folds 
1 
Mild Shallow but visible nasolabial fold with a slight indentation 
2 
Moderate: Moderately deep nasolabial fold 
3 
Severe Very deep nasolabial fold with prominent facial feature 
4 
Extreme Extremely deep and long nasolabial fold with skin redundancy 
6.4.6 
Aesthetic improvement/GA/$ assessment 
The aesthetic improvement after correction of nasolabial folds will be evaluated at Week 4, 24 and 36 
after initial treatment by the investigator using the Global Aesthetic Improvement Scale (GAIS) 18, 
presented in Table 5, and recorded in the CRF. 
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Table 5. Global Aesthetic Improvement Scale (GAIS) 
Category 
Description 
Very much improved 
Optimal aesthetic result for the implant in this patient. 
Much improved 
Marked improvement in appearance from the initial condition, but not completely optimal for this 
patient. A Touch-up would slightly improve the result.  
Improved 
Obvious improvement in appearance from the initial condition, but a Touch-up or retreatment is 
indicated. 
No change 
The appearance is essentially the same as the original condition. 
Worse 
The appearance is worse than the original condition. 
 
6.4.7 
Pain assessment 
After initial administration and optional Touch-up treatment of the investigational device, the subject 
will be asked by the investigator to quantify the pain associated with the procedure by means of a 
semi-quantitative 11-point Numeric Pain Rating Scale (NPRS), where 0 corresponds to no pain, and 
10 to the worst pain imaginable15. Pain intensity will be assessed twice, immediately after injection, 
and approximately 15 minutes thereafter, by asking the subject one of the following questions, as 
appropriate: 
 
“How would you rate the pain you have felt during the treatment, if “0” is no pain at all, and “10” is 
the worst pain you can imagine?” 
 
“How would you rate the pain you have felt during recovery from the treatment, if “0” is no pain at 
all, and “10” is the worst pain you can imagine?” 
Subject’s response will be recorded in the Pain assessment form and the CRF. To avoid over-
reporting of pain, a non-leading question „How do you feel?“ should be asked prior to pain 
assessment. Only spontaneously reported pain, or pain graded ≥4 will be recorded as an AE.  
6.4.8 
Subject’s satisfaction assessment 
Each subject will be asked to grade their satisfaction with the treatment using one of the following 
categories: “Very unsatisfied”, “Unsatisfied”, “Neither unsatisfied nor satisfied”, “Satisfied”, or “Very 
satisfied”. 
The statement selected by the subject will be recorded in the Subject’s satisfaction form and the CRF. 
6.4.9 
Outcome evaluation by the independent reviewer of photographs 
An independent reviewer will evaluate the treatment outcome using the NLF-SRS scale and based on 
the photographs. This independent photographic reviewerwill be dislocated from the investigation sites 
and will not discuss any findings with the investigators during the trial and until the final database lock.  
6.4.10 Safety monitoring 
The safety of the investigational device will be monitored throughout the investigation, from Day 0/Visit 
1 until the final visit (Visit 5). AEs will be collected at each visit. In addition, the subjects will be 
instructed to immediately contact the investigator by phone in case of occurrence of any untoward 
event between the visits. The procedure for collection, recording and reporting of AEs is described in 
Section 14. 
6.4.11 Prior and concomitant medication and non-drug therapies 
Prior medication is defined as all medication taken within ten days (whether continuing or not) prior to 
Day 0. Concomitant medication is defined as all medication taken from Day 0 (including medication 
taken immediately pre-injection and post-injection) until the Week 36 visit.  
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At each visit the subject must be asked about any new medication taken or changes in current 
medication, as well as, about any aesthetic procedure applied in the area treated with the 
investigational device. 
All prior and concomitant medication and non-drug therapies will be recorded in the subject’s medical 
record and the CRF. 
Prohibited medication and aesthetic treatments 
 
Immune therapy, i.e., treatment with biologics designed to boost the body's natural defences (from 
Day 0 until the end of the clinical investigation) 
 
Anticoagulant, antiplatelet, or thrombolytic drugs (from ten days pre- until three days post-injection) 
 
Facial surgery or implantation of dermal fillers other than the investigational device (from twelve 
months prior to Day 0 until the end of the clinical investigation) 
 
Absorbable and non-absorbable sutures, laser therapy or dermabrasion (from twelve months prior 
to Day 0 until the end of the clinical investigation) 
 
Botulinum toxin treatment in the area treated with the investigational device (from twelve months 
prior to Day 0 until the end of the clinical investigation) 
 
Chemical peeling (from three months prior to Day 0 until the end of the clinical investigation) 
 
Skin needling or mesotherapy (from Day 0 until the end of the clinical investigation) 
6.4.12 Factors that may compromise the outcome 
There are no foreseeable factors that may significantly compromise the outcome. A substantial body 
weight change could possibly affect the results in individual subjects. Since this is a post-market 
investigation, designed to mimic a real-life situation, this random and relatively rare event that can 
either improve or deteriorate the outcome will not be controlled. It is possible that women will prevail in 
the study population, but this reflects common clinical practice. 
6.5 
Monitoring plan 
The conduct of this clinical investigation will be monitored by the Sponsor’s representative, who will 
appoint a Monitor of the investigation. The extent of monitoring and source data verification will be 
specified in the Monitoring plan. 
Prior to initiation of the clinical investigation at any of the investigation sites, the Monitor will discuss 
the CIP and the CRF with the investigator and their staff. The site must not enroll any study participant 
before this initiation visit. During the investigation, further monitoring visits will be performed according 
to ISO 14155:2011, the applicable standard operating procedures, and local regulations. The CRF will 
be reviewed against source data for adherence to the CIP, as well as for completeness, accuracy and 
consistency of data. Additionally, the Monitor will check the progress of enrolment, and will ensure that 
the investigational device is stored, dispensed and accounted for according to the respective 
specifications. Key study personnel must be available to assist the Monitor during these visits. The 
Monitor will inform the investigator or their authorized designee of any CRF entry error, omission, or 
illegibility. The Monitor should ensure that appropriate corrections, additions, or deletions are made, 
dated, explained (if necessary), and initialed by the investigator or their authorized designees. 
The investigator and their institution must permit the monitoring of the investigation, and provide the 
Monitor direct access to those portions of the subject’s primary medical records, which directly concern 
this clinical investigation.  
7 Statistical considerations 
Planned statistical analyses are briefly summarized below. Data analyses will be described in detail in 
the Statistical analysis plan (SAP). 
7.1 
Sample size 
Up to 60 subjects with moderate to severe nasolabial folds will be enrolled in order to obtain the 
24-week performance and safety data from at least 40 of them. If less than 60 subjects will be 
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recruited at the point when at least 40 subjects complete the Week 24 assessment, a decision to 
continue the recruitment up to 60 subjects in total will be made by the Sponsor.This sample size is 
arbitrarily selected and is considered appropriate for the post-market follow-up clinical investigation 
and sufficient to provide robust estimations on performance and safety parameters in the study 
population. With a sample size of 60, a two-sided 95% confidence interval for a single proportion using 
the large sample normal approximation will extend 0.076 from the observed proportion for an expected 
proportion of 0.900. Thus, a robust estimation of the success rate at week 24 can be derived..  
7.2 
Analysed data sets 
The primary data set for analysis will contain all data collected in the Intent-to-treat population, which is 
defined as all subjects who received the investigational device and have at least one post-treatment 
assessment. Certain sensitivity analyses may be also done in the Per-protocol population, which is 
defined as all subjects who received the investigational device and have completed the investigation 
without major CIP deviations. 
7.3 
Missing data 
Missing data will not be estimated and/or imputed in any way. 
7.4 
Methods of analysis 
In general, collected data will be listed and descriptive statistics will be performed, with all repeating 
measurements being tabulated by the visit. For continuous variables, descriptive statistics will include 
the number of observations, minimum, maximum, mean and standard deviation, or median and 
interquartile range, as appropriate based on data distribution. For discrete variables, summary 
statistics will include the total number of observations, frequency and percentages. 
Demographic data, use of additional anaesthetic, initial amount of the filler applied, and occurrence of 
the Touch-up treatment with the amount of the filler applied will be listed by subject and summarized 
using descriptive statistics. Other data collected will be listed per subject and summarized as 
described in the SAP. 
7.4.1 
Performance endpoints 
As two facial folds of each subject will be considered, there are two measurements per subject for 
NLF-SRS. No great differences between the folds are expected, thus the mean of both measurements 
will be used for analyses. Individual NLF-SRS grades per visit will be calculated as the mean of grades 
assigned to the left and the right nasolabial fold, respectively. The absolute NLF-SRS change versus 
baseline will be computed by subtracting the value obtained on Day 0 from that of the corresponding 
visit. Absolute NLF-SRS change from baseline will be summarized by the visit using descriptive 
statistics and additionally the 95% confidence intervals of the mean will be given. In addition, the 
proportion of the NLF-SRS change values ≥1, or ≥2, respectively, will be calculated. 
Individual GAIS grades, subjects’ satisfaction with aesthetic outcome, and pain ratings will be 
summarized and tabulated by visit using descriptive statistics. 
7.4.2 
Safety endpoints 
AEs will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) and listed by subject. 
Incidence of AEs will be summarised by preferred term (PT) and system organ class (SOC), and also 
by intensity, relationship to the investigational medical device or procedure, and seriousness.  
8 Data management 
8.1 
Case report forms 
A CRF will be completed for each subject enrolled in the investigation who received the investigational 
device.  
A web-based standardized electronic CRF (eCRF) will be used to document the subjects’ data during 
the course of the study. The eCRF is designed to accommodate the specific features of the study 
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design. All data obtained after the subject has given informed consent must be recorded in the eCRF. 
The investigator will assure that all data are entered promptly, completely, and accurately according to 
the eCRF instructions, and conform to source documents. Data for all subjects screened for study 
have to be documented on a respective form (see Section 6.3.9) but no eCRF entry for 
screening/baseline failures will be made.  
Only investigators and authorized designees are allowed to make entries in the eCRF. This will be 
regulated by appropriate reading and writing access. Completed eCRFs per visit, must be 
electronically signed by the investigator or authorized designee. Any change or addition will be 
recorded by an audit trail system.  
The investigator or designee has to carefully answer queries issued by Data Management in the 
eCRF. 
It is the investigators’ obligation to assure documentation of all relevant data in the subject’s file, such 
as medical history, concomitant diseases, date of study enrolment, visit dates, results of examinations, 
administrations of medication, and AEs.  
8.2 
Data management procedures 
All data management activities will be conducted by the Sponsor's representative following their 
Standard Operating Procedures. The database will be built by the Sponsor's representative, and they 
will handle the data cleaning process, including logical check, medical checks, and query processes. 
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 using 
DCFs and addressed to the investigator.  
Regarding self-evident corrections (such as spelling and header corrections) if applicable, 
investigator’s agreement will be obtained that these will be made by the Data Manager and 
documented in the audit trail. 
The database will be soft locked when it is considered complete and accurate (i.e. all CRF pages 
entered, all data cleaning activities performed). The database will be hard locked after all the changes 
following the data review meeting have been performed and the database is considered complete and 
accurate. All changes will be tracked (audit trail). Sponsor approval prior to database hard lock is 
mandatory. 
8.3 
Data retention 
The investigator shall retain all study records during the clinical investigation and for the period 
required by the applicable regulatory requirements, or for at least 15 years after the premature 
termination or completion of the clinical investigation, whichever is longer. However, the investigator 
should 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 or in case of changes in between in 
the duration of the clinical documents archiving according to GCP. In addition, the Sponsor should be 
contacted if the investigator plans to leave the site, so that arrangements can be made for transfer of 
records. 
The medical files of study participants 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. 
8.4 
Report of the clinical investigation 
Following completion of the clinical investigation, the results will be evaluated and the Clinical 
investigation report will be generated, including a summary of all available data, statistical measures, 
tabulated results, graphical results, and interpretations. A complete list of all adverse events will be 
enclosed. This report will be submitted to authorities as appropriate, within the timeframes defined per 
national regulation or by the EC. 
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9 Amendments to the clinical investigation plan 
Any change to the CIP concerning the purpose of the study, the study design or the subject’s eligibility 
can only be made in form of a written amendment to the CIP. Such amendments have to be discussed 
and signed by the Sponsor, and the other investigators before implementation. 
Amendments that might have an impact on study procedures to be performed and/or the well-being of 
the subjects require additional informed consent, which has to be given in writing by all subjects 
enrolled in the clinical investigation who are affected by the amendment. 
10 Deviations from the clinical investigation plan 
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 EC 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 EC 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 EC as soon as 
possible in accordance with national regulations. 
All CIP deviations will be listed and their impact on evaluability of respective subjects will be discussed 
in a data review meeting prior to the hard data base lock. 
11 Device accountability 
Investigational device accountability is described in Section 6.2.7. 
12 Statements of compliance 
This clinical investigation will be conducted in compliance with the clinical investigation plan (CIP) and 
the following standards and regulatory requirements:  
 
International Standard ISO 14155:2011: Clinical investigation of medical devices for human 
subjects - Good clinical practice; 
 
Declaration of Helsinki, in its currently adopted version; 
 
Applicable sections of the national medical device law. 
By acting in accordance with this CIP, the investigators and the study site personnel fulfil the 
requirements of the International Standard ISO 14155:2011. 
The clinical investigation will not commence until a favourable opinion from the respective EC has 
been received. All additional requirements imposed by the EC will be followed.  
A prior regulatory approval will also be sought, if required by national regulations. 
Insurance coverage for damages emerging from the clinical investigation will be provided according to 
applicable legal requirements. 
13 Informed consent process 
Written informed consent must be obtained from each subject prior to initiation of any of the 
investigation-specific procedures.  
The investigator or their authorized designee must give each subject complete and adequate verbal 
and written information about the investigation. The investigator must ensure that the subject is fully 
informed about the aims, procedures, potential risks, 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 any justification and without prejudice. The 
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subject must then sign and date the ICF prior to the conduct of any study procedures. The consent 
taker (investigator or study team member) 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 study participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this clinical investigation 
or in case of withdrawal of their consent during the 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 Sheet and the ICF must be updated to incorporate 
this modification, and the subject must sign the amended ICF indicating that they re-consent to 
participate in the clinical investigation. 
14 Adverse events, adverse device effects and device deficiencies 
14.1 Definitions 
Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or untoward 
clinical sign (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
 
For study subjects this definition includes events related to the procedures involved, as well 
pregnancy in females.  
 
For users or other persons this definition is restricted to events related to the investigational 
medical device.  
Adverse Device Effect (ADE): is an AE related to the use of the investigational medical device. 
 
This includes any AE resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device. In addition, this includes any event that is a result of a use error or 
intentional misuse. 
Serious Adverse Event (SAE) is an AE that led to any of the following conditions: 
 
Death;  
 
Serious deterioration in the health of the subject that either resulted in: 
o 
A life-threatening illness or injury, or 
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, or 
o 
Malignant tumour; 
 
Foetal distress, foetal death, a congenital abnormality or birth defect. 
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) is an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
Unanticipated Serious Adverse Device Effect (USADE) is defined as an SADE which by its nature, 
incidence, severity or outcome has not been identified in the current version of the investigator’s 
Brochure. 
Device deficiency is any inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use errors, and inadequate labelling. 
Device deficiency that might have led to an SAE if a) suitable action had not been taken, or b) 
intervention had not been made, or c) if circumstances had been less fortunate, is classified as a 
special type of deficiency and is handled under the SAE reporting system. 
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14.2 Method of detecting AEs 
AEs will be detected at each visit by clinical examination and by asking the subject about the 
occurrence of AEs. Care should be taken not to introduce bias when eliciting AE information from the 
subject. Open-ended and non-leading verbal questioning is the preferred method and appropriate 
questions include: 
 
“How are you feeling?” 
 
“Have you had any medical problems since your last visit/contact?” 
 
“Have you taken any new medication since your last visit/contact?” 
In addition, the subjects will be instructed to immediately contact the investigator/study site in case of 
occurrence of any untoward event between visits. 
14.3 AE/SAE documentation 
For each AE the following must be reported:  
 
description of the event (event term) 
 
start date 
 
start time (for events occurring on the treatment day) 
 
outcome 
 
end date (if applicable) 
 
severity 
 
action taken (none, medical and/or surgical) 
 
the relationship to the investigational device, the relationship to the procedure 
 
seriousness criteria.  
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the 
individual signs/symptoms. 
Each AE should be reported separately. The investigator will record all AEs on the ”AE” page of the 
CRF. For SAEs, the Serious Adverse Event Form must also be completed. Complete description of all 
AEs should be also available in the source documents.  
AEs occurring after provision of informed consent and prior to application of the investigational medical 
device will be recorded as part of the medical history. Any medical condition that is present at 
screening should also be considered as medical history and not recorded as an AE. However, if the 
condition deteriorates after administration of the investigational device, at any time during the course 
of the investigation, it should be recorded and reported as an AE. 
If the severity or seriousness of an AE changes over time, the most severe intensity or seriousness of 
the AE will be recorded and included in the analysis. No separate AEs will be recorded for each 
intensity level.  
Changes in the assessment of the relationship to the investigational medical device 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. 
14.4 AE/SAE assessment 
All AEs will be assessed in terms of: 
 
seriousness (yes, no) 
 
severity 
 
relationship to the investigational medical device or study procedures 
 
outcome. 
14.4.1 Severity assessment 
The severity of an AE/SAE will be graded as follows: 
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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 
14.4.2 Causality assessment 
The investigator is obligated to estimate the relationship between each AE/SAE and the investigational 
medicinal device or study procedure. Clinical judgement should be used and the relevant documents 
like IB consulted. The presence of confounding factors, such as concomitant medication/treatment, the 
natural history of the underlying disease, other concurrent illness or risk factors shall also be 
considered. The relationship should be determined using one of the following causality levels19: 
Definite: 
The AE/SAE is associated with the investigational device or with procedures beyond 
reasonable doubt when it is a known side effect of the product category the device 
belongs to, or of similar devices and procedures; has a temporal relationship with 
investigational device use/application or procedures; involves a body-site or organ that 
the investigational device or procedures are applied to or have an effect on; follows a 
known response pattern to the medical device (if the response pattern is previously 
known); 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; 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; and/or harm to the subject is due to error in use. 
Probable: The relationship with the use of the investigational device seems relevant and/or the 
event cannot be reasonably explained by another cause, but additional information may 
be obtained. 
Possible: 
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: 
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 the AE/SAE is not a 
known side effect of the product category the device belongs to or of similar devices and 
procedures; has no temporal relationship with the use of the investigational device or the 
procedures; does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 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; involves a body-site or an organ not expected to be affected by the device 
or procedure; 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); and/or 
harm to the subject are not clearly due to use error. 
14.4.3 Outcome assessment 
The outcome of an AE will be assessed as follows: 
Resolved: 
The subject has fully recovered from the event, or the condition has returned 
to the level observed at baseline. 
Ongoing: 
The event is ongoing at the time of reporting and the subject has still not 
recovered. 
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Resolved with sequelae: As a result of the AE, the subject suffered persistent and significant disability/ 
incapacity (e.g. became blind, deaf or paralyzed). 
Fatal: 
The subject died due to the event.  
Unknown: 
If outcome is not known or not reported. 
14.5 AE/SAE reporting requirements and contact details 
For any AE (including a SAE) all appropriate sections of the CRF must be completed. 
Any SAE must be reported by the investigator to the Medical Monitor within 24 hours of awareness of 
the event via eCRF. Only in case of any problem with the eCRF the SAE must to be reported via fax: 
 
 
 
 
  
 
 
 
This also applies to any significant AE, which in the investigator’s opinion could affect the safety of the 
study subjects or the conduct of the study. 
Information about an SAE will be collected and recorded on the SAE Report Form. The investigator 
will be requested to supply as much detailed information as possible regarding the SAE that is 
available at the time of the initial contact. The investigator should also complete missing or requested 
information and submit follow-up reports to the Medical Monitor until the SAE has resolved or, in the 
case of permanent impairment, until the SAE has stabilized. 
The Medical Monitor will inform the sponsor about all SAEs without undue delay after receipt of the 
respective report from the Investigator. 
Reporting to ECs and regulatory authorities will follow pertinent national legislation. 
At the end of the study, a reconciliation of all reported SAEs will take place and be enclosed as a list in 
the Clinical investigation report (see Section 8.4). 
14.6 AE/SAE follow-up 
The investigator will take all appropriate and necessary measures required for resolution of the AE. 
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. 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 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 investigational medical device (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.  
14.7 Foreseeable AEs and anticipated ADEs 
Foreseeable AEs and anticipated ADEs are listed in Section 4.2 Anticipated adverse device effects. 
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14.8 Device deficiency reporting requirements 
All investigational medical device deficiencies will be recorded on a Device Deficiency Report Form.  
Device deficiencies should be reported by the investigator to the Medical Monitor within 24 hours after 
the site became aware of the device deficiency. Contact information is provided in Section 14.5. 
The Medical Monitor will forward the deficiency report to the Sponsor within 24 hours after receipt of 
the respective report from the investigator.  
If a device deficiency is associated with an AE, the corresponding AE documentation procedures must 
be adhered to as well. 
14.8.1 Handling of deficient medical devices 
Any medical device alleged to be deficient must not be used by the investigator and must be returned 
to the Sponsor. 
14.9 Data monitoring committee 
Not applicable. 
15 Vulnerable populations 
Vulnerable populations will not be included in this clinical investigation. 
16 Suspension or premature termination of the clinical investigation 
The Sponsor reserves the right to terminate the clinical investigation for any reason (e.g. safety, new 
data on the risk/benefit, ethical or administrative reasons). Written notice, outlining the reasons for the 
termination, will be submitted to the investigators in advance of such termination. The Sponsor will 
provide instructions if assessments beyond the regular per protocol procedures should be necessary. 
The Sponsor may suspend enrolment or terminate the study at a specific site for reasons including, 
but not limited to, inadequate data collection, low subject enrolment rate, achievement of the total 
enrolment, or non-compliance with the CIP or other clinical research requirements. 
The investigator, EC, or regulatory authority (if applicable) 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 relevant authority (if applicable) of the termination and its reason(s); the 
investigator or the Sponsor (or representative) will promptly inform the EC, as specified in applicable 
regulations. 
17 Publication policy 
The results of the clinical investigation may be published and/or presented at scientific meetings. The 
results, however, 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 for at least 6 months after receipt of the manuscript or 
abstract. 
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