A Prospective, Randomized, Multicenter Study Evaluating Saypha® VOLUME Lidocaine* for the Correction of Nasolabial Fold
Phase: NA
Conditions: Moderate to Severe Nasolabial Folds
Sponsor: Croma-Pharma GmbH

CIP_CPH-101-201477 (V6.0, 18Mar2021) 
Page 1 of 47 
 
 
 
 
CLINICAL INVESTIGATION PLAN (CIP) 
Title of the clinical 
investigation/CIP: 
A prospective, randomized, multicenter study evaluating saypha® 
VOLUME Lidocaine* for the correction of nasolabial folds 
Short title: 
SAVINO (saypha® Volume LIdocaine in Nasolabial FOlds) 
Investigation ID: 
 CPH-101-201477 
CIP version: 
6.0 
CIP version date: 
18.03.2021 
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 
Coordinating 
investigator: 
 
 
Investigation site(s): 
At least 3 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) 
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. 
* Beside saypha® Volume Lidocaine the product is also registered in some countries under the name Princess® Volume 
Lidocaine

 
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Investigators and administrative structure of the clinical investigation  
 
Investigators: 
This is a multicenter clinical investigation, which will be conducted in the 
European Union. An updated list of investigation sites and corresponding 
principal investigators will be kept separately from the CIP. 
Sponsor: 
CROMA-PHARMA GmbH 
The Sponsor will be responsible for overall implementation and oversight of the 
clinical investigation.  
Sponsor’s address and other contact details are provided on the cover page.  
 
Medical Monitor  
 
 
 
 
 
 
Other institutions: 
 
 
This is a contract research organization, also referred as Sponsor’s 
representative in this CIP, which will be responsible for clinical project 
management, ethics and regulatory submissions, clinical investigation 
monitoring, investigational device vigilance and expedited safety reporting, data 
management, statistical analysis, and clinical investigation report writing. 
The address and other contact details of Sponsor’s representative are provided 
on the cover page. 
Contact for reportable events 
 
 
 
 
 
An updated list of individuals responsible for various aspects of the investigation 
at Sponsor’s representative will be kept separately from the CIP. 
An updated list of all key persons involved in the clinical investigation, including other institutions, if 
any, will be kept and maintained in the Trial Master File. 
 
 
 

 
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Approval and signature pages 
 
Clinical investigation plan agreed to by the Coordinating investigator 
 
 
 
 
 
 
 
 
 
 
 
 
__________________________________ 
 
 
__________________________ 
                                                           Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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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, randomized, multicenter study evaluating saypha® VOLUME 
Lidocaine for the correction of nasolabial folds 
Short title 
SAVINO (SAypha Volume LIdocaine in Nasolabial FOlds) 
Investigation ID 
CPH-101-201477 
Investigation sites 
At least 3 sites located in Austria 
Phase of 
development 
Investigation according to § 40 (2) MPG 
Aesthetic Indication 
Moderate to severe nasolabial folds 
Planned duration 
The duration of the clinical investigation will be a maximum of 24 months for 
each participating subject. The total expected duration of the clinical 
investigation is about 27 months with an expected recruitment period of about 
3 months. Recruitment halts due to COVID-19 pandemic lead to the 
prolongation of the recruitment period and the extension of the total duration 
of the clinical investigation. In case it is observed by the investigators that at a 
given visit no aesthetic effect is any more visible in approximately 75 % of the 
subjects, the study can be terminated at an earlier time point, but not before 
week 52.  
Objectives 
• To evaluate the performance of saypha® VOLUME Lidocaine for the 
correction of nasolabial folds using injection into the deep dermis or 
supraperiostal 
• To evaluate the safety and long term safety of saypha® VOLUME Lidocaine 
when used for correction of nasolabial folds 
• To evaluate the duration of the aesthetic effect 
Study design 
A prospective, randomized, multicenter investigation. 
Following informed consent and screening, eligible subjects with moderate to 
severe nasolabial folds will be injected with saypha® VOLUME Lidocaine into 
the deep dermis or supraperiostal, and will return for follow-up assessments at 
Week 2, 4, 24, 36, 52 and optional at Week 65, 78 and 104 after the treatment. 
A Touch-up treatment may be done at Week 2, 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) at Week 4, 24, 36, 52 after 
the treatment and optional at Week 65, 78 and 104 and in comparison to Day 
0. Telephone visits will be performed approximately 24 hours post-
administration to monitor possible adverse events. In case any adverse events 
are reported during the telephone visits an unscheduled visit should be 
performed.  
A ‘responder’ is defined having at least ≥ 1 grade improvement as evaluated 
with the 5 point-validated NLF-SRS at week 24 relative to Baseline (Day 0) 
score on both sides. Individual NLF-SRS grades per visit will be assessed 
separately for the right and left NLF. The assessment of the aesthetic effect by 
the investigator and the global aesthetic improvement (by the investigator and 
by subject), using the GAIS will be assessed at Week 4, 24, 36, 52 and optional 
at Week 65, 78, and 104 after the treatment. The subject will evaluate pain 
intensity associated with the treatment at Day 0 and at Week 2 (if Touch-up 

 
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treatment occurred), and satisfaction with the treatment at Week 4, 24, 36, 52 
and optional at Week 65, 78 and 104 after the treatment. Eligible patients will 
be randomized according the ratio 1:1 (manufacturing site C1: manufacturing 
site HQ). 
The safety will be evaluated based on occurrence of adverse events, which will 
be collected throughout the investigation. The concomitant medication will be 
documented throughout the study.  
Number of subjects 
Approximately 100+10 subjects will be included, to obtain the Week 24 
performance data in at least 100 subjects. Approximately 10 drop outs are 
estimated  
Eligibility criteria 
Inclusion criteria: 
A subject must meet ALL of the following criteria to be eligible for the study: 
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 with 2 or 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: 
A subject who meets ANY of the following criteria is NOT eligible for the study: 
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. Any superficial or deep facial surgery or injection or implantation of any 
dermal fillers (including but not limited to hyaluronic acid, collagen, calcium 
hydroxylapatite, poly-l-lactic acid, polymethylmethacrylate, autologous fat 
injections), application of any absorbable and non-absorbable sutures 
(thread) for any purpose including wound care and facial lifting, any laser 
therapy (including but not limited to Neodym-YAG, KTP, IPL, Diode lasers 
as well as Erbium-YAG, CO2 or other ablative lasers), dermoabrasion, or 
botulinum toxin application in the nasolabial region within previous 12 
months prior to enrolment, or any chemical peeling procedures (including 
but not limited to glycolic acid, trichloroacetic acid or phenolic peels) within 
previous 3 months prior to enrolment, 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 (3 times 
a year) herpes simplex in the treated area  
10. Tendency to hypertrophic scars and/or keloid formation 
11. History or presence of any autoimmune or connective tissue disease, or 
current treatment with immune therapy 
 
12. Uncontrolled systemic diseases (such as diabetes mellitus)  
13. Bariatric surgery within 12 months prior to enrollment or planned during 
the clinical investigation 
14. Use of anticoagulant or thrombolytic medication from 10 days pre- to 3 
days post injection 
15. Any medical condition which, in the investigator’s opinion, prohibits the 
inclusion in the study 
16. Current or previous (within 30 days of enrolment) treatment with another 
investigational drug and/or medical device or participation in another 
clinical study 
17. Previous enrolment in this clinical investigation 
18. 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) 
19. Any dental procedures one month before until one month after treatment 
with the investigational device  
Investigational 
device and mode of 
administration 
saypha® VOLUME Lidocaine is a sterile, biodegradable, viscoelastic, 
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. 

 
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saypha® VOLUME Lidocaine is administered by injection into the deep dermis 
or supraperiostal. The volume applied depends on the size of the area which 
requires correction and will be selected by the investigator. It is recommended 
that a maximum volume of 4 ml per treatment is applied, but should 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 proportion of subjects with the NLF-SRS grade reduced by ≥1 point 
versus baseline at Week 24, within each manufacturing site, C1 and HQ, 
separately and for the whole analysis population 
Secondary 
performance 
endpoints 
The following secondary performance endpoints will be evaluated within each 
manufacturing site, C1 and HQ, separately and for the whole analysis 
population:  
• 
The average change versus baseline in the NLF-SRS grade at Week 4, 
Week 24, Week 36, Week 52 and, optional at Week 65, Week 78 and 
Week 104 as evaluated by the investigator 
• 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point 
versus baseline at Week 4, Week 36, Week 52 and optional at Week 65, 
Week 78 and Week 104   
Exploratory 
performance 
endpoints 
The primary and secondary performance endpoints will be evaluated within the 
subgroups defined by the injection technique and device, needle and cannula, 
respectively. 
The following endpoints will be assessed for the whole analysis population: 
 
• 
The proportion of subjects with the NLF-SRS grade reduced by ≥2 point 
versus baseline at Week 4, Week 24, Week 36 and Week 52 and optional 
at Week 65, Week 78 and Week 104. 
• 
The proportion of subjects with aesthetic improvement at Week 4, Week 
24, Week 36, Week 52 and optional at Week 65, Week 78 and Week 104, 
as evaluated by the investigator using the Global Aesthetic Improvement 
Scale (GAIS) 
• 
The proportion of subjects with aesthetic improvement at Week 4, Week 
24, Week 36, Week 52 and optional at Week 65, Week 78 and Week 104, 
as evaluated by the subject using the Global Aesthetic Improvement Scale 
(GAIS) 
• 
Subjects’ satisfaction with aesthetic outcome of the treatment at Week 4, 
Week 24, Week 36, Week 52 and optional at Week 65, Week 78 and Week 
104 using the Face-Q Satisfaction with outcome Scale 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 4, Week 36, Week 52 and optional at Week 65, 
Week 78 and Week 104 as evaluated by the independent reviewer of 
photographs. 

 
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• 
Percentage of subjects having an aesthetic effect at Weeks 24, Week 36, 
Week 52 and optional at Week 65, Week 78 and Week 104 based on the 
investigator's life assessment. 
Safety endpoints 
• Occurrence and frequency of adverse events within each manufacturing 
site, C1 and HQ, separately and for the whole analysis population 
• Occurrence and frequency of adverse events within each subgroup defined 
by the injection device, needle and cannula, respectively. 
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. 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.  
A ‘responder’ is defined having at least ≥ 1 grade improvement as evaluated 
with the 5 point-validated NLF-SRS at week 24 relative to Baseline (Day 0) 
score on both sides. Individual NLF-SRS grades per visit will be assessed 
separately for the the right and left NLF. A Response rate of 90% at week 24 
is estimated. 
Additionally, the two-sided 95% confidence intervals of the expected change 
from baseline will be given and proportions (with two-sided 95% confidence 
intervals) of subjects with NLF-SRS improvement (i.e, reduction in NLF-SRS 
grades) of ≥1 or ≥2, respectively, will be calculated. For it, the changes from 
baseline are assumed to be normal distributed and the count of responders 
follows a binomial distribution. 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. A formal interim 
analysis of performance and safety data will be done upon completion of the 
Week 24 visit. 
Summaries will be provided for the whole analysis population, as well as within 
each manufacturing site, C1 and HQ, separately. 

 
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Schedule of procedures and events 
 
Table 1. Schedule of procedures and events 
 
Assessment 
VISIT 1* 
VISIT 2∞ 
VISIT 3 
VISIT 4∞Ω 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
VISIT 9§ 
VISIT 10§ 
VISIT 11§ 
 
Baseline 
TC 
 
TC 
 
 
 
 
 
 
 
 
Day 0 
24 h after 
treatment 
Week 2 
(± 2 days) 
24 h after 
treatment 
Week 4 
(± 4 days) 
Week 24 
(± 7 days) 
Week 36 
(± 7 days) 
Week 52 
(± 7 days) 
Week 65 
(± 7 days) 
Week 78 
(± 7 days) 
Week 104 
(± 7 days) 
Informed consent 
x** 
 
 
 
 
 
 
 
 
 
 
Demographic dataa 
x** 
 
 
 
 
 
 
 
 
 
 
Medical/ aesthetic 
history 
x** 
 
 
 
 
 
 
 
 
 
 
Prior medicationb 
x** 
 
 
 
 
 
 
 
 
 
 
NLF-SRS grading 
of nasolabial foldsc 
x** 
 
 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
Urine pregnancy testd 
x** 
 
x** 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
Eligibility assessment 
x** 
 
 
 
 
 
 
 
 
 
 
Treatment 
x 
 
x# 
 
 
 
 
 
 
 
 
Photography 
x** 
 
x** 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
Pain assessmente 
x 
 
xΩ 
 
 
 
 
 
 
 
 
GAIS assessmentf 
 
 
 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
GAIS assessment by 
the subject 
 
 
 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
Subject satisfactiong 
 
 
 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 

 
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Assessment 
VISIT 1* 
VISIT 2∞ 
VISIT 3 
VISIT 4∞Ω 
VISIT 5 
VISIT 6 
VISIT 7 
VISIT 8 
VISIT 9§ 
VISIT 10§ 
VISIT 11§ 
 
Baseline 
TC 
 
TC 
 
 
 
 
 
 
 
 
Day 0 
24 h after 
treatment 
Week 2 
(± 2 days) 
24 h after 
treatment 
Week 4 
(± 4 days) 
Week 24 
(± 7 days) 
Week 36 
(± 7 days) 
Week 52 
(± 7 days) 
Week 65 
(± 7 days) 
Week 78 
(± 7 days) 
Week 104 
(± 7 days) 
Assessment of 
aesthetic effect by the 
investigator 
 
 
 
 
 
x 
x 
x 
x§ 
x§ 
x§ 
Adverse eventsh 
x*** 
x∞ 
x 
x∞ Ω 
x 
x 
x 
x 
x§ 
x§ 
x§ 
Concomitant 
medicationh 
x*** 
 
x 
 
x 
x 
x 
x 
x§ 
x§ 
x§ 
 
* 
Includes screening and treatment.  
** Prior to application of the investigational device 
*** From beginning of the treatment onwards 
§ 
Optional the evaluation of the duration of the clinical investigation is planned for 104 Weeks at a maximum. In case it is observed by the investigators that no aesthetic effect is any more 
visible in approximately 75 % of the subjects, the study can be terminated at an earlier time point, but not before week 52.. 
# 
Touch-up treatment is optional (at investigator’s discretion, if full correction was not achieved after initial treatment). 
∞    Telephone communication approximately 24 hours post-administration in order to monitor adverse events. In case of AEs an unscheduled visit should take place. 
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 using the FACE Q Satisfaction with Outcome  
h 
To be collected throughout the investigation, from beginning of the treatment until the last visit, in order to identify potential adverse events post-administration an safety evaluation after 15 
minutes needs to take place. 
 

 
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List of abbreviations 
 
ADE 
Adverse device effect 
AE 
Adverse event 
BDDE 
1,4-butanediol diglycidyl ether 
C1 
Manufacturing site C1 Beautyplant 
CIP 
Clinical investigation plan 
CRF 
Case report form 
DCF 
Data clarification form 
DR 
Deviation Report 
EC 
Ethics Committee 
eCRF 
Electronic Case report form 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good clinical practice  
HA 
Hyaluronic acid 
HQ 
Manufacturing site Headquarter 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
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/WW 
Weight/WeightW 
 

 
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Table of contents 
 
Investigators and administrative structure of the clinical investigation .................................................... 2 
Synopsis .................................................................................................................................................. 6 
Schedule of procedures and events ...................................................................................................... 11 
List of abbreviations ............................................................................................................................... 13 
1 
Background .................................................................................................................................... 17 
2 
Identification and description of the investigational device ............................................................ 17 
2.1 
Device description .................................................................................................................... 17 
2.2 
Manufacturer ............................................................................................................................. 18 
2.3 
Intended Aesthetic purpose and mode of administration ......................................................... 18 
2.4 
Traceability ............................................................................................................................... 18 
3 
Justification for the design of the clinical investigation .................................................................. 18 
3.1 
Non-clinical data and biocompatibility ...................................................................................... 18 
3.2 
Clinical data .............................................................................................................................. 19 
3.3 
Justification for the clinical investigation ................................................................................... 20 
4 
Risks and benefits of the investigational device and clinical investigation .................................... 20 
4.1 
Anticipated clinical benefits ...................................................................................................... 20 
4.2 
Anticipated adverse device effects ........................................................................................... 20 
4.3 
Possible interactions with concomitant medical treatments ..................................................... 21 
4.4 
Risk mitigation strategy ............................................................................................................. 22 
4.5 
Risk-to-benefit rationale ............................................................................................................ 22 
5 
Objectives and hypotheses of the clinical investigation ................................................................ 23 
5.1 
Objectives ................................................................................................................................. 23 
5.2 
Hypotheses ............................................................................................................................... 23 
5.3 
Claims and intended aesthetic performance of the investigation that are to be verified .......... 23 
6 
Design of the clinical investigation ................................................................................................. 24 
6.1 
Design description .................................................................................................................... 24 
6.1.1 
Randomization ..................................................................................................................... 24 
6.1.2 
Primary performance endpoints .......................................................................................... 24 
6.1.3 
Secondary performance endpoints ..................................................................................... 24 
6.1.4 
Exploratory performance endpoints .................................................................................... 24 
6.1.5 
Safety endpoints .................................................................................................................. 25 
6.1.6 
Schedule of procedures and events .................................................................................... 25 
6.1.7 
Replacement of subjects ..................................................................................................... 26 
6.2 
Investigational device ............................................................................................................... 27 
6.2.1 
Packaging, labelling and storage ........................................................................................ 27 

 
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6.2.2 
Methods of use .................................................................................................................... 27 
6.2.3 
Applied volume of the device............................................................................................... 28 
6.2.4 
Touch-up treatment ............................................................................................................. 28 
6.2.5 
Precautions .......................................................................................................................... 28 
6.2.6 
Rescue medication .............................................................................................................. 29 
6.2.7 
Investigational device accountability ................................................................................... 29 
6.3 
Subjects .................................................................................................................................... 29 
6.3.1 
Number of subjects and duration of the clinical investigation ............................................. 29 
6.3.2 
Recruitment strategy ........................................................................................................... 30 
6.3.3 
Subject identification ............................................................................................................ 30 
6.3.4 
Inclusion criteria ................................................................................................................... 30 
6.3.5 
Exclusion criteria ................................................................................................................. 30 
6.3.6 
Withdrawal criteria and procedures ..................................................................................... 31 
6.3.7 
Life-style and other restrictions............................................................................................ 31 
6.3.8 
Medical care upon termination of the clinical investigation ................................................. 32 
6.3.9 
Screening/baseline failures ................................................................................................. 32 
6.3.10 
Subject identification, privacy and data confidentiality ........................................................ 32 
6.4 
Assessments and procedures .................................................................................................. 33 
6.4.1 
Demographic data ............................................................................................................... 33 
6.4.2 
Medical history ..................................................................................................................... 33 
6.4.3 
Pregnancy test ..................................................................................................................... 33 
6.4.4 
Photography ........................................................................................................................ 33 
6.4.5 
NLF-SRS grading of nasolabial folds .................................................................................. 33 
6.4.6 
Aesthetic improvement/GAIS assessment .......................................................................... 34 
6.4.7 
Assessment of aesthetic effect ............................................................................................ 35 
6.4.8 
Pain assessment ................................................................................................................. 35 
6.4.9 
Subject’s satisfaction assessment ....................................................................................... 35 
6.4.10 
Outcome evaluation by the independent reviewer of photographs ..................................... 35 
6.4.11 
Safety monitoring ................................................................................................................. 36 
6.4.12 
Prior and concomitant medication and non-drug therapies ................................................. 36 
6.4.13 
Factors that may compromise the outcome ........................................................................ 36 
6.4.14 
Early Termination Visit ......................................................................................................... 37 
6.4.15 
Unscheduled Visit ................................................................................................................ 37 
6.5 
Monitoring plan ......................................................................................................................... 37 
7 
Statistical considerations ............................................................................................................... 38 
7.1 
Sample size .............................................................................................................................. 38 

 
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7.2 
Analysed data sets ................................................................................................................... 38 
7.3 
Missing data .............................................................................................................................. 38 
7.4 
Methods of analysis .................................................................................................................. 38 
7.4.1 
Performance endpoints ....................................................................................................... 38 
7.4.2 
Safety endpoints .................................................................................................................. 39 
8 
Data management ......................................................................................................................... 39 
8.1 
Case report forms ..................................................................................................................... 39 
8.2 
Data management procedures ................................................................................................. 39 
8.3 
Data retention ........................................................................................................................... 40 
8.4 
Report of the clinical investigation ............................................................................................ 40 
9 
Amendments to the clinical investigation plan ............................................................................... 40 
10 Deviations from the clinical investigation plan ............................................................................... 40 
11 Device accountability ..................................................................................................................... 41 
12 Statements of compliance ............................................................................................................. 41 
13 Informed consent process ............................................................................................................. 41 
14 Adverse events, adverse device effects and device deficiencies .................................................. 42 
14.1 
Definitions ................................................................................................................................. 42 
14.2 
Method of detecting AEs........................................................................................................... 42 
14.3 
AE/SAE documentation ............................................................................................................ 43 
14.4 
AE/SAE assessment ................................................................................................................. 43 
14.4.1 
Severity assessment ........................................................................................................... 43 
14.4.2 
Causality assessment .......................................................................................................... 44 
14.4.3 
Outcome assessment .......................................................................................................... 44 
14.5 
AE/SAE reporting requirements and contact details ................................................................ 45 
14.6 
AE/SAE follow-up ..................................................................................................................... 45 
14.7 
Foreseeable AEs and anticipated ADEs .................................................................................. 45 
14.8 
Device deficiency reporting requirements ................................................................................ 45 
14.8.1 
Handling of deficient medical devices ................................................................................. 46 
14.9 
Data monitoring committee ....................................................................................................... 46 
15 Vulnerable populations .................................................................................................................. 46 
16 Suspension or premature termination of the clinical investigation ................................................ 46 
17 Publication policy ........................................................................................................................... 46 
 
 

 
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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 (HA), 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. HA 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 saypha® VOLUME Lidocaine Investigator’s brochure (IB)8 for detailed information on 
the investigational device. 
2.1 
Device description 
saypha® VOLUME Lidocaine is a sterile, biodegradable, viscoelastic, clear, transparent, isotonic and 
homogenized injectable gel implant. The implant consists of HA obtained from Streptococcus equi 
bacteria, which is highly 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.  
saypha® VOLUME 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 the deep dermis or supraperiostal and remains in long term 
contact with human skin and connective tissues. HA is a natural component of human skin, hence 
saypha® VOLUME Lidocaine is naturally absorbed, with the lifetime of the device anticipated to last up 
to 9 months after treatment. The ancillary component, lidocaine hydrochloride, is rapidly released from 

 
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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 13485:2016. No materials of human or animal 
origin are used during manufacture or as raw materials. 
Saypha® VOLUME Lidocaine is designed for single use and upon opening should not be re-sterilized or 
reused. 
2.2 
Manufacturer 
saypha® VOLUME Lidocaine is manufactured by CROMA-PHARMA GmbH, Industriezeile 6, 2100 
Leobendorf, Austria. 
Enclosed needles are manufactured by 
 
 
Additionally, 25G x 2”, 0.5 x 50 mm cannulas are provided to the investigational site to be used with the 
investigational deviceand manufactured by
  
2.3 
Intended Aesthetic purpose and mode of administration 
saypha® VOLUME Lidocaine is a soft tissue filler, to be used in adults (18 years and older).  
The device is intended to correct moderate to severe nasolabial folds. It is intended to be injected into 
the deep dermis or supraperiostal. 
The amount injected depends on the size of the area to be corrected and the desired level of soft tissue 
augmentation. It is estimated that a maximum volume of 4 ml per treatment is needed9,10, but should not 
exceed 10 mL in total per treatment or 20 mL per year.  
A maximum of 4 mL is a commonly used amount to be injected for nasolabial fold treatment. 
The injection technique, which is described in Section 6.2.2 Methods of use, is essential for success of 
the treatment. Therefore, saypha® VOLUME Lidocaine should be administered exclusively by physicians 
who have received specific training on its application and use in respective indications. 
In the present clinical investigation, saypha® VOLUME Lidocaine will be used for correction of moderate 
to severe nasolabial folds. 
2.4 
Traceability 
Each carton of saypha® VOLUME Lidocaine is identified and tracked by its code number and a unique 
kit number. Peel-off labels are attached on the carton box of the kit showing the code number and kit 
number. To ensure the traceability of each device the peel-off label should be placed in the medical file 
of the subject treated with the device.  
 
3 Justification for the design of the clinical investigation 
3.1 
 Non-clinical data and biocompatibility 
HA 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. HA has a considerable water-
binding capacity, and by this mechanism it increases dermal volume and compressibility11. 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 fibroblasts12. HA 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 HA is degraded via the same mechanisms as native 

 
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safety endpoint indicated that Princess® VOLUME Lidocaine is safe and well tolerated. All reported AEs 
were mild. No serious AEs or deaths were reported in the investigation.   
3.3 
Justification for the clinical investigation 
The current clinical investigation is designed to evaluate the performance of saypha® VOLUME 
Lidocaine for the correction of nasolabial folds using injection into the deep dermis or supraperiostal and 
to compare two different manufacturing sites. 
In addition, this investigation should support the approval by obtaining clinical data on the performance 
and safety of saypha® VOLUME Lidocaine for the correction of nasolabial folds. 
A prospective, 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 
randomization regarding manufacturing site, C1 and HQ, will be performed according the ratio 1:1 to 
present the resuts of the two manufacturing sites descriptively. 
The primary performance endpoints are 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 24 weeks after administration of the device to address the minimum required durability of effect. 
Follow-up is extended a maximum up to 104 weeks, to get additional information on long-term effects 
and to evaluate the aesthetic outcome. 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)17.  
 
4 Risks and benefits of the investigational device and clinical investigation 
4.1 
Anticipated clinical benefits 
The treatment with saypha® VOLUME 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 6-12 months. 
4.2 
Anticipated adverse device effects 
The safety profile of BDDE-cross-linked HA dermal fillers, with or without lidocaine, is well established. 
In general, these devices are well tolerated and safe, with a low frequency of side effects18. Adverse 
effects that have been observed with devices similar to saypha® VOLUME Lidocaine are summarized 
in Table 2, on the following page. 
“A prospective, open label, multicenter, post market study evaluating Princess® VOLUME Lidocaine for 
the correction of nasolabial folds” all 62 screened and enrolled subjects were treated with the 
investigational medical device at Baseline. The mean number of used devices was 2.7 (standard 
deviation [SD]: 0.8) and the mean injected volume was 1.15 mL (SD: 0.46) for the right nasolabial folds, 
and 1.16 mL (SD: 0.45) for the left nasolabial folds. At Week 2, eight subjects received touch-up 
treatment using a mean of 1.1 mL (SD: 0.4) investigational medical devices. The mean injected volume 
for touch-up treatment was 0.45 mL (SD: 0.3) for the right nasolabial folds, and 0.29 mL (SD: 0.3) for 
the left nasolabial folds. The results show that adverse device effects include injection site hematoma, 
hypoesthesia and pain, one subject showed nervous system disorder and one subject had syncope. 
However, all ADEs were mild and had resolved within a maximum of 13 days of their onset. 
 
 
 

 
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Table 2. Adverse effects of cross-linked hyaluronic acid dermal fillers (with or without lidocaine) 
Common 
Rare 
Very rare 
• Redness, erythema 
• Swelling, oedema 
• Pain, itching, burning, discomfort 
• Tenderness  
• Bleeding 
• Bruising, hematoma 
• 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 
• Teleangiectasia (generalized) 
• Vasculitis cutaneous 
• Vasospasm 
• Vasovagal reaction during injection 
• 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. 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 HA filler-induced impending necrosis recommends immediate treatment with high 
doses of hyaluronidase (e.g., at least 200 units of Vitrase®, 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.  
In case of an adverse event the Expert Consensus Recommendations for treatment of Soft Tissue Filler 
Complications19should be followed in the discretion of the investigator. The current Expert Consensus 
Recommendations for treatment of Soft Tissue Filler Complication are filed in the Investigator´s File. 
4.3 
Possible interactions with concomitant medical treatments 
No studies on drug interactions with saypha® VOLUME 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. 

 
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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 104 weeks (maximum), which will allow for timely 
recognition and management of potential AEs. After insertion of the needle / cannula, and just before 
injection, the plunger rod should be withdrawn slightly to aspirate and verify that the needle is not 
intravascular. 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 
HA-based dermal fillers, such as saypha® VOLUME 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 saypha® VOLUME, 
with few ADEs reported among almost 2 million units sold since 2009, combined with favorable safety 
data from one clinical trial.  
The performance and safety of lidocaine-containing HA dermal fillers for correction of nasolabial folds 
have been well documented in medical literature, and saypha® VOLUME 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. 
Participation in any clinical trial is currently associated with increased risk and additional challenges due 
to the COVID-19 pandemic caused by SARS-CoV-2. First and top priority of CROMA-PHARMA GmbH 
and 
 is the safety of the subjects and all persons involved in the clinical investigation. 
Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as well 
as national health authorities in Europe have issued guidelines that aim to provide recommendations 
for conduct of clinical trials during the COVID-19 pandemic. Given the circumstances of the recurrently 
relapsing pandemic or dynamically evolving epidemic situation with regard to the spread of COVID-19, 
CROMA-PHARMA GmbH and 
 will pay special attention to protect subjects participating 
in the investigation and clinical site staff involved in clinical investigations against infection with SARS-
CoV-2 as requested by the EMA guidelines. Both, CROMA-PHARMA GmbH and 
, will 
continue to observe the situation with care and will re-evaluate and amend the risk mitigation measures, 
if deemed appropriate. 
CROMA-PHARMA GmbH has evaluated all currently available safety data on saypha® VOLUME 
Lidocaine. Based on the local mode of administration once or twice, the low systemic exposure, and the 
safety profile, it is concluded that the treatment with saypha® VOLUME Lidocaine is not believed to put 
trial subjects under an increased risk for viral infections including SARS-CoV-2. At present, there is no 
change in the risk-benefit ratio foreseen that mandates any changes to the current protocol instructions.  
However, the risk of exposure to infected people cannot be excluded as the subjects may need to 
expose themselves to public areas (e.g. commute to the investigation site) and have additional human 
contact (e.g. with clinical site staff). Appropriate risk assessments and mitigation measures will be 
considered to protect the health and well-being of involved persons and to ensure the integrity of the 
data obtained during the clinical investigation. 
If site visits are not possible, safety data will be collected remotely by the Clinical Research Associate 
via telephone or electronic communication to ensure subject safety. 
Investigators are responsible for taking appropriate measures to ensure the safety of individual subjects 
in accordance with preventive measures enacted by local authorities. 

 
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4.6 
COVID-19 pandemic contingency plan 
Without compromising the safety of subjects and integrity of the investigation, it is expected that all 
efforts are made to secure attendance of subjects at the clinical investigation site for all visits, ensuring 
efficacy and safety assessments for the investigation. This includes but is not limited to complying with 
recommendations/regulations issued by local health authorities, the increase of protective safety and 
hygiene measures (e.g. mask obligation, hand disinfection, distance control) for both subjects and site 
personnel, and the regular monitoring of the health status of subjects. Those safety and hygiene 
measures will have no influence on the conduct of the investigation but are being implemented to 
minimize the risk of spread of COVID-19 infection. 
To minimize exposure of subjects to public areas and transportation, CROMA-PHARMA GmbH is 
reimbursing the travel costs of subjects on their way to and from the investigation site when using a taxi.  
It will be at the discretion of the investigator to decide whether subject on-site visits are considered 
necessary to ensure subject safety in periods when on-site visits are not interfering with the primary 
endpoint of the CIP (e.g. for visits 5, 7, 8-11). ). If deemed necessary, the investigator may provide a 
letter to the subjects on the way to sites explaining why commuting is required in this case. 
If on-site visits are not possible due to preventive measures issued by city or local authorities or site 
obligations, the affected site will postpone on-site visits and will perform phone calls and collect safety 
and performance data to ensure subject safety as far as possible. 
In general, more intense telephone contacts between clinical site staff and enrolled subjects will be 
utilized to closely monitor the situation and status of subject participation. In the eCRF, it will be recorded 
whether a given assessment was done remotely or not done. Any telephone contact or unscheduled 
visit will be recorded. For any of these records, it will be reported if this was due to the COVID-19 
pandemic.  
If a subject is tested positive for COVID-19, the investigator may withdraw the subject from further 
participation. The continuation may be decided in cooperation between the investigator and the sponsor 
if the subject recovers prior to the next scheduled visit. A COVID-19 infection will be documented as AE.  
 
5 Objectives and hypotheses of the clinical investigation 
5.1 
Objectives 
The objectives of this clinical investigation are: 
• 
To evaluate the performance of saypha® VOLUME Lidocaine for the correction of nasolabial folds 
using injection into the deep dermis or supraperiostal. 
• 
To evaluate the safety of saypha® VOLUME Lidocaine when used for correction of nasolabial folds. 
• 
To evaluate the duration of the aesthetic effect. 
5.2 
Hypotheses 
This is a non-comparative study and does not entail formal hypothesis testing. 
5.3 
Claims and intended aesthetic performance of the investigation that are to be verified 
The device is intended to correct moderate to severe nasolabial folds.  
The intended aesthetic purpose of the device is to create volume and thereby improve moderate to 
severe nasolabial folds and to achieve aesthetic improvement. The product is designed to be injected 
into the deep dermis or supraperiostal. 
The device is an absorbable implant intended to be used for adult human beings. It is totally resorbed. 
The device is intended for single use, it is sterile, non-active and without measuring function. No 
materials of animal origin are used during manufacturing or as raw materials. A drug substance 
(Lidocaine) is integrated into the device. The ancillary role of Lidocaine is to reduce the pain associated 
with injections into the skin. 

 
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The safety profile of lidocaine-containing HA dermal fillers is well established. Based on the equivalence 
of saypha® VOLUME 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, non-comparative, randomized, multicenter 
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 11 visits (the three last visits are optional): the baseline (Day 0) visit, 
which will entail informed consent, screening assessments, the treatment, and early post-treatment 
assessments, telephone communication approximately 24 hours post-administration for monitoring of 
adverse events and follow-up visits at Week 2, 4, 24, 36, 52, 65 (optional), 78 (optional) and 104 
(optional) after the treatment. Procedures to be performed at each visit are specified in  
Table 1. Schedule of procedures and events, which is located on page 11 and in section 6. 
In case it is observed by the investigators that at a given visit no aesthetic effect is any more visible in 
approximately 75 % of the subjects, the study can be terminated at an earlier time point, but not before 
week 52. 
6.1.1 
Randomization 
Subjects will be randomly assigned to manufacturing site (C1 and HQ) by means of a computer-
generated randomization list with a 1:1 allocation. Eligible subjects are assigned random numbers in 
ascending order within each block beginning with the lowest number available. It is mandatory to stick 
to this procedure throughout the study.  
6.1.2 
Primary performance endpoints 
The performance of the investigational device will be evaluated using the following primary endpoints 
(see section 7.4.1) (justification is provided in Section 3.3): 
• 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point versus baseline at Week 
24, within each manufacturing site, C1 and HQ, separately and for the whole analysis population. 
6.1.3 
Secondary performance endpoints 
The following secondary performance endpoints will be evaluated within each manufacturing site, C1 
and HQ, separately and for the whole analysis population (see section 7.4.1): 
• 
The average change versus baseline in the NLF-SRS grade at Week 4, Week 24, Week 36 and 
Week 52 and optional at Week 65, Week 78 and Week 104 as evaluated by the investigator. 
• 
The proportion of subjects with the NLF-SRS grade reduced by ≥1 point versus baseline at Week 
4, Week 36 and Week 52 and optional at Week 65, Week 78 and Week 104. 
6.1.4 
Exploratory performance endpoints 
The primary and secondary performance endpoints will be evaluated within the subgroups defined by 
the injection device, needle and cannula, respectively.  
The following endpoints will be assessed for the whole analysis population: 

 
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• 
The proportion of subjects with the NLF-SRS grade reduced by ≥2 point versus baseline at Week 
4, Week 24, Week 36 and Week 52 and optional at Week 65, Week 78 and Week 104. 
• 
The proportion of subjects with aesthetic improvement at Week 4, Week 24, Week 36 and week 52 
and optional at Week 65, Week 78 and Week 104 as evaluated by the investigator using the Global 
Aesthetic Improvement Scale (GAIS). 
• 
The proportion of subjects with aesthetic improvement at Week 4, Week 24, Week 36 and week 
52 and optional at Week 65, Week 78 and Week 104 as evaluated by the subject using the Global 
Aesthetic Improvement Scale (GAIS). 
• 
Subjects’ satisfaction with aesthetic outcome of the treatment at Week 4, Week 24, Week 36 and 
week 52 and optional at Week 65, Week 78 and Week 104 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 
4, Week 24, Week 36 and week 52 and optional at Week 65, Week 78 and Week 104 as evaluated 
by the independent reviewer of photographs. 
• 
Percentage of subjects having an aesthetic effect at Weeks 24, Week 36, Week 52 and optional at 
Week 65, Week 78 and Week 104 based on the investigator's life assessment. 
6.1.5 
Safety endpoints 
The safety of the investigational device will be evaluated using the following endpoint: 
• 
Occurrence and frequency of adverse events within each manufacturing site, C1 and HQ, separately 
and for the whole analysis population.  
• 
Occurrence and frequency of adverse events within each subgroup defined by the injection device, 
needle and cannula, respectively. 
6.1.6 
Schedule of procedures and events 
 
Baseline Visit (Visit 1) 
After written informed consent is obtained, the following assessments will be performed during Baseline 
Visit at Day 0: 
• 
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 
 
 
Telephone communication approximately 24 h after initial treatment (Visit 2) 
• 
Monitoring of post-administration adverse events 
• 
In case of AEs an unscheduled visit may take place. 

 
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Week 2 Visit (Visit 3) 
The following assessments will be performed 2 weeks (± 2 days) after Visit 1: 
• 
Photography (only if Touch-up treatment performed) 
• 
Touch-up treatment (optional, to the discretion of the injector) 
• 
Pain assessment (only if Touch-up treatment performed) 
• 
Urine pregnancy test (in women of child-bearing potential) 
• 
Adverse events 
• 
Concomitant medication  
 
 
Telephone communication 24 h after Touch-up treatment (Visit 4) 
• 
Monitoring of post-administration adverse events 
• 
In case of AEs an unscheduled visit may take place. 
 
 
Week 4 (Visit 5), Week 24 (Visit 6), Week 36 (Visit 7), Week 52 (Visit 8), Week 65 (Visit 9, 
optional), Week 78 (Visit 10, optional) and Week 104 (Visit 11, optional) Visits 
The following assessments will be performed respectively 4 weeks (± 4 days), 24 weeks (± 7 days), 36 
weeks (± 7 days) and 52 weeks (± 7 days) and 65 weeks (± 7 days), 78 weeks (± 7 days) and 104 
weeks (± 7 days) after Visit 1 (last 3 visits are optional): 
• 
Photography 
• 
Urine pregnancy test (in women of child-bearing potential) 
• 
NLF-SRS grading of nasolabial folds by the investigator 
• 
GAIS assessment by the investigator  
• 
GAIS assessment by the subject 
• 
Subject satisfaction 
• 
Assessment of aesthetic effect by the investigator 
• 
Adverse events 
• 
Concomitant medication  
 
 
Unscheduled Visits due to COVID-19 pandemic 
In case a planned on-site visit cannot take place due to COVID-19, the investigator may perform an 
unscheduled visit either as delayed on-site visit or as safety phone call.  
• 
In case of unscheduled on-site visits, the investigator will perform all assesments forseen at 
the on-site visit that was cancelled due to COVID-19 pandemic. 
• 
In case of unscheduled safety phone calls the investigator will record adverse events and 
concomitant medication. The investigator will additionally record the scores from the GAIS 
assessment by the subject and the subject satisfaction questionnaire via phone. The subject 
will confirm the correctness of the scores recorded via phone during the next on-site visits with 
his name, date and signature. The questionnaires will remain with the source data and will not 
be transferred into the TMF. 
 
6.1.7 
Replacement of subjects 
Subjects withdrawn from the investigation or lost for follow-up will not be replaced. 

 
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6.2 
Investigational device 
6.2.1 
Packaging, labelling and storage 
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. Peel-off labels are attached on 
the carton box of the kit showing the code number and a unique kit number. To ensure the traceability 
of each device the peel-off label should be placed in the medical file of the subject treated with the 
device. 
Additionally, 25G x 2”, 0.5 x 50 mm cannulas are provided to the investigational site to be used with the 
investigational 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. 
6.2.2 
Methods of use 
The investigational device will be administered to eligible subjects on study Day 0. A Touch-up treatment 
at week 2 is optional at investigator’s discretion, if full correction was not achieved after initial treatment. 
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.  
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 or cannula 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 injection technique used is essential for success of the treatment. Therefore, all investigators must 
complete a specific training in the injection technique before using the medical device.  
The investigational device should be injected into the deep dermis or supraperiostal. 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 or cannula, and just before injection, the plunger rod should be withdrawn 
slightly to aspirate and verify that the needle or cannula is not intravascular.  
The following injection techniques should be used:  
Retrograde technique (Linear Threading technique): introduction of the entire needle/cannula along 
the wrinkle or skin depression and injecting while slowly withdrawing the needle/cannula. 
Bolus technique: 
The vertical supraperiosteal depot technique, where small depots of the filler (0.02-0.05 mL) are placed 
via serial vertical injections (2-3 mm apart) directly on the periosteum. 
A minimum of 30 subjects should be treated either with the Retrograde technique or with the Bolus 
technique.  

 
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Lateral movements of the needle must be avoided since these may result in a fanlike dissection of the 
sub-epidermal plane, increasing the incidence of local AEs like bruising, swelling, redness, pain, or 
tenderness at the injection site. 
The device should be injected slowly with the least amount of possible pressure for the same reason. If 
the needle or cannula is blocked, the pressure on the plunger rod should not be increased, but the 
injection stopped and the needle or cannula 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 or cannula 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. 
 
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. 
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 eCRF, 
together with information on injection technique, area of application, date, and exact start time and end 
time of injection. 
The maximum recommended dosage is a volume of 4 mL per treatment, but should not exceed 10 mL 
in total per treatment or 20 mL per year. 
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 eCRF with the same level 
of details as the initial treatment. For the Touch-up treatment the same injection technique and the same 
device (needle or cannula) as used during initial treatment at visit 1 must be applied for a respective 
subject. 
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 or cannula and syringe provided by the 
manufacturer. 

 
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maximum of 27 months. Recruitment halts due to COVID-19 pandemic lead to the prolongation of the 
recruitment period and the extension of the total duration of the clinical investigation. 
6.3.2 
Recruitment strategy 
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 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 
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. Any superficial or deep facial surgery or injection or implantation of any dermal fillers (including but 
not 
limited 
to 
hyaluronic 
acid, 
collagen, 
calcium 
hydroxylapatite, 
poly-l-lactic 
acid, 
polymethylmethacrylate, autologous fat injections), application of any absorbable and non-
absorbable sutures (thread) for any purpose including wound care and facial lifting, any laser 
therapy (including but not limited to Neodym-YAG, KTP, IPL, Diode lasers as well as Erbium-YAG, 
CO2 or other ablative lasers), dermoabrasion, or botulinum toxin application in the nasolabial region 
within previous 12 months prior to enrolment, or any chemical peeling procedures (including but not 
limited to glycolic acid, trichloroacetic acid or phenolic peels) within previous 3 months prior to 
enrolment, 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 

 
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8. Known human immune deficiency virus-positive individuals 
9. History of allergies against aesthetic filling products and recurrent (3 times a year) herpes simplex 
in the treated area  
10. Tendency to hypertrophic scars and/or keloid formation 
11. History or presence of any autoimmune or connective tissue disease, or current treatment with 
immune therapy 
12. Uncontrolled systemic diseases (such as diabetes mellitus)  
13. Bariatric surgery within 12 months prior to enrollment or planned during the clinical investigation 
14. Use of anticoagulant or thrombolytic medication from 10 days pre- to 3 days post injection 
15. Any medical condition which, in the investigator’s opinion, prohibits the inclusion in the study 
16. Current or previous (within 30 days of enrolment) treatment with another investigational drug and/or 
medical device or participation in another clinical study 
17. Previous enrolment in this clinical investigation 
18. 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) 
19. Any dental procedures one month before until one month after treatment with the investigational 
device 
 
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. 
Reasons, circumstances and findings related to early withdrawal should be fully described in the eCRF 
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 104 visit. In the event that the withdrawal is 
caused by an AE, the procedures stated in Section 14.6 must be followed. 
6.3.7 
Life-style and other restrictions 
Contraception 
The safety of saypha®VOLUME Lidocaine for use during pregnancy has not been established, so 
females of childbearing potential should use contraception or avoid unprotected sexual intercourse 

 
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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 (screened 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 eCRF. 
6.3.10 Subject identification, privacy and data confidentiality 
Subjects’ privacy and data confidentiality will be protected in line with the principles of good clinical 
practice, the European Data Protection Directive and other applicable international and national 
requirements. Subjects will provide authorisation for use of their personal data in accordance with the 
applicable regulations regarding privacy and data protection. A unique numerical subject identification 
code will be assigned to each subject at screening. The investigator will assign the codes in ascending 
order, in line with the order of the informed consent date and time.  The investigator must ensure that 
anonymity of the subjects will be maintained and that their identities are protected from unauthorized 
parties. In the eCRF or any other document submitted to the Sponsor or Sponsor's representative, 
subjects must be identified only by their identification codes; use of names, initials, complete birthdates, 
addresses, telephone numbers, electronic addresses or similar information is prohibited. The 
investigator will keep the Subject Identification Log (including complete name, date of birth, and contact 
details of each subject) in their file. The investigator must maintain these documents in strict confidence. 
All subjects will be informed and consented regarding the access to their personal investigation related 
data by the monitors, auditors and inspectors of the clinical investigation, as well as transmission of their 
coded data to the Sponsor or Sponsor’s representative and data retention for the duration defined in 
Section 8.3. Professionals with access to subjects’ data for monitoring, audits and inspections are bound 
to preserve strict confidentiality. This CIP, other investigation-related documentation, collected 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.  
 
 

 
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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 6.1.6. 
It is the investigator’s obligation to assure documentation of all relevant data in the subject’s medical 
record, such as informed consent, subjects eligibility, 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 12 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 eCRF. 
This test must be done at each on-site visit except visits 2 and 4 which will be performed by telephone 
communication approximately 24h post-treatment. 
6.4.4 
Photography 
Clinical photography of the subject’s face will be taken by the investigator or their designee using the 
3D LifeViz mini camera with dual beamer pointers (Quantificare). 
A standardized procedure for study photography, which will be described in a separate Photo Manual, 
will be provided to the investigators. This Photo Manual will ensure consistency of the background, 
camera settings, lighting, and subject position between the visits and across the sites. Obtained 
photographs must be immediately uploaded to a secure storage system and a backup copy keep in the 
investigator physician's computer. 
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. The visual guide is provided in Figure 1. 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 eCRF. 
 
Table 3. Nasolabial Folds Severity Rating Scale (NLF-SRS) 
CROMA NLF-
SRS grade 
Description 
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 

 
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6.4.7 
 Assessment of aesthetic effect 
The investigator will assess whether the aesthetic effect is still present in the subject. A live-
assessment of the treated areas will be performed and the treated areas will be compared to the 
subject’s photographs obtained at the Baseline Visit. The presence of the aesthetic effect will be 
recorded as either “Yes” or “No” in the subject’s medical record and in the eCRF. 
If a subject no longer has an aesthetic effect as of Week 52, this may prematurely lead to the 
termination of the clinical examination of the respective subject. 
In this case new injections can be placed at previously injected locations. 
 
6.4.8 
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 imaginable17. Pain intensity will be assessed twice, immediately after injection, and 
approximately 15 (±5) 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 eCRF. 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.  
6.4.9 
Subject’s satisfaction assessment 
Subject’s satisfaction with the treatment in order to evaluate the performance of the device and 
consistency in alignment with subject expectation will be assessed using the FACE-Q questionnaire 
“Satisfaction with Outcome” scale. This is a validated instrument for evaluation of satisfaction with the 
outcome of a facial aesthetic procedure.21 The subject will be asked to complete the questionnaire. 
The statement selected by the subject will be recorded in the Subject’s satisfaction form and the 
eCRF. 
In case a scheduled on-site visit is not possible due to COVID-19 pandemic situation, the investigator 
will record the scores for the FACE-Q questionnaire by the subject as reported by the subject via phone. 
The correctness of the latter records will be confirmed by the subject during the next possible on-site 
visit with name, date and signature. The countersigned subject questionnaire has to be kept in the 
source data and not to be transferred into the TMF.  
 
6.4.10 Outcome evaluation by the independent reviewer of photographs 
An independent photo reviewer will evaluate the treatment outcome using the NLF-SRS scale and based 
on the photographs. The independent photographic reviewer, who will assess treatment effect based 
on photographs of the subjects, will be dislocated from the investigation sites and will not discuss any 
findings with the investigators or independent clinical evaluators during the trial and until the final 
database lock. Moreover, an evaluation of nasolabial folds severity by an independent blinded 
photographic reviewer using the 5-point NLF-SRS scale and based on photographs will take place at 
the end of the study. 

 
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6.4.11 Safety monitoring 
The safety of the investigational device will be monitored throughout the investigation, from Day 0/visit 
1 until the final visit (visit 9). 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. 
In order to identify potential adverse events post-administration a safety evaluation after 15 minutes 
needs to take place. 
In case a scheduled on-site visit cannot take place due to COVID-19 pandemic, the investigator should 
attempt to postpone the visit or make a safety-phone call to monitor the safety of the investigational 
device. 
6.4.12 Prior and concomitant medication and non-drug therapies 
Prior medication is defined as all medication taken within 10 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 104 visit.  
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 eCRF. 
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). COVID-19 vaccination is not prohibited. 
• 
Anticoagulant, or thrombolytic drugs (from 10 days pre- until 3 days post-injection) 
• 
Treatment with any investigational drug or other investigational medical device (throughout the 
clinical investigation). 
• 
Facial surgery or implantation of dermal fillers other than the investigational device (from 12 months 
prior to Day 0 until the end of the clinical investigation) 
• 
Absorbable and non-absorbable sutures (thread), laser therapy or dermabrasion (from 12 months 
prior to Day 0 until the end of the clinical investigation) 
• 
Botulinum toxin treatment in the area treated with the investigational device (from 12 months prior 
to Day 0 until the end of the clinical investigation) 
• 
Chemical peeling (from 3 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) 
• 
Bariatric surgery (from 12 months prior to Visit 1 until the end of the clinical investigation) 
• 
Dental/oral surgery or modification like bridge-work or implants (from four weeks before until four 
weeks after the IMD injection) 
6.4.13 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 an 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. 

 
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6.4.14 Early Termination Visit 
At Early Termination Visit, or whenever the subject is withdrawn from the clinical investigation, all 
attempts should be made to perform the assessments described for Visit 6 (see section 6.1.6.5).  
For safety reasons, the following assessments are recommended to be completed at a minimum:  
• 
Record any new AE or changes of AEs  
• 
Record changes in concomitant medication and procedures  
• 
NLF assessment – investigator  
6.4.15 Unscheduled Visit  
An unscheduled visit may be performed at any time during the study if judged necessary by the 
investigator, such as for a severe reaction, clinically significant AE or suspected pregnancy. The 
investigator should treat these side effects appropriately.  
In case the unscheduled visit results in early termination of the subject, the assessments for the Early 
Termination Visit should be performed (see section 6.4.14). Details of the event are to be recorded in 
the subject’s records and in the eCRF.  
In case a planned on-site visit cannot take place due to COVID-19, the investigator may perform an 
unscheduled visit either as delayed on-site visit and/or as safety phone call.  
• 
In case of unscheduled on-site visits, the investigator will perform all assesments forseen at 
the on-site visit cancelled due to COVID-19 pandemic. 
• 
In case of unscheduled safety phone calls the investigator will record adverse events and 
concomitant medication. The investigator will additionally record the scores from the GAIS 
assessment by the subject and the subject satisfaction questionnaire via phone. The subject 
will confirm the correctness of the scores recorded via phone during the next on-site visits with 
name, date and signature. 
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 eCRF 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 eCRF 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 eCRF 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. In the course of risk-mitigation strategy adaption due to the pandemic situation 
the Monitoring plan was adapted and the option to perform remote monitoring was included in the 
monitoring strategy and submitted to the ethics committees and regulatory authority. Remote monitoring 

 
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will be implemented in case on-site monitoring is not possible to ensure patient safety. Remote 
monitoring will not include SDV and will be limited to eCRF checks until on-site visits can be resumed.  
 
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 approx. 100 + 10 subjects with moderate to severe nasolabial folds will be randomized with a 1:1 
allocation to the manufacturing sites C1 and HQ, in order to obtain the 24-week performance and safety 
data from approximately 50 of them in each manufacturing site. This sample size is considered 
appropriate for the clinical investigation and sufficient to provide robust estimations on performance and 
safety parameters in the study population. A sample size of approximately 50 allows a meaningful range 
estimation, the confidence interval, for the true proportion of success (reduction in NLF-SRS grades of 
≥1) at week 24. With a sample size of 50, a confidence level of (1- α) with α=0.05 and an estimated 
proportion of 0.9 a two-sided 95% confidence interval for the true proportion using the large sample 
normal approximation is given through [0.817; 0.983]. Thus, in compliance with the study design, the 
true proportion is expected in the range of the confidence interval with an error probability of 5%.  
A ‘responder’ is defined having at least ≥ 1 grade improvement as evaluated with the 5 point-validated 
NLF-SRS at week 24 relative to Baseline (Day 0) score on both sites. Individual NLF-SRS grades per 
visit will be assessed separately for the right and left NLF. A Response rate of 90% at week 24 is 
estimated. 
7.2 
Analysed data sets 
The primary data set for analyses of performance of the investigational device and of aesthetic effects 
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 Week 24 assessments without major CIP deviations. 
All safety analyses will be based on the safety analysis set, defined as all subjects who received the 
investigational device. 
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, 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 within 
each manufacturing site, C1 and HQ, separately and for the whole analysis population. 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. NLF-SRS grades per visit will be calculated as the mean of grades assigned to 

 
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the left and the right nasolabial fold, respectively. The absolute NLF-SRS change versus baseline will 
be computed by subtracting the value obtained on the corresponding visit from that obtained on Day 0 
. Absolute NLF-SRS change from baseline will be summarized by the visit using descriptive statistics 
and additionally the 95% confidence intervals of the expected change from baseline will be given. In 
addition, the proportion (with two-sided 95% confidence intervals) of subjects with NLF-SRS 
improvement (i.e., reduction on both sides in NLF-SRS grades) of ≥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. 
Summaries will be provided for the whole analysis population, as well as within each manufacturing site, 
C1 and HQ, separately. 
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. 
Summaries will be provided for the whole analysis population, as well as within each manufacturing site, 
C1 and HQ, separately and within each subgroup defined by the injection device, needle and cannula, 
respectively.  
 
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 validated 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 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) and entered in the eCRF. 
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.  
 
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 in the EDC 
and addressed to the investigator or designee. The investigator or their designee must carefully answer 
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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. 
A formal interim report will be established as described above for the final report after week 24 visits. 
 
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, the Coordinating Investigator, and the other investigators before 
implementation. 
Any amendment which may affect the validity of the data or information resulting from original CIP, the 
risk-benefit ratio for the subject, the scientific soundness of the investigation, or the rights, safety or 
welfare of subjects taking part in the investigation will also have to be reviewed and approved by the EC 
and regulatory authorities, if applicable, prior to 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. 

 
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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. 
Given the pandemic situation due to COVID-19, an increase of CIP deviations is assumed.  The conduct 
of the investigation may be affected by lockdowns, restrictions, illness or other reasons which may 
prevent the subject to visit the site and perform the assessments as defined in the CIP (e.g. missed 
visits, delayed visits, unscheduled visits, safety phone calls). COVID-19 pandemic related deviations 
from the CIP are defined separately from the other CIP deviations to allow a more accurate assessment 
and classification of PDs for this investigation. The monitor is responsible to verify the relatedness of 
CIP deviations to the COVID-19 pandemic and include it in the deviation report in case not documented 
in the eCRF.  
 
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 subject must 
then sign and date the ICF prior to the conduct of any study procedures. The consent taker (investigator) 
must sign and date the ICF as well. 
A copy of the Subject information Sheet and ICF will be given to the subjects for their records. The rights 
and welfare of the study participants will be protected by emphasizing to them that the quality of their 

 
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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 a 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. 
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: 

 
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• 
“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 
eCRF. 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. The duration of the recorded AE will cover the 
period of all intensity/seriousness levels. 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 eCRF. 
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: 
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 

 
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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 levels22: 
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. 
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.  

 
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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 eCRF must be completed. 
Any SAE must be reported by the investigator to the Medical Monitor within 24 hours of awareness of 
the event via fax. Contact details are as follows: 
 
 
 
 
 
 
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. 
 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 notified to
 within the same timelines as an SAE 
(within 24 hours after being made aware of the pregnancy) on a Pregnancy Notification Form. The 
pregnant subject should be withdrawn immediately from the clinical investigation upon confirmation. 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. 
14.8 Device deficiency reporting requirements 
All investigational medical device deficiencies will be recorded on a Device Deficiency Report Form.  

 
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Device deficiencies with SADE potential should be reported by the investigator to 
 
 within 24 hours after the site became aware of the device deficiency. Contact 
information is provided in Section 14.5. 
 will forward the deficiency with SADE potential 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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