A Prospective, Open-label, Multicentre, Randomized Study to Evaluate the Effectiveness, Safety and Long Term Safety of Saypha® FILLER Lidocaine for Lip Augmentation
Phase: NA
Conditions: Abnormal Lip
Sponsor: Croma-Pharma GmbH

 
Clinical Investigation Plan 
CPH-101-201479 
 
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Client Confidential 
 
Saypha® FILLER Lidocaine 
 
CLINICAL INVESTIGATION PLAN (CIP) 
Title of the clinical 
investigation/CIP: 
A prospective, open-label, multicentre, randomized study to evaluate 
the effectiveness, safety and long term safety of Saypha® FILLER 
Lidocaine for lip augmentation 
Short title: 
SayLip 
Investigation ID: 
CPH-101-201479 
CIP version: 
2.0 
CIP version date: 
27 JUN 2019 
Sponsor: 
Croma-Pharma GmbH 
Industriezeile 6, 2100 Leobendorf, Austria 
Phone: +43 2262 684 680; Fax: +43 2262 6846 8165 
E-mail: office@croma.at; Web: www.croma.at 
Investigation site(s): 
Up to three 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. 
 
 

 
 
CONFIDENTIAL 
 
 
 
Clinical Investigation Plan 
CPH-101-201479 
 
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Approval and signature pages 
 
Sponsor approval 
CIP identifier: CPH-101-201479 
 
 
 
 
 
 
__________________________________ 
 
 
__________________________ 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
__________________________________ 
 
 
__________________________ 
 
 
 
 
 
 
 
 
 
 
 
croma 
-

 
 
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Clinical Investigation Plan 
CPH-101-201479 
 
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Coordinating investigator agreement 
CIP identifier: CPH-101-201479 
 
I agree: 
 
To assume responsibility for the proper conduct of the clinical investigation at the site specified 
below, and to conduct the investigation in compliance with this Clinical Investigation 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 favorable opinion from the Ethics Committee, and 
approval from the Competent Authority, if applicable, except where necessary to eliminate an 
immediate hazard to the subject(s) or for administrative aspects of the clinical investigation (where 
permitted by all applicable regulatory requirements). 
 
That I am familiar with the appropriate use of the investigational medical device as described in 
this CIP and any other information provided by the Sponsor including, but not limited to, 
Investigator´s Brochure (IB) and the Instructions for Use (IFU). 
 
To ensure that all persons providing assistance during the clinical investigation are adequately 
informed about the investigational medical device and of their investigation-related duties and 
functions. 
 
That I have been informed that certain regulatory authorities require the Sponsor to obtain and 
supply details about the investigator’s ownership interest in the Sponsor or the product under 
investigation, 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: 
 
Investigation site: 
 
Address: 
 
 
 
Investigator's signature: 
 
 
 
Date: 
 
 
 
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Clinical Investigation Plan 
CPH-101-201479 
 
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Principal investigator agreement 
CIP identifier: CPH-101-201479 
I agree: 
 
To assume responsibility for the proper conduct of the clinical investigation at the site specified 
below, and to conduct the investigation in compliance with this Clinical Investigation 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 favorable opinion from the Ethics Committee, and 
approval from the Competent Authority, if applicable, except where necessary to eliminate an 
immediate hazard to the subject(s) or for administrative aspects of the clinical investigation (where 
permitted by all applicable regulatory requirements). 
 
That I am familiar with the appropriate use of the investigational medical device as described in 
this CIP and any other information provided by the Sponsor including, but not limited to, 
Investigator´s Brochure (IB) and the Instructions for Use (IFU). 
 
To ensure that all persons providing assistance during the clinical investigation are adequately 
informed about the investigational medical device and of their investigation-related duties and 
functions. 
 
That I have been informed that certain regulatory authorities require the Sponsor to obtain and 
supply details about the investigator’s ownership interest in the Sponsor or the product under 
investigation, 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: 
 
Investigation site: 
 
Address: 
 
 
 
 
 
Investigator's signature: 
 
 
 
Date: 
 
 
 
croma 

 
 
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Clinical Investigation Plan 
CPH-101-201479 
 
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Client Confidential 
Investigators and administrative structure of the clinical investigation  
 
Investigators: 
This is a multicentre clinical investigation, which will be conducted in Austria. 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.  
Other institutions: 
 
This is a contract research organization (CRO), also called Sponsor’s 
representative elsewhere in this CIP. The address and other contact details of 
Sponsor’s representative are provided on the cover page.  
Contact project management: 
 
Contact for reportable events is provided in section 14 
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 (TMF). 
 
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CONFIDENTIAL 
Synopsis 
Investigation title 
A prospective, open-label, multicentre, randomized study to evaluate 
the effectiveness, safety and long term safety of ~ha® FILLER 
Lidocaine for !le. augmentation 
Short title 
Saylip 
Investigation ID 
CPH-101-201479 
Phase of 
lnterventional 
development 
Indication 
Moderate to severe deficiency of lip volume 
PLANNED CLINICAL INVESTIGATION PERIOD 
Planned duration 
The duration of the clinical investigation will be a maximum period of 18 
months after the initial treatment for each participating subject. 
The estimated enrolment period is two to three months, hence the overall 
study duration is planned to be about 21 months. 
CLINICAL INVESTIGATION OBJECTIVES AND PURPOSE 
Objectives 
Main objectives: 
• 
To evaluate the effectiveness, safety and long-term safety of Saypha® 
FILLER Lidocaine for lip augmentation; 
• 
To assess the duration of the aesthetic effect of Saypha® FILLER 
Lidocaine for lip augmentation. 
Additional objectives: 
• 
To compare the effectiveness of Saypha® FILLER Lidocaine ('IMO-HQ' 
and 'IMD-C1 ') produced in the two different manufacturing sites ('HQ' and 
'C1'). 
• 
To compare the IMO injection techniques: 'retrograde technique' and 
'bolus technique' 
• 
To compare the injection equipment used: '27G ½" needle' versus 
cannula ('25G x 50mm cannula' or '22G x 70mm cannula') 
CLINICAL INVESTIGATION DESIGN 
Study design 
Clinical Investigation Plan 
CPH-101-201479 
This is a prospective, open-label, multicentre, randomized study. 
Eligible subjects will undergo bilateral lip augmentation treatments with 
Saypha® FILLER Lidocaine in order to correct moderate to severe 
deficiency of lip volume (defined as grade 1 to grade 3 within Lip Fullness 
Scale; LFS). 
The treatment will be administered at the Baseline visit (Day 0). 
There will be an optional touch up treatment at Week 3 after initial treatment 
in order to achieve optimal cosmetic corrections. 24 hours after each 
treatment a telephone visit will be performed for safety evaluation (Visit 1 a 
and Visit 2a in case of touch-up treatment). 
Baseline severity of lips volume deficiency will be determined at 
Screening/Baseline visit by the investigator using a validated Lip Fullness 
Scale (LFS) before the initial treatment (Visit 1/Day 0), at 6 weeks, and 6, 12 
and optional 18 months post treatment. Independent blinded photographic 
reviews of lip fullness will be performed for the same time points by using the 
LFS. A 'responder' is defined having at least 2: 1 grade improvement as 
evaluated with the 5 point-validated LFS at a given visit relative to Baseline 
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CONFIDENTIAL 
score. Individual LFS grades per visit will be calculated separately for the 
upper and the lower lip. Photos for the independent review will be taken 
before the initial treatment, at 6 weeks and 6, 12 and optional 18 months post 
initial treatment. 
Assessment of aesthetic improvement 
using the Global Aesthetic 
Improvement Scale (GAIS) and assessment of subject satisfaction using the 
Face-a™ "Satisfaction with outcome" scale and the "Satisfaction with Lips" 
scale will be performed at 6 weeks and 6, 12 and optional 18 months after 
initial treatment. 
Assessment of the aesthetic effect of Saypha® FILLER Lidocaine will be 
performed by the investigator at 6 weeks and 6, 12 and optional 18 months 
after initial treatment. 
Subject's perception of pain will be evaluated immediately after injections 
were administered and 15 minutes after each treatment. 
The safety will be evaluated based on occurrence of adverse events, which 
will be collected at each visit throughout the clinical investigation. 
SUBJECT SELECTION 
Number of 
investigation sites 
Up to 3 sites located in Austria (AT) 
Number of subjects 
Approximately 110 subjects 
Inclusion criteria 
A subject must meet ALL of the following criteria to be ELIGIBLE for the 
study: 
Exclusion criteria 
Clinical Investigation Plan 
CPH-101-201479 
1. Adult female or male subjects 18 years of age at Screening/Baseline visit 
(Visit 1) 
2. 
Presence of approximately symmetrical "very thin" lips (minimal red lip 
shows) to "moderately thick" lips (moderate red lip shows) as assessed 
with the LFS (severity grade of 1 to 3 on both lips) as determined by the 
investigator at Visit 1 
3. 
For females of childbearing potential only: negative urine pregnancy test 
at Visit 1, and must agree to use an highly effective method of 
contraception for the duration of the clinical investigation 
4. Healthy skin in the treatment area and free of diseases that could 
interfere in evaluation of treatment 
5. Willingness to abstain from any cosmetic or surgical procedures in the 
treatment area for the duration of the clinical investigation 
6. Willingness to take part in this clinical investigation documented by a 
personally signed/dated informed consent. 
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. Prior surgery, scars or tattoo to the upper or lower lip or lip line; surgery 
and tattooing are prohibited until end of clinical investigation 
5. Tooth gap, overbite, beard longer three-day beard, or excessive facial 
hair that could interfere in evaluation of treatment as judged by the 
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Clinical Investigation Plan 
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investigator 
6. Presence of any abnormal lip structure, such as a scar or lump or severe 
lip asymmetry, as judged by the investigator  
7. Previous tissue augmenting therapy in the lip area (including lips, oral 
commissures, nasolabial folds, marionette and perioral lines) with HA or 
collagen filler, or laser treatment, chemical peeling, dermabrasion or 
mesotherapy within 12 months before Visit 1 and until end of clinical 
investigation 
8. Previous permanent implant or treatment with non-HA or non-collagen 
filler in the lip area (including lips, oral commissures, nasolabial folds, 
marionette and perioral lines) and until end of the investigation 
9. Previous toxin treatment in the lip area (including lips, oral commissures, 
nasolabial folds, marionette and perioral lines) within 9 months before 
Visit 1 and until end of clinical investigation 
10. Presence of cutaneous lesions, inflammatory and/or infectious processes 
(e.g. acne, herpes, etc.) or proliferative lesions in the treatment area 
11. Known human immune deficiency virus-positive individuals 
12. History of allergies against aesthetic filling products and recurrent (3 
times a year) herpes simplex in the treated area  
13. Tendency to hypertrophic scars, keloid formation and/or pigmentation 
disorders  
14. History or presence of any autoimmune or connective tissue disease, or 
current treatment with immune therapy 
15. Uncontrolled systemic diseases (such as diabetes mellitus) 
16. Use of anticoagulant, antiplatelet or thrombolytic medication (e.g. 
acetylsalicylic acid) from 10 days pre- to three days post IMD injections  
17. Planned dental/oral surgery or modification (bridge-work, implants) within 
two weeks prior to initial IMD injection and to a minimum of four weeks 
post IMD injections 
18. Any medical condition which, in the investigator’s opinion, prohibits the 
inclusion in the study 
19. Current or previous (within 30 days of enrolment) treatment with another 
investigational drug and/or medical device or participation in another 
clinical study 
20. Previous enrolment in this clinical investigation 
21. Any dependent relationship of the subject with the investigator, 
investigation site or Sponsor (e.g. employees or relatives) 
22. 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) 
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CONFIDENTIAL 
INVESTIGATIONAL DEVICE(S), DOSE AND MODE OF ADMINISTRATION 
lnvestigational 
device and mode of 
administration 
Saypha® FILLER 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 3 mg/ml 
(0.3%) lidocaine hydrochloride. 
Saypha® FILLER Lidocaine is administered by injection into the lips. The 
volume applied depends on the size of the area which requires correction 
and will be selected by the investigator. A maximum volume of 2 ml for both 
lips in total (i.e., for upper plus lower lip) including touch up might be needed 
per treatment but the treatment should not exceed 10 ml in total per 
treatment or 20 ml per year. 
The manufacturing process of Saypha® FILLER Lidocaine established at 
Croma's manufacturing site 'Croma 1' ('C1 ') was recently implemented in 
addition in a new manufacturing facility (manufacturing site 'headquarter' 
('HQ')). No changes were done to the finished product design or 
manufacturing technology or method of sterilization. The ingredients, the 
formulation, the packaging and the finished product specifications were not 
changed. The implementation of the second manufacturing site is not 
considered to impact the safety and effectiveness of the product. 
This study will compare the IMD produced at the new manufacturing site 'HQ' 
with the IMD produced at 'C1' site. Therefore, each subject will randomly be 
assigned to one of the two IMDs ('IMD-HQ' or 'IMD-C1 ') at a 1:1 ratio. 
Treatment duration 
Maximum 18 months 
SUBJECT SELECTION 
Primary 
performance 
endpoints 
Safety endpoints 
Clinical Investigation Plan 
CPH-101-201479 
The proportion of subjects ('responders') with the lip volume improved by .:1 
point versus baseline value at 6 weeks after initial treatment based on the 
investigator live assessment using the validated Lip Fullness Scale (LFS). 
'Responder' is defined having at least .: 1 grade improvement as evaluated 
with the 5 point-validated LFS at a given visit relative to Baseline score. 
Individual LFS grades per visit will be calculated separately for the upper and 
the lower lip. 
Occurrence and frequency of adverse events 
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Secondary 
performance 
endpoints 
CONFIDENTIAL 
• 
The percentage of responders, based on the investigator live assessment 
at 6, 12 and optional 18 months after the initial treatment using the 
validated LFS. 
• 
The percentage of responders based on the independent photographic 
reviewer's assessments before initial treatment and at Week 6, Month 6, 
12 and optional Month 18 after initial treatment, based on photographs 
and using the validated LFS. 
• 
The percentage of subjects with an improvement relative to baseline 
photographs, (subjects who have been rated as "very much improved" or 
"much improved" or "improved"), based on the investigator assessment at 
Week 6, Month 6, 12 and optional Month 18 after initial treatment using 
the 5-point GAIS. 
• 
The percentage of subjects with an improvement relative to baseline 
photographs (subjects who have been rated as "very much improved" or 
"much improved" or "improved"}, based on subject assessment at Week 
6, Month 6, 12 and optional Month 18 after initial treatment, using the 5-
point GAIS. 
• 
The extent of subject's satisfaction with overall outcome of the treatment, 
at Week 6, Month 6, 12 and optional Month 18 after initial treatment, 
assessed by the subject using the F ace-Q TM Questionnaire "Satisfaction 
with Outcome". 
• 
The extent of subject's satisfaction with augmentation of lips, at Week 6, 
Month 6, 12 and optional Month 18 after initial treatment, assessed by 
the subject using the Face-Q TM Questionnaire "Satisfaction with Lips". 
• 
Subject's perception of pain after initial and touch-up treatment with 
Saypha® FILLER Lidocaine using the 11-point Numeric Pain Rating 
Scale (NPRS), where O is no pain and 10 is the worst pain imaginable. 
• 
Percentage of subjects demonstrating an aesthetic effect at Week 6, 
Month 6, 12 and optional Month 18 based on the investigator's life 
assessment. 
• 
Injection volume (initial and touch-up) required for an optimal 
augmentation of the lips with Saypha® FILLER Lidocaine. 
STATISTICAL ANALYSIS 
Sample Size 
Calculation 
Analysis Sets 
Clinical Investigation Plan 
CPH-101-201479 
The sample size calculation was made for the primary performance endpoint 
taking the overall population and the subgroups by IMD manufacturing site 
into account. 
With a sample size of 100, a two-sided 95% confidence interval for a single 
proportion using the large sample normal approximation will extend 0.059 in 
the overall population and 0.083 in the two manufacturing site subgroups 
from the observed proportion for an expected proportion of 0.900 (i.e., a 
responder rate of 90%). 
In order to cover subjects' drop-out or lost to follow-up the sample size will be 
increased by 10 %, following 110 subjects will be enrolled (with 55 subjects 
per manufacturing site). Thus, a sufficiently precise estimation of the 
percentage of responders based on the investigator's live assessment at 
Week 6 using the LFS can be derived. 
Safety Analysis Set (SAF/ 
The Safety Analysis Set (SAF) consists of all subjects who received at least 
one administration of the investigational medical device (IMD). 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) comprises all subjects who received at least one 
administration of the IMD and who had at least one post-treatment evaluation 
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Clinical Investigation Plan 
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of the LFS. 
Per-Protocol Set (PPS): 
The Per-Protocol Set (PPS) includes all subjects of the FAS who have no 
major protocol deviations. 
General Statistical 
Considerations  
All effectiveness analyses will be done in the FAS and PPS. All safety 
analyses will be based on the SAF. 
Addionally an interim analysis (IA) assessing the safety and effectiveness will 
be performed after all subjects have completed the follow-up visit at Month 6 
(Visit 4). For the interim analysis the Statistical Analysis Plan (SAP) will be 
finalized prior to the IA database lock. The IA database will be cleaned and a 
data base lock prior to export for data analysis will be done.  
Planned Statistical 
Analysis 
All statistical analyses will be done using descriptive statistics. All summary 
tables and subject data listings will be prepared by visit if applicable.  
Summary statistics (mean, standard deviation, minimum, first quartile, 
median, third quartile, and maximum) will be provided for continuous 
variables, and the number and percentage of each category will be provided 
for categorical data. If applicable and unless otherwise specified statistical 
tests will be non-parametric and 2-sided at 0.05 level of significance.  
Two-sided 95% confidence intervals for the percentages of responders and 
mean LFS improvement at various time points will be given and proportions 
for the LFS improvements of ≥1 point will be calculated. Individual LFS 
grades per visit will be calculated as the mean of grades assigned to the 
upper lip and lower lip, respectively. 
All statistical analyses including will be outlined in detail in the statistical 
analysis plan (SAP) including all aspects of the interim analysis (IA), tables, 
figures and subject data listings. Any changes in the original statistical 
methodology will be documented in the statistical analysis plan as well. 
All data collected will be presented in subject data listings. 
Subgroup Analyses 
Besides the ‘overall population’ (including all subjects enrolled in the 
investigation), the following subgroups will be analyzed descriptively for the 
primary and main secondary performance endpoints:  
 
IMD from manufacturing sites: ‘HQ’ and ‘C1’ 
 
Injection technique: ‘retrograde technique’ and ‘bolus technique’ 
 
Injection equipment: ‘27G ½″ needle’ versus cannula (‘25G x 50mm 
cannula’ or ‘22G x 70mm cannula’) 
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Schedule of procedures and events  
Table 1. Schedule of procedures and events 
Assessment 
Screening/ 
Baseline 
Telephone 
Visit 
Touch up 
Telephone 
Visit 
 
Month 6 
Month 12 
Optional††  
Month 18 
Day 0* 
24h after 
IMD 
admin.) 
Week 3 
24h after 
IMD 
admin.) 
Week 6 
Week 26 
Week 52 
Week 76 
 
± 2 days 
± 5 days 
± 7 days 
± 7 days 
± 7 days 
Visit 1  
Visit 1a 
Visit 2  
Visit 2a 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Informed consent 
x** 
 
 
 
 
 
 
 
Eligibility assessment 
x** 
 
 
 
 
 
 
 
Urine pregnancy testb 
x** 
 
 
 
x 
x 
x 
x 
Demographic dataa 
x** 
 
 
 
 
 
 
 
Medical history 
x** 
 
 
 
 
 
 
 
Photography  
x** 
 
 
 
x 
x 
x 
x 
Initial treatment 
x 
 
 
 
 
 
 
 
Touch-up treatment 
 
 
(x)† 
 
 
 
 
 
LFS  - independent photographic reviewer 
x 
 
 
 
x 
x 
x 
x 
LFS - investigator c 
x**  
 
 
 
x 
x 
x 
x 
GAIS - investigator  
 
 
 
 
x 
x 
x 
x 
GAIS - subject  
 
 
 
 
x 
x 
x 
x 
FACE-QTM “Satisfaction with outcome” - subject 
 
 
 
 
x 
x 
x 
x 
FACE-QTM “Satisfaction with lips” - subject 
 
 
 
 
x 
x 
x 
x 
Assessment of aesthetic effect - investigator 
 
 
 
 
x 
x 
x 
x 
Pain assessment e using the NPRS - subject 
x 
 
(x)† 
 
 
 
 
 
Prior and concomitant medication 
x** 
x 
x 
x 
x 
x 
x 
x 
Adverse event d 
x*** 
x§ 
x*** 
x§ 
x 
x 
x 
x 
Device deficiencies 
x 
 
(x)† 
 
 
 
 
 
 
 

 
 
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* 
Includes screening and (initial) treatment 
** 
Prior to application of the investigational device 
*** 
In order to identify potential AEs post-administration of IMD, AEs should be assessed 15 minutes after each administration (initial and touch-up treatment). 
† 
Touch-up treatment is optional (at investigator's discretion, if full correction was not achieved after initial treatment). 
†† 
The duration of the clinical investigation is planned for 18 months at a maximum and depends on the assessment of the aesthetic effect. In case it is observed by the investigator that no 
aesthetic effect is any more visible the study can be terminated at Month 12 (Visit 5) for the respective subject. 
§ 
Safety follow-up via telephone: Any adverse events since injection? In case of an AE an unscheduled on-site visit should be performed.  
a 
Includes year of birth, sex, race, and smoking status  
b 
In females of child-bearing potential only, including women who are postmenopausal for less than 12 months 
c 
Evaluated by the investigator using LFS. The upper and lower lip will be graded separately 
d 
To be collected throughout the investigation, beginning immediately after start of initial treatment until the last visit.  
e 
NPRS: Immediately and 15 minutes after initial and touch-up IMD treatment.  
Abbreviations: LFS: Lip Fullness Scale; GAIS: Global Aesthetic Improvement Scale, NPRS: Numerical Pain Rating Scale 
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List of abbreviations 
ADE 
Adverse device effect 
AE 
Adverse event 
BDDE 
1,4-butanediol diglycidyl ether 
C1 
Manufacturing site ‘Croma 1’ 
CE 
Conformité Européene (European conformity) 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRO 
Contract Research Organization 
DDVS 
Database Design Validation Specification 
DMP  
Data Management Plan 
DRM 
Data Review Meeting 
EC 
Ethics committee 
eCRF 
electronic Case Report Form 
EU 
European Union 
ExC 
Exclusion criterion 
FAS 
Full Analysis Set 
GAIS 
Global Aesthetic Improvement Scale 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HA 
Hyaluronic acid 
HQ 
Manufacturing site ‘Headquater’ 
IA 
Interim analysis  
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
IFU 
Instructions for use 
IMD 
Investigational medical device 
ISO 
International Organization for Standardization 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LFS 
Lip Fullness Scale 
MDD 
Medical Device Directive 
MedDRA 
Medical dictionary for regulatory activities 
mIU 
Milli-international unit 
mL 
Milliliter  
NLF 
Nasolabial fold 
NLF-SRS 
Nasolabial folds severity rating scale  

 
 
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Clinical Investigation Plan 
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NPRS 
Numeric Pain Rating Scale 
PPS 
Per-Protocol Set 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
TMF 
Trial master file 
USADE 
Unanticipated serious adverse device effect 
UV 
Ultraviolet 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
w/w 
Weight/weight 
 
Glossary 
Saypha® FILLER Lidocaine and Princess® FILLER Lidocaine are the same product marketed under 
different brand names in different countries. There is no difference in production, packaging and 
labelling. For the sake of simplicity the brand name of Saypha® FILLER Lidocaine will be used within 
the underlying CIP (contrary to the Investigator´s Brochure). 
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Clinical Investigation Plan 
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Table of contents 
Approval and signature pages ................................................................................................................. 2 
Coordinating investigator agreement ....................................................................................................... 3 
Investigators and administrative structure of the clinical investigation .................................................... 5 
Synopsis .................................................................................................................................................. 6 
Schedule of procedures and events ...................................................................................................... 12 
List of abbreviations ............................................................................................................................... 14 
Glossary ................................................................................................................................................. 15 
Table of contents ................................................................................................................................... 16 
List of text tables .................................................................................................................................... 19 
1 
Background .................................................................................................................................... 20 
2 
Identification and description of the investigational device ............................................................ 21 
2.1 
Device description..................................................................................................................... 21 
2.2 
Manufacturing ........................................................................................................................... 23 
2.3 
Manufacturer ............................................................................................................................. 23 
 
Saypha® FILLER Lidocaine ................................................................................................ 23 
2.3.1
 
Needles and cannulas for application.................................................................................. 23 
2.3.2
2.4 
Intended use and mode of administration ................................................................................ 23 
2.5 
Traceability ................................................................................................................................ 24 
3 
Justification for the design of the clinical investigation .................................................................. 24 
3.1 
Non-clinical data and biocompatibility ...................................................................................... 24 
3.2 
Clinical data .............................................................................................................................. 24 
3.3 
Justification for the clinical investigation ................................................................................... 25 
4 
Risks and benefits of the investigational device and clinical investigation .................................... 25 
4.1 
Anticipated clinical benefits ....................................................................................................... 25 
4.2 
Anticipated adverse device effects ........................................................................................... 25 
 
Saypha® FILLER (without lidocaine)................................................................................... 26 
4.2.1
 
Saypha® FILLER Lidocaine ................................................................................................ 27 
4.2.2
4.3 
Possible interactions with concomitant medical treatments ..................................................... 27 
4.4 
Risk mitigation strategy ............................................................................................................. 27 
4.5 
Risk-to-benefit rationale ............................................................................................................ 27 
5 
Objectives and hypotheses of the clinical investigation ................................................................. 28 
5.1 
Objectives ................................................................................................................................. 28 
5.2 
Hypotheses ............................................................................................................................... 28 
5.3 
Claims and intended performance of the IMD to be verified .................................................... 28 
5.4 
Risks and anticipated adverse device effects that are to be assessed .................................... 28 
6 
Design of the clinical investigation ................................................................................................. 29 
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6.1 
Design description .................................................................................................................... 29 
 
Criteria for evaluation (endpoints) ....................................................................................... 30 
6.1.1
 
Randomization ..................................................................................................................... 30 
6.1.2
 
Blinding ................................................................................................................................ 31 
6.1.3
 
Discussion of clinical investigation design ........................................................................... 31 
6.1.4
6.2 
Investigational medical device (IMD) ........................................................................................ 31 
 
Packaging, labelling and storage ......................................................................................... 31 
6.2.1
 
Methods of use .................................................................................................................... 31 
6.2.2
 
Applied volume of the device ............................................................................................... 33 
6.2.3
 
Touch-up treatment ............................................................................................................. 33 
6.2.4
 
Precautions and warnings for the investigator .................................................................... 33 
6.2.5
 
Rescue medication .............................................................................................................. 34 
6.2.6
 
Investigational medical device accountability ...................................................................... 34 
6.2.7
 
Handling of deficient investigational medical devices ......................................................... 35 
6.2.8
6.3 
Subjects .................................................................................................................................... 35 
 
Number of subjects and duration of the clinical investigation ............................................. 35 
6.3.1
 
Recruitment strategy............................................................................................................ 35 
6.3.2
 
Inclusion criteria ................................................................................................................... 35 
6.3.3
 
Exclusion criteria .................................................................................................................. 36 
6.3.4
 
Withdrawal criteria and procedures ..................................................................................... 37 
6.3.5
 
Replacement of subjects ..................................................................................................... 37 
6.3.6
 
Life-style and other restrictions ............................................................................................ 37 
6.3.7
 
Prohibited medication and aesthetic treatments ................................................................. 38 
6.3.8
 
Medical care upon termination of the clinical investigation ................................................. 38 
6.3.9
 
Screening/Baseline failures and dropouts ........................................................................... 39 
6.3.10
 
Subject identification, privacy and confidentiality ................................................................ 39 
6.3.11
6.4 
Assessments and procedures .................................................................................................. 39 
 
Demographic data ............................................................................................................... 40 
6.4.1
 
Medical history and aesthetic procedures history ............................................................... 40 
6.4.2
 
Prior and concomitant medication and non-drug therapies ................................................. 40 
6.4.3
 
Pregnancy test ..................................................................................................................... 40 
6.4.4
 
Photography ........................................................................................................................ 40 
6.4.5
 
Injection volume, injection technique and injection equipment ........................................... 41 
6.4.6
 
Lip Fullness Scale (LFS) - Grading of lip  volume deficiency .............................................. 41 
6.4.7
 
Numeric Pain Rating Scale (NPRS) - Pain assessment ..................................................... 42 
6.4.8
 
Global Aesthetic Improvement Scale (GAIS) - “Aesthetic improvement” ............................ 42 
6.4.9
 
FACE-QTM Questionnaire – “Satisfaction with overall outcome” ......................................... 43 
6.4.10
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FACE-QTM Questionnaire – “Satisfaction with lips” ............................................................. 44 
6.4.11
 
Assessment of aesthetic effect ............................................................................................ 44 
6.4.12
 
Safety monitoring ................................................................................................................. 45 
6.4.13
6.5 
Schedule of procedures ............................................................................................................ 45 
 
Visit 1 -Screening / Baseline Visit - Day 0 ........................................................................... 45 
6.5.1
 
Visit 1a - Telephone Visit - Day 1 (24h after 1st injection) .................................................. 46 
6.5.2
 
Visit 2 – Week 3 (after Visit 1) ± 2 days ............................................................................... 46 
6.5.3
 
Visit 2a - Telephone Visit - Day 1 (24h after touch-up) – only in case of touch-up treatment
6.5.4
 
46 
 
Visit 3 to 6 – Week 6 to Month 18 (after Visit 1) .................................................................. 47 
6.5.5
 
Early Termination Visit ......................................................................................................... 47 
6.5.6
 
Unscheduled Visit ................................................................................................................ 47 
6.5.7
6.6 
Factors that may compromise the outcome ............................................................................. 48 
6.7 
Monitoring plan ......................................................................................................................... 48 
6.8 
Audits ........................................................................................................................................ 48 
7 
Statistical considerations ............................................................................................................... 49 
7.1 
Sample size .............................................................................................................................. 49 
7.2 
Analysed data sets.................................................................................................................... 49 
7.3 
Methods of analysis .................................................................................................................. 49 
 
Interim analysis .................................................................................................................... 50 
7.3.1
 
Final analysis ....................................................................................................................... 50 
7.3.2
 
Subject disposition ............................................................................................................... 50 
7.3.3
 
Demographics and baseline characteristics ........................................................................ 50 
7.3.4
 
Medical and aesthetic procedures history ........................................................................... 50 
7.3.5
 
Prior and concomitant medication and non-pharmacological procedures .......................... 50 
7.3.6
 
Performance endpoints ....................................................................................................... 51 
7.3.7
 
Safety endpoints .................................................................................................................. 51 
7.3.8
 
Multicentre trial .................................................................................................................... 51 
7.3.9
 
Analysis of subgroups.......................................................................................................... 51 
7.3.10
7.4 
Subject data listings .................................................................................................................. 52 
7.5 
Missing data .............................................................................................................................. 52 
7.6 
Software used for statistical analysis ........................................................................................ 52 
7.7 
Deviations from the planned statistical analysis ....................................................................... 52 
8 
Data handling and data management ............................................................................................ 52 
8.1 
Source documents and other records maintained by the investigator ..................................... 52 
8.2 
Case report forms ..................................................................................................................... 53 
8.3 
Data management procedures ................................................................................................. 53 
8.4 
Data retention ........................................................................................................................... 54 
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8.5 
Report of the clinical investigation ............................................................................................ 54 
9 
Amendments to the clinical investigation plan (CIP) ..................................................................... 54 
10 Deviations from the clinical investigation plan ............................................................................... 54 
11 Device accountability ..................................................................................................................... 55 
12 Statements of compliance.............................................................................................................. 55 
13 Informed consent process.............................................................................................................. 55 
14 Adverse events, adverse device effects and device deficiencies .................................................. 56 
14.1 
Definitions ................................................................................................................................. 56 
14.2 
Method of detecting AEs ........................................................................................................... 56 
14.3 
AE/SAE documentation ............................................................................................................ 57 
14.4 
AE assessment ......................................................................................................................... 58 
 
Seriousness ......................................................................................................................... 58 
14.4.1
 
Intensity ............................................................................................................................... 58 
14.4.2
 
Causality .............................................................................................................................. 58 
14.4.3
 
Outcome assessment .......................................................................................................... 59 
14.4.4
14.5 
AE/SAE reporting requirements and contact details ................................................................ 59 
14.6 
AE/SAE follow-up...................................................................................................................... 60 
14.7 
Foreseeable AEs and anticipated ADEs .................................................................................. 60 
14.8 
Device deficiency reporting requirements ................................................................................ 60 
14.9 
Data monitoring committee ....................................................................................................... 60 
15 Vulnerable populations .................................................................................................................. 60 
16 Suspension or premature termination of the clinical investigation................................................. 61 
17 Publication policy ........................................................................................................................... 61 
18 Bibliography ................................................................................................................................... 61 
19 Protocol Amendments .................................................................................................................... 63 
19.1 
Protocol Amendment 1 ............................................................................................................. 63 
 
List of text tables 
Table 1. Schedule of procedures and events ........................................................................................ 12 
Table 2. Main Characteristics of Saypha® Filler Lidocaine ................................................................... 22 
Table 3. Main Characteristics of single components of Saypha® FILLER Lidocaine ........................... 22 
Table 4. Adverse effects of cross-linked hyaluronic acid dermal fillers (with or without lidocaine) ....... 26 
Table 5. Croma - Lip Fullness Scale (LFS) ........................................................................................... 41 
Table 6. Global Aesthetic Improvement Scale (GAIS) .......................................................................... 42 
Table 7. FACE-QTM Questionnaire – “Satisfaction with outcome” ......................................................... 43 
Table 8. FACE-QTM Questionnaire – “Satisfaction with lips” ................................................................. 44 
 
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1 Background 
Age is the most significant factor contributing to the overall change in the appearance of an individual's 
face, including the lips, over time. Young faces tend to be convex with full lips, while aged face tends 
to be concave with flat lips.1 During aging, photo damage, hereditary factors, gravity, loss and 
displacement of fat, bone resorption and smoking contribute to loss of lip volume. Furthermore, 
genetically thin lips and cosmetic asymmetries of the lips are also issues for many persons.2,3 
Perception of age and health is critical in the judgement of attractiveness. Forming an impression in 
other humans about facial attractiveness is fast, automatic and mandatory, and impacts impressions of 
other social traits of a person with real-world consequences.4 
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-
confidence.5 Dermal fillers are widely used for facial rejuvenation and correction of deep wrinkles (e.g., 
nasolabial folds) and to increase lip volume. These treatments provide desirable aesthetic outcomes 
with minimal invasiveness and without the downtime associated with surgery.  
Hyaluronic acid 
Hyaluronic acid is a naturally occurring glycosaminoglycan that consists of repeating non-sulfated 
disaccharide units of glucuronic acid and N-acetylglucosamine. It is an essential component of the 
animal and human extracellular matrix, present in all tissues, most abundantly in the skin. Hyaluronic 
acid has a considerable water-binding capacity, and by this mechanism it increases dermal volume 
and compressibility.6 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 
fibroblasts.7 Hyaluronic acid is degraded by enzymatic depolymerization via hyaluronidases and 
oxidation by free radicals. Native chains have a short half-life of 24-48 h, which may be significantly 
extended by cross-linking of the chains. The most commonly used cross-linking agent is 1,4-
butanediol diglycidyl ether (BDDE). The cross-linked hyaluronic acid is degraded via the same 
mechanisms as native chains, but at a much slower rate, extending the clinical effect of BDDE-cross-
linked hyaluronic acid for up to one year.8 
Hyaluronic acid dermal filler for aesthetic use  
Soft tissue fillers are nowadays widely used for smoothing skin wrinkles and folds, and volumizing 
facial contours. Various fillers are available on the market, but hyaluronic acid (HA) gels are most 
popular because of their versatility, ease of administration, predictable effectiveness, safety track 
record established during decades of use, and quick subject recovery after administration.1,3 
Since the launch of the first BDDE-cross-linked hyaluronic acid dermal filler for aesthetic use in Europe 
in 1996, over 50 clinical studies have been conducted with this type of medical device, which included 
more than 9,000 subjects.8 Hyaluronic acid gels are currently considered as the gold standard for 
dermal fillers and are widely used in aesthetic dermatology for facial rejuvenation and re-contouring, 
with a remarkable track record of performance and safety.7 Over time, their use was extended to 
medical reconstructive purposes in the treatment of pathologic conditions like facial lipoatrophy, 
morphologic asymmetry of the face, and depressed scars.  
Lidocaine hydrochloride 
In order to improve the comfort of filler injections, novel formulations containing a local anaesthetic, 
lidocaine hydrochloride, have been developed to reduce procedural pain and to bypass the need for 
additional anaesthesia.9 
Lidocaine hydrochloride is a well-known local anaesthetic, which has been in clinical use for over 60 
years. It is currently one of the most widely used local anaesthetics. Lidocaine exerts its anaesthetic 
effects by blocking fast voltage-gated sodium channels in the cell membrane of postsynaptic neurons, 
which prevents depolarization and inhibits the generation and propagation of nerve impulses.10 Rapid 
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release of lidocaine from hyaluronic acid gel, allowing for fast onset of action after injection, has been 
demonstrated in vitro. 11  
When used for infiltrative anaesthesia, lidocaine hydrochloride has fast onset of action (< 2min) and 
moderate duration of effect lasting 1.5-2 h.12 Absorbed lidocaine is metabolized in the liver and 
eliminated via the kidneys with a half-life of around 90 minutes.13 Lidocaine is generally well tolerated 
and safe. Adverse reactions are rare and usually result from high plasma concentrations due to 
accidental intravascular injection, excessive dosage (>400 mg), or rapid absorption from highly 
vascular areas. Early symptoms of toxicity include a metallic taste, tinnitus, light-headedness and 
confusion, and may be followed by tremors, shivering, seizures and, ultimately, respiratory arrest. 
Cardiovascular toxicity may be manifested by hypotension, bradycardia, arrhythmia and cardiac 
arrest.12, 13  
In soft tissue fillers the addition of lidocaine hydrochloride reduces pain and distress and provides a 
more comfortable injection experience.14 The performance and safety of hyaluronic acid dermal fillers 
supplemented with lidocaine hydrochloride have been studied in several randomized clinical trials, 
which were mostly designed as split face trials, where the same dermal filler was administered with 
and without ancillary lidocaine. A detailed analysis of nine randomized clinical trials with the equivalent 
devices 
 has confirmed a statistically significant reduction in pain 
with formulations which contained lidocaine. The pain reduction was consistent across the studies, and 
present irrespective of the dermal filler tested. The frequency and severity of adverse events (AEs) 
was not different for dermal fillers with or without lidocaine, indicating no incremental safety risk.15, 11 
2 Identification and description of the investigational device 
Please refer to the Saypha® FILLER Lidocaine Investigator’s brochure (IB11) for detailed information 
on the investigational device. Saypha® FILLER Lidocaine and Princess® FILLER Lidocaine are the 
same product marketed under different brand names in different countries. There is no difference in 
production, packaging and labelling. For the sake of simplicity the brand name of Saypha® FILLER 
Lidocaine will be used within the underlying CIP (contrary to the IB). 
In this study Saypha® FILLER Lidocaine from two different manufacturing sites will be used and 
analyzed (IMD-HQ and IMD-C1, see section 2.2 for details). As the device from both manufacturing 
sites do not differ they are described in the following sections in one consolidated description. 
2.1 
Device description 
Saypha® FILLER Lidocaine is conceived for medical purposes and aims to address reconstructive 
purposes in the treatment, for instance, of facial lipoatrophy, debilitating scars or morphological 
asymmetry and increase lip volume. The device received the CE mark in 2016 allowing device sales in 
European Union (EU). The chemical, physical and biological properties of Saypha® FILLER Lidocaine 
were extensively characterized during development (see sections 4 and 5 of the IB11 for details). 
Compliance with general requirements defined in EN ISO 14630A was demonstrated.  
Saypha® FILLER Lidocaine was classified as an implantable medical device in permanent contact 
with tissues or bones according to EN ISO 10993-1B. Hence, cytotoxicity, acute, repeated dose and 
subchronic systemic toxicity, local effects after implantation, sensitization, irritation, pyrogenicity and 
genotoxicity of Saypha® Filler Lidocaine were evaluated in vitro and in vivo in biocompatibility studies. 
All of the studies were conducted under GLPC principles and results are described in section 5.1 of the 
IB.  
Table 2 shows the components and main characteristics of Saypha® Filler Lidocaine and Table 3 
tabulates the single components of Saypha® Filler Lidocaine.  
 
                                                     
A EN ISO 14630: Non-active surgical implants — General requirements 
B EN ISO 10993-1: Biological evaluation of medical devices — Part 1: Evaluation and testing 
C GLP: Good Laboratory Practice 
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Table 2. Main Characteristics of Saypha® Filler Lidocaine 
Components of Saypha® Filler Lidocaine 
 23 mg/mLin a physiologic buffer (phosphate buffer pH 6.7–7.3 q.s., sodium chloride) 
 3 mg/g [0.3%] lidocaine hydrochloride 
Description of Saypha® FILLER Lidocaine 
 is a class III medical device incorporating the ancillary medicinal substance lidocaine hydrochloride as an integral part 
 is a sterile, biodegradable, viscoelastic, clear, isotonic and homogenized injectable gel implant (pre-filled in 1 mL glass 
syringes) 
 is designed for single use and must not be re-sterilized 
 has an anticipated lifetime up to nine months after treatment 
In this investigation, Saypha® FILLER Lidocaine is administered by injection into the lips. The volume to be injected per lip 
depends on the size of the area which requires correction and will be selected by the investigator. A maximum volume of 2 
mL for both lips in total (i.e., for upper plus lower lip) might be needed per treatment (i.e., initial treatment and touch-up 
treatment, respectively)23 but should not exceed the maximum recommended volume of 10 mL per treatment session and 20 
mL per year (also refer to section 6.2). 
 
Table 3. Main Characteristics of single components of Saypha® FILLER Lidocaine 
Component 
Concentration 
Description 
Hyaluronic acid (HA) 
23 mg/g  
 
HA, a natural polysaccharide, is obtained from Streptococcus equi 
bacteria is cross-linked using BDDED.  
 
BDDE covalently binds native HA molecules to each other with 
repeating bridges, creating a polymer ‘network’, transforming the 
viscous liquid into a gel.  
 
Compared with native HA, the highly crosslinked HA gel is 
considerably more resistant against enzymatic and free radical 
breakdown, so that its tissue residence time is dramatically 
increased.  
 
Native HA is added in order to adjust the rheological properties and 
injectability of the fillers.  
 
HA is a natural component of human skin, hence the IMD is naturally 
absorbed. 
Lidocaine hydrochloride  
3 mg/g  
[0.3% w/w] 
 
Lidocaine hydrochloride (a medicinal product) is a well-known local 
anesthetic; it is added to Saypha® FILLER Lidocaine as an ancillary 
substance for reduction of procedural pain. and to improve the 
comfort of filler injections thus bypassing the need for additional 
anaesthesia;  
 
Lidocaine hydrochloride is rapidly released from the implant and 
quickly eliminated from the body, with a half-life of around 
90 minutes.13 
 
 
                                                     
D BDDE: 1,4-butanediol diglycidyl ether 
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2.2 
Manufacturing 
Saypha® FILLER Lidocaine is manufactured in compliance with several Regulatory Requirements 
including GMPE (see section 4.1.3 and section 10 of the IB11). The device is manufactured under clean 
room conditions in compliance with EN ISO 14644-1F. No materials of human or animal origin are used 
during manufacture or as raw materials; moreover, the use of non-animal origin substances 
theoretically reduces any potential for hypersensitivity. 
The manufacturing process of Saypha® FILLER Lidocaine established at the current Croma’s facility 
(‘C1’) was additionally implemented in a new manufacturing site (‘HQ’ = Headquater). Different 
process parameters were adapted and optimized during the transfer. While most production 
equipment was newly implemented to reflect the latest state of the art technology and to allow an 
upscaling of the manufacturing processes, the principle of the manufacturing process and sterilization 
were maintained. No changes were done to the finished product design or manufacturing technology 
or method of sterilization. The ingredients, the formulation, the packaging and the finished product 
specifications were not changed. Of note, the material used at the new manufacturing site ‘HQ’ is not 
CE-certified.  
In this study, IMD from both manufacturing sites (‘C1’ and ‘HQ’) will be used and subjects will be 
randomly assigned in a 1:1 ration to IMD-C1 or IMD-HQ, respectively.  
2.3 
Manufacturer 
 
Saypha® FILLER Lidocaine 
2.3.1
 
Design, manufacturing, primary packaging, secondary packaging, labelling inspection, final 
inspection, moist heat sterilization and release of the device are undertaken at the facilities ‘C1’ 
(Beautyplant, Industriezeile 6, 2100 Leobendorf, Austria) and ‘HQ’ (Croma-Pharma GmbH, 
Cromazeile 2, 2100 Leobendorf) in accordance with EN ISO 13485G and Good Manufacturing 
Practice (GMP).  
 
The device contains the medicinal substance lidocaine hydrochloride as an ancillary substance. 
 
Needles and cannulas for application 
2.3.2
 
The device is delivered with two sterile single use needles (27G ½’’) per syringe; the needles are 
Ethylene oxide sterilised and are medical devices according to their field of application, under 
class IIa (MDD 93/42/EEC, Annex IX, rule 6). The CE-Manufacturer is 
 
 
 
Additionally, cannulas are provided with the investigational device. The cannulas are 25G x 50mm 
and 22G x 70mm.  
2.4 
Intended use and mode of administration 
Saypha® FILLER Lidocaine is a soft tissue filler, approved for use in adults (EU: 18 years and older) 
for the correction of moderate to severe facial wrinkles and folds and to increase lip volume, and for 
medical reconstructive purposes in the treatment of, e.g., facial lipoatrophy, debilitating scars, or 
morphological asymmetry of the face.16 
The device is designed to be injected into the submucosa of the lips. The amount injected depends on 
the size of the area to be corrected and the desired level of soft tissue augmentation. A maximum 
volume of 2 mL for both lips in total (i.e., for upper plus lower lip) might be needed per treatment23, but 
should not exceed 10 mL per treatment session and 20 mL per year.  
                                                     
E GMP: Guideline for Good Manufacturing Practice for Pharmaceutical products 
F EN ISO 14644-1: Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness 
G EN ISO 13485: Medical devices — Quality management systems — Requirements for regulatory purposes 
 
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In the present clinical investigation, Saypha® FILLER Lidocaine will be used for correction of volume 
deficiency of the lips. 
2.5 
Traceability 
Each kit of Saypha® FILLER Lidocaine is identified and tracked by its batch number (lot number). A 
set of two labels showing the batch number is situated at the bottom of each box. One of these labels 
should be attached to the subject’s medical record. The investigational medical device is labelled 
according to applicable guidelines and national legal requirements. 
3 Justification for the design of the clinical investigation 
3.1 
Non-clinical data and biocompatibility 
Nonclinical biocompatibility studies have been conducted with Saypha® FILLER Lidocaine in vitro and 
in vivo.  
Toxicity potential (including genotoxicity, see IB11 sections 5.1.1, 5.1.2 and 5.1.6 to 5.19) of Saypha® 
FILLER Lidocaine were investigated by adding device extracts to cell cultures, by intradermal 
administration in rabbits and guinea pigs and by intraperitoneal administration of device extracts/final 
product in rats and mice. No acute toxicity was evident in an acute systemic toxicity study in mice, in 
repeated dose systemic toxicity and subchronic systemic toxicity studies in rats. A panel of three 
genotoxicity studies showed Saypha® FILLER Lidocaine to be non-genotoxic. The device was shown 
to be non-pyrogenic. 
The tolerability of Saypha® FILLER Lidocaine was tested by implanting the device into intradermal 
tissue of rabbits (see IB section 5.13). Skin sensitization was perforemd in guinea pigs (see IB 
section 5.1.4) The potential to produce irritation following intracutaneous injection of Saypha® FILLER 
Lidocaine was evalutated in albino New Zealand White rabbits (see IB section 5.1.5). According to 
these nonclinical safety studies, Saypha® FILLER Lidocaine was observed to be biocompatible and is 
expected to be well-tolerated. The device was classified as non-irritant and a non-sensitizer. For 
details refer to the IB (section 5).  
3.2 
Clinical data 
Saypha® Filler Lidocaine is an implantable class III medical device. Clinical data is available for 
Saypha® FILLER Lidocaine from one investigation (FINO trial; see below). However, clinical data is 
available for Saypha® FILLER, which is virtually the same dermal filler but without lidocaine.  
A post-market clinical follow-up study (FLASH 1; CPH-410-201259) with Saypha® FILLER (without 
lidocaine) showed that the treatment was safe, well tolerated and efficacious in the treatment of facial 
lipoatrophy, morphological asymmetry and debilitating scars (53 subjects overall). It confirmed the 
effectiveness of the investigational device over a six-month period. The treatment outcome was 
declared highly successful by subjects, investigators and independent reviewer. There were no SAEs 
observed, and only few adverse device effects (ADEs) were recorded during the investigation (see 
section 4.2.1 for details on safety); all ADEs were limited to the injection site, apart from two events of 
headache, and have already been described in the literature as common adverse effects of 
crosslinked hyaluronic acid dermal fillers (see section 4.2). For details on this investigation refer to 
section 6.2.1 of the IB.11 
Saypha® FILLER Lidocaine obtained the CE mark in 2016. Since its first market entry in 2016 up to 
the end of June 2018, 205,714 units of Saypha® FILLER Lidocaine have been released. The 
complaint ratio of 0.0112% confirms the favourable benefit/risk ratio of the device.11 
FINO (CPH-401-201324) was a prospective, open-label, multicentre, post-market study evaluating the 
performance and safety of Saypha® FILLER Lidocaine for the correction of nasolabial folds (NLF). 
The study including 60 subjects showed that the IMD was effective in reducing NFLs. At the primary 
endpoint (Week 24 assessment) 96.7% of the intention-to-treat subjects demonstrated ≥1 grade 
improvement in their nasolabial folds severity based on the nasolabial folds severity rating scale (NLF-
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SRS) compared with the baseline status. Saypha® FILLER Lidocaine was shown to be safe and well 
tolerated when used for correction of nasolabial folds (see section 4.2.1 for details on safety).11 
However, there are no own data for use of Saypha® FILLER Lidocaine for bilateral lip augmentation 
available yet. 
3.3 
Justification for the clinical investigation 
Saypha® FILLER Lidocaine has been approved for use in adults (EU: 18 years and older) for the 
correction of moderate to severe facial wrinkles and folds and to increase lip volume, and for medical 
reconstructive purposes in the treatment of, e.g., facial lipoatrophy, debilitating scars, or morphological 
asymmetry of the face. The current clinical investigation is designed to evaluate the effectiveness, 
safety and long-term safety of Saypha® FILLER Lidocaine for bilateral lip augmentation and to assess 
the duration of the aesthetic effect of the device.  
A prospective, open label 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 deficiency 
of lip volume, it is reasonable to assume that the treatment effect can be adequately assessed by 
comparing the post-treatment observations versus baseline, eliminating the need for a control group. 
The primary performance endpoint is based on evaluation using a 5-point scale for assessment of 
deficiency of lip volume validated Lip Fullness Scale (LFS) and is set at six weeks after initial 
administration of the device to address the minimum required durability of effect. Follow-up is, 
however, extended to 18 months at a maximum, to get additional information on long-term effects. In 
case it is observed by the investigator that no aesthetic effect is any more visible the study can be 
terminated after 12 months. 
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 
Approximately 110 subjects will be included in this investigation to have 100 evaluable subjects. This 
sample size is considered sufficient to provide robust estimations on performance and safety 
parameters in the underlying overall study population as well as the IMD manufacturing site subgroups 
(subjects will be randomized 1:1 to IMD from either site 'C1' ('IMD-C1') or site 'HQ' ('IMD-HQ')). 
4 Risks and benefits of the investigational device and clinical investigation 
4.1 
Anticipated clinical benefits 
The treatment with Saypha® FILLER Lidocaine may remove or reduce a distressing aesthetic defect 
in subjects with volume deficiency of lips (“very thin” lip shows to “moderately thick” lip shows, see 
section 6.4.7), 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 anticipated to last up to nine months after treatment. 
4.2 
 Anticipated adverse device effects 
The safety profile of BDDE-cross-linked hyaluronic acid dermal fillers, with or without lidocaine, is well 
established. In general, these devices are well tolerated and safe, with a low frequency of side 
effects.18 Adverse effects that have been observed with devices similar to Saypha® FILLER Lidocaine 
are summarized in Table 4. 
Additional information on AEs, especially serious events like arterial occlusion and necrosis is provided 
in the IB.11 Physicians must inform the subject that there are potential side effects and/or 
incompatibilities associated with implantation of this device, which may occur immediately or may be 
delayed.  
 
 
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Table 4. Adverse effects of cross-linked hyaluronic acid dermal fillers (with or without lidocaine) 
Commonly reported treatment 
related AEs  
(also refer to Section 8.2.1 of the IB) 
Rare AEs 
(also refer to Section 8.2.2 of the IB) 
Very rare SAEs (device related) 
(refer to Section 8.2.3 of the IB) 
 Redness 
 Erythema 
 Swelling 
 Edema 
 Pain 
 Itching 
 Tenderness  
 Bruising 
 Hematoma 
 Bleeding 
 Abscess* 
 Angioedema* (antibody-mediated 
edema) 
 Bacterial infections 
 Burning 
 Beading, lumpiness 
 Discomfort 
 Discoloration 
 Dispigmentation  
 Delayed erythema* 
 Firmness  
 Granuloma 
 Herpes reactivation* 
 Hypersensitivity 
 Induration 
 Implant visibility, implant site mass, 
mass formation, migration 
 Inflammation 
 Irritation 
 Nodules* (inflammatory and non-
inflammatory) 
 Malar edema* 
 Numbness 
 Paresthesia* 
 Puncture marks 
 Scar sarcoidosis 
 Scleromyxedema (generalized) 
 Teleangiectasia  
 Vasculitis  
 Vasospasm 
 Vasovagal reaction during injection 
 Vascular Compromise/Arterial 
Occlusion† 
 Retinal artery / vein occlusion† 
 Necrosis† 
 
These events are typically managed 
with the application of ice. 
These events are typically mild in 
intensity and should resolve within 
one to two days after injection. 
 
These very rare device-related serious 
adverse events (SADEs) have been 
reported after use with similar HA 
dermal fillers. 
 
* for more details refer to Section 
8.2.2 of the IB 
† for more details refer to Section 8.2.3 
of the IB 
 
Saypha® FILLER (without lidocaine) 
4.2.1
Saypha® Filler (without lidocaine) obtained the CE mark in 2008. FLASH1 (CPH-410-201259) was a 
post-market clinical follow-up study evaluating performance, tolerability and safety of Saypha® FILLER 
for the correction of facial lipoatrophy, morphological asymmetry or debilitating scars. A total of 53 
subjects were split up into the three study indications: facial lipoatrophy (23 subjects), morphological 
asymmetry (17 subjects) and debilitating scars (13 subjects). A total of 13 AEs were documented in 
eleven subjects (20.8%). Neither deaths, nor other serious AEs (SAEs) occurred during the 
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investigation. Out of these 13 AEs, seven AEs (in 9.4% of the subjects, n=5) were classified as ADE, 
all being classified as procedure-related and four additionally as investigational device-related. There 
were three cases of injection site hematoma, two events of injection site pain and two events of 
headache. All ADEs were assessed as of mild (42.9% of ADEs) or moderate (57.1% of ADEs) severity 
and had been resolved at the end of the clinical investigation.  
 
Saypha® FILLER Lidocaine 
4.2.2
Saypha® FILLER Lidocaine differs from Saypha® FILLER only by the inclusion of lidocaine and a 
slightly altered buffer formulation. 
Saypha® FILLER Lidocaine received the CE mark in 2016. Post-market surveillance data from 2016 
to end of June, 2018 confirm the safety and effectiveness of the device. Overall, more than 205,714 
units of Saypha® FILLER Lidocaine were released (complaint ratio of 0.0112%).  
FINO (CPH-401-201324) was a prospective, open label, multicentre, post-marketing clinical follow-up 
study evaluating Saypha® FILLER Lidocaine for correction of NFLs. Overall 60 subjects were 
included. 31 AEs reported by 26 subjects (43.3%) were assessed as definitely related to the procedure 
and therefore classified as ADEs. These were mostly injection site hematoma (reported in 16 
subjects), injection site pain (in 12 subjects), and injection site swelling (in 2 subjects). Reported AEs 
were mostly mild or moderate and had resolved within a maximum of 25 days of their onset. Two AEs 
were serious, of which one subject reported a severe AE (papillary thyroid gland carcinoma) and the 
other a moderate hematoma infection. However, these AEs were not related to the IMD or the 
procedure. 
4.3 
Possible interactions with concomitant medical treatments 
No studies on drug interactions with Saypha® FILLER Lidocaine have been conducted in humans. 
Anticoagulant and antiplatelet drugs may increase the risk of bleeding or bruising, so the subject 
should be asked about use of such medications (also see Exclusion Criterion (ExC) #16, section 
6.3.4). 
Sodium hyaluronate is incompatible with quaternary ammonium compounds such as benzalkonium 
chloride solutions. The device should never be placed in contact with these substances or with 
medical-surgical instruments that have been in contact with these substances. 
4.4 
Risk mitigation strategy 
The risks will be mitigated by careful selection of the subjects and exclusion of those who may have an 
increased risk of developing certain types of AEs (see section 4.2), appropriate training of the 
investigators to ensure correct application of the device, and regular follow-up visits, which will allow 
for timely recognition and management of potential AEs. Furthermore, the subjects will be instructed to 
immediately contact the investigator in case of occurrence of any AE between the scheduled visits. 
Aspiration technique will be used as injection technique, to mitigate the subject’s risk. I.e. 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 (also see section 6.2.2), 
4.5 
Risk-to-benefit rationale 
Hyaluronic acid-based dermal fillers, such as Saypha® FILLER (with and without) Lidocaine, are 
generally considered very safe and effective, and have been widely used for soft tissue augmentation 
worldwide. The benefits and risks of the clinical use of Saypha® FILLER Lidocaine were evaluated 
based on a review of relevant scientific literature and post-marketing safety data of other well 
established CE marked and FDA approved medical devices (see sections 6.1 (Data from Clinical 
Studies) and 8.2 (Adverse Events) of the IB11 for details).  
Furthermore, when using of Saypha® FILLER Lidocaine, only a very low number of product quality 
and adverse event complaints compared to the total number of devices sold have been reported since 
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its first market entry (see section 4.2.2). All adverse events mentioned above are described in the 
instructions for use16 as commonly reported after use of dermal fillers.  
Subjects in this study will be treated with IMD from 2 different manufacturing sites (see section 2.2). 
The implementation of the new manufacturing site is not considered to impact the safety and 
effectiveness of the IMD.  
Considering the potential benefits of correction, in particular the immediate and long lasting 
improvement of distressing aesthetic defect, it was concluded that the therapeutic benefits of Saypha® 
FILLER Lidocaine outweigh the potential risks. The overall residual design, manufacturing, and use 
risks, and the benefit/risk ratio of the device when used on subjects by experienced and trained 
physicians, according to the manufacturer’s instructions for use, are fully acceptable.  
5 Objectives and hypotheses of the clinical investigation 
5.1 
Objectives 
The main objectives of this investigation are: 
 
To evaluate the effectiveness, safety and long-term safety of Saypha® FILLER Lidocaine for lip 
augmentation; 
 
To assess the duration of the aesthetic effect of Saypha® FILLER Lidocaine for lip augmentation. 
Additional objectives: 
 
To compare the effectiveness of Saypha® FILLER Lidocaine (‘IMD-HQ’ and ‘IMD-C1’) produced in 
the two different manufacturing sites (‘HQ’ and ‘C1’).  
 
To compare the IMD injection techniques ‘retrograde technique’ and ‘bolus technique’ 
 
To compare the injection equipment used: ‘27G ½″ needle’ versus cannula (‘25G x 50mm cannula’ 
or ‘22G x 70mm cannula’)   
5.2 
Hypotheses 
This is a non-comparative study and does not entail formal hypothesis testing. 
5.3 
Claims and intended performance of the IMD to be verified 
Saypha® FILLER Lidocaine has recently been approved for the correction of moderate to severe facial 
wrinkles and folds and to increase lip volume.11 The approval was based on clinical experience with 
similar devices. In the meantime, more than 205,714 units of Saypha® FILLER Lidocaine were 
released and data on safety were obtained (see section 4.2.2). Besides, a prospective, open-label, 
multicentre, post-market clinical follow-up study evaluating Saypha® FILLER Lidocaine for the 
correction of nasolabial folds (FINO; CPH-401-201324) was conducted showing that Saypha® FILLER 
Lidocaine is effective in reducing nasolabial folds. Furthermore, Saypha® FILLER Lidocaine was 
shown to be safe and well tolerated. Reported AEs were mostly mild or moderate. One severe AE and 
the two reported serious AEs were not related to the IMD or the procedures. The present investigation 
is undertaken to support these claims. 
5.4 
Risks and anticipated adverse device effects that are to be assessed 
The safety profile of lidocaine-containing hyaluronic acid dermal fillers is well established. Based on 
the equivalence of Saypha® FILLER Lidocaine with these products and available non-clinical and 
clinical safety data of the IMD under investigation (as well as of Saypha® FILLER without lidocaine), it 
is anticipated that it will share the same safety profile (details described in section 4.1). All AEs and 
device deficiencies occurring during the investigation will be collected and reported. 
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6 Design of the clinical investigation 
6.1 
Design description 
This is a prospective, open-label, multicentre, randomized investigation to evaluate the effectiveness, 
safety and long-term safety of Saypha® FILLER Lidocaine for bilateral lip augmentation and to assess 
the duration of the aesthetic effect of the device. 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 comprises of six on-site visits within 18 months (76 weeks):the Screening/Baseline 
visit (Visit 1/Day 0) and 5 follow-up visits at 3 weeks (Visit 2), 6 weeks (Visit 3), 6, 12, and 18 months 
after initial treatment (Visits 4, 5 and 6). Visit 6 at Month 18 is an optional visit. In case it is observed by 
the investigator at the 12 months visit (Visit 5) that no aesthetic effect is any more visible the study can 
be terminated at Visit 5. Subjects will randomly be assigned to one of the two IMDs at a 1:1 ratio 
(‘IMD-HQ’ : ‘IMD-C1’).   
The Screening/Baseline visit (Visit 1) will entail informed consent and screening assessments as 
specified in section 6.5.1. During this visit the investigator will determine the inclusion of subjects 
based on inclusion/exclusion criteria (see sections 6.3.3 and 6.3.4).  
Eligible subjects will be randomized to one of the IMDs (‘IMD-HQ’ or ‘IMD-C1’) and undergo bilateral 
lip augmentation treatment with Saypha® FILLER Lidocaine in order to correct moderate to severe 
deficiency of lip volume at Visit 1 (Day 0). In addition to this initial treatment an optional touch-up 
treatment can be performed at Visit 2 (Week 3) in order to achieve optimal cosmetic corrections (in the 
discretion of the investigator). The injection volume will be recorded at each treatment visit (i.e., Visit 1 
and Visit 2) (see section 6.4.6). 24 hours after each treatment a telephone visit will be performed for 
safety evaluation (Visit 1a and Visit 2a in case of touch-up treatment; see sections 6.5.2 and 6.5.4). 
Baseline severity of lip volume deficiency will be determined at Visit 1 by the investigator using a 
validated 5-point Lip Fullness Scale (LFS) before the initial treatment. The LFS will be repeated 6 
weeks and 6, 12 and optional 18 months after the initial IMD treatment. Independent photographic 
reviews will be performed at the same time points using LFS on photographs (see section 6.4.7). 
Subject’s pain during treatment and recovery from treatment will be evaluated by means of a 
numerical pain rating scale (NPRS) immediately and 15 minutes after each IMD administration (see 
section 6.4.8).  
Global aesthetic improvement (GAIS) relative to baseline photographs will be evaluated by both - the 
investigator and the subject - at 6 weeks and 6, 12 and optional 18 months after initial IMD treatment 
(see section 6.4.9). 
Subject´s satisfaction with the outcome of the treatment will be assessed with the Face-QTM 
questionnaires “Satisfaction with Outcome” (see section 6.4.10) and “Satisfaction with Lips“ (see 
section 6.4.11) at 6 weeks and 6, 12 and optional 18 months after initial treatment.  
Assessment of the aesthetic effect of injection of Saypha® FILLER Lidocaine will be performed by the 
investigator at 6 weeks and 6, 12 and optional 18 months after initial treatment (see section6.4.12). 
The safety will be evaluated based on occurrence of adverse events, which will be collected at each 
visit throughout the clinical investigation, beginning immediately after start of initial treatment until the 
last visit. In order to identify potential adverse events post-administration a safety evaluation after 15 
minutes needs to take place (see section 6.4.13).  
A detailed schedule of procedures is given in section 6.5 and Table 1; Description of assessments can 
be found in section 6.4.  
 
 
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Criteria for evaluation (endpoints) 
6.1.1
Primary performance endpoints 
The performance of the investigational device will be evaluated using the following primary endpoint 
(justification is provided in section 3.3): 
 
The proportion of subjects (‘responders’) with the lip volume improved by ≥1 point versus baseline 
value at 6 weeks after initial treatment based on the investigator live assessment using the 
validated Lip Fullness Scale (LFS).  
‘Responder’ is defined having at least ≥ 1 grade improvement as evaluated with the 5 point-
validated LFS at a given visit relative to Baseline score. Individual LFS grades per visit will be 
calculated separately for the upper and the lower lip. 
Safety endpoints 
The safety of the investigational device will be evaluated using the following endpoint: 
 
Occurrence and frequency of adverse events 
Secondary performance endpoints 
 
The percentage of responders, based on the investigator live assessment at 6, 12 and optional 
18 months after the initial treatment using the validated LFS. 
 
The percentage of responders based on the independent photographic reviewer´s assessments 
before initial treatment and at Week 6, Month 6, 12 and optional Month 18 after initial treatment, 
based on photographs and using the validated LFS. 
 
The percentage of subjects with an improvement relative to baseline photographs, (subjects who 
have been rated as “very much improved” or “much improved” or “improved”), based on the 
investigator assessment at Week 6, Month 6, 12 and optional Month 18 after initial treatment using 
the 5-point GAIS. 
 
The percentage of subjects with an improvement relative to baseline photographs (subjects who 
have been rated as “very much improved” or “much improved” or “improved”), based on subject 
assessment at Week 6, Month 6, 12 and optional Month 18 after initial treatment, using the 5-point 
GAIS.  
 
The extent of subject´s satisfaction with overall outcome of the treatment, at Week 6, Month 6, 12 
and optional Month 18 after initial treatment, assessed by the subject using the Face-QTM 
Questionnaire “Satisfaction with Outcome”.  
 
The extent of subject’s satisfaction with augmentation of lips, at Week 6, Month 6, 12 and optional 
Month 18 after initial treatment, assessed by the subject using the Face-QTM Questionnaire 
“Satisfaction with Lips”.  
 
Subject’s perception of pain after initial and touch-up treatment with Saypha® FILLER Lidocaine 
using the 11-point Numeric Pain Rating Scale (NPRS), where 0 is no pain and 10 is the worst pain 
imaginable.  
 
Percentage of subjects demonstrating an aesthetic effect at Week 6, Month 6, 12 and optional 
Month 18 based on the investigator's life assessment. 
 
Injection volume (initial and touch-up) required for an optimal augmentation of the lips with 
Saypha® FILLER Lidocaine. 
 
Randomization 
6.1.2
 Subjects providing written informed consent and having met all inclusion and none of the exclusion 
criteria will be randomized in a 1:1 ratio to one of the two IMDs (either IMD from manufacturing site 
'HQ' or 'C1') (see section 2.2 for details). The site staff can perform the randomization via the eCRF 
sytem and distribute the respective IMD (‘IMD-HQ’ and ‘IMD-C1’) to the subjects accordingly.  
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Blinding 
6.1.3
Not applicable.  
 
Discussion of clinical investigation design 
6.1.4
This clinical investigation is undertaken to evaluate the effectiveness, safety and long term safety of 
Saypha® FILLER Lidocaine for lip augmentation and to assess the duration of the aesthetic effect 
after implantation.  
The primary and one of the secondary performance endpoints (see section 6.1.1) is based on the 5-
grade LFS (Lip Fullness Scale), a validated instrument for semi-quantitative assessment of lip fullness 
(see section 6.4.7). Difference of one grade on this scale is considered to be clinically meaningful 
since it can be visually recognized by various observers as demonstrated during validation of the 
scale.  
In view of multicenter conduct of the investigation, the LFS assessment will be also evaluated 
centrally, by an experienced independent photographic reviewer (see section 6.4.7). This will allow for 
unified assessment of treatment responses across the sites and checking if any bias was introduced 
by inter-observer variability between the sites.  
The clinical relevance of the investigation will be also supported by several secondary endpoints (see 
section 6.1.1), related to global aesthetic improvement (by using the GAIS) and subject’s satisfaction 
with outcome (overall and the lips by using Face-QTM scales). 
A randomization to IMD produced by one of the manufacturing sites ‘HQ’ and ‘C1’ will be done. It shall 
be shown that there is no difference in effectiveness and safety of the two IMDs between the two 
manufacturing sites. 
Safety and long term safety of Saypha® FILLER Lidocaine for lip augmentation will be monitored by 
documentation of safety parameters (AEs and device deficiencies) (see section 6.4.13).  
6.2 
Investigational medical device (IMD) 
 
Packaging, labelling and storage 
6.2.1
Each device will be provided in a folding box containing one glass syringe prefilled with 1.0 mL of the 
injectable gel implant and two 27G ½″ disposable sterile needles, and a product leaflet (Instructions for 
Use; IFU16). Additionally. cannulas (25G x 50mm and 22G x 70mm) will be provided.   
Two labels showing the batch number are attached to the boxes. One of these should be attached to 
the subject’s medical record. IMDs from the two different manufacturing sites (see section 2.2) can 
separately be identified and differentiated by investigator. The IMD is labeled according to applicable 
guidelines and national legal requirements indicating that the device is exclusively for use in a clinical 
investigation. 
The IMD must be stored in the original box, at 2-25°C (36-77 °F) in a dry place, protected from light, 
heat and frost. The shelf life of finished sterilized Saypha® FILLER Lidocaine is 24 months at the 
specified storage conditions. 
The investigator must ensure that upon receipt of the IMD and other study supplies, these are kept in 
an appropriate and secure location, with access limited to authorized individuals. 
 
Methods of use 
6.2.2
Prior to administration 
 
Prior to administration, the subjects should be evaluated for any possible contraindications or risks 
and should be informed of all possible risks and warnings associated with treatment (also refer to 
section specified in the IB11).  
 
 
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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 / cannula firmly attached. The needle / 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 
(IFU). 
Injection technique 
The IMD should be injected into the submucosa of the lips23. 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 / cannula, and just before injection, the plunger rod should be withdrawn 
slightly to aspirate and verify that the needle is not intravascular.  
The 27G ½″ needle or either 25G x 50mm cannula or 22G x 70mm cannula, which are provided with 
the kit, have to be used. A minimum of 30 subjects will be treated either with 27G ½'' needle or 
cannula (25G x 50mm or 22G x 70mm cannula). 
The technique used is essential for the success of the treatment. The following injection techniques 
should be employed based on investigator's preference and characteristics of the defect under 
correction.  
These include: 
Retrograde technique: introduction of the entire needle / cannula along the wrinkle or skin 
depression and injecting while slowly withdrawing the needle / cannula. 
Bolus technique: deposition of a small bolus just before withdrawing the needle. Placing the bolus on 
mucosa in the white portion of the lip and under the muscle is absolutely necessary. The bolus 
injections are placed subdermal from the white portion of the lip directly into the mucosa. 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 device should be injected slowly with the least 
amount of possible pressure for the same reason. 
If the needle / cannula is blocked, the pressure on the plunger rod should not be increased, but the 
injection stopped and the needle /cannula replaced.  
The injection must be stopped just before the needle / cannula is pulled out of the skin to prevent 
leakage of the device or placement too superficially in the skin. 
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.19 
In case of any other adverse event the Expert Consensus Recommendations for treatment of Soft 
Tissue Filler Complications19 should be followed in the discretion of the investigator. More details are 
provided in section 6.2.6. 
The remainder of the IMD from the same syringe after application to one lip can be used for the 
application to the other lip of the same subject at the same visit but not for any other subject or any 
other visit of the same subject. Note: If the remaining IMD from one syringe will be used for the 
application to the other lip, the injection volume for the first lip must be documented beforehand (see 
section 6.4.6).  
 
 
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Completion of administration 
After injection the investigator may apply a light massage for uniform distribution of the filler. 
Application of ice packs for 5-10 min. post injection and after subject’s pain assessment has been 
performed (see section 6.4.8) is optional and may reduce redness and swelling.   
In order to identify potential AEs (e.g., possible blanching caused by arterial occlusions) post-
administration a safety evaluation by the investigator after 15 minutes needs to take place. Therefore, 
the subject should be requested to stay on site for at least 15 minutes after the injection.  
Prior to discharge the subject should be advised to follow restrictions specified in section 6.3.7 and to 
inform their investigator as soon as possible about any unwanted event, especially inflammatory 
reactions persisting for more than one week or any other occurring secondary effect (also refer to 
section 14). 
 
Applied volume of the device 
6.2.3
Saypha® FILLER Lidocaine is administered by injection into the lips. The volume applied depends on 
the size of the area which requires correction and will be selected by the investigator. A maximum 
volume of 2 mL for both lips in total (i.e., for upper plus lower lip)23 might be needed per treatment (i.e., 
initial treatment and touch-up treatment, respectively) but the maximum recommended volume is up to 
10 mL per treatment session and up to 20 mL per subject per year; these amounts include potential 
touch-up treatments (also see section 6.4.6). 
 
Touch-up treatment 
6.2.4
A touch-up treatment may be performed at the Week 3 visit (Visit 2) at the investigator’s discretion, if 
correction is not deemed satisfactory after the first injection at Visit 1.  
If applicable, it will be documented in the subject’s records and the eCRF with the same level of details 
as the initial treatment (see section 6.4.6 for details). 
 
Precautions and warnings for the investigator 
6.2.5
Refer also to the current IB11 (esp. sections 8.1.5 and 8.1.6) and to the IFU16:  
 
The device must only be used by qualified medical healthcare personnel trained on the respective 
injection technique.  
 
The device must be injected into non-inflamed, disinfected, healthy skin.  
 
After use the syringe, needle /cannula and remaining contents should be disposed after use in a 
special container and the device shall never be re-used.  
 
The device should not be re-used; quality and sterility can only be guaranteed for a syringe in its 
original package; Re-use of the device creates potential infection risk for subjects or users.  
 
Verify the integrity of the syringe and expiry date before use. The device must not be used if the 
expiry date has lapsed, or if the packaging or contents are damaged. Syringes with an open or 
shifted tip cap within the protective packaging must not be used. In such case follow instructions 
given in section 14.8.  
 
The device should only be used with the syringe, the needle or the additionally provided cannula 
provided by the manufacturer. 
 
The needle / cannula must not be manipulated or bent. If the needle / cannula is blocked, do not 
increase the pressure on the plunger rod but stop the injection and replace the needle. Discard the 
needle /cannula in a special container 
 
There are no available clinical data (effectiveness, tolerance) about injecting the device into an 
area which has already been treated with another filling product.  
 
The device should not be injected into blood vessels, bones, tendons, ligaments, nerves, muscles 
or naevi. The treating physicians should be familiar with the face’s vascular anatomy to avoid the 
incidence of arterial inclusion.  During the pretreatment planning phase, proximity of susceptible 
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vessels to common treatment areas should be considered, being aware that anatomical location of 
blood vessels can vary between different subjects. 
 
Overcorrection should be avoided. 
 
The device should never be placed in contact with quaternary ammonium compounds (such as 
benzalkonium chloride solutions) or with medical-surgical instruments that have been in contact 
with these substances. 
 
The device shall not be used in women who are pregnant or breastfeeding (see section 6.3.7 for 
more information).  
 
Subjects should be advised to follow restrictions as given in section 6.3.7.  
 
Subjects must be advised to inform their investigator as soon as possible about any unwanted 
event. Special focus should be on inflammatory reactions persisting for more than one week or 
any other occurring secondary effect. The investigator should treat these side effects 
appropriately11 and document as AE in the subject’s medical record and in the eCRF (see section 
14 for more details).  
 
Rescue medication 
6.2.6
Any rescue medication / procedure applied should be documented in the subject´s medical record and 
in the eCRF as concomitant medication/prodcedure (see section 6.4.3).  
Use of Hyaluronidase 
In case of overcorrection or occurrence of nodules (see IB11, section 8.2.2) or vascular compromise 
(see IB, section 8.2.3), a commercially available hyaluronidase injection (e.g. 
 
, or similar) may be used at the discretion of the investigator. 
In case impending tissue necrosis, which may occur with any dermal filler, a recent consensus 
statement on the treatment of hyaluronic acid filler-induced impending necrosis recommends 
immediate treatment with high doses of hyaluronidase (e.g., at least 200 units of 
 or 
equivalent), followed by warm compress, vigorous massage and topical nitroglycerin paste. If no 
improvement is seen within 60 minutes, additional quantities of hyaluronidase should be injected (3-4 
cycles in total). An oral aspirin regimen (e.g., 650 mg per day) should help prevent further clot 
formation. Daily follow-up is advised. If no improvement or progression of necrosis is observed, the 
above regimen of hyaluronidase, nitroglycerin paste and aspirin should be repeated daily, typically for 
2-3 days.19  
In case of any other adverse event the Expert Consensus Recommendations for treatment of Soft 
Tissue Filler Complications should 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.19 
 
Investigational medical device accountability 
6.2.7
The IMD must not be used outside the context of this clinical investigation plan (CIP) and the 
Instructions for Use (IFU). The IMD must be handled in accordance with the Sponsor's instructions 
(see section 6.2.2 to 6.2.5 and refer to the current version of the IB11 / IFU16).  
Considering the number of subjects to be enrolled, the average volume of the device administered in 
the clinical investigation of Saypha® FILLER Lidocaine (maximum volume of 2 mL for both lips in 
total), and potential additional touch-up treatment, when including 110 subjects it is anticipated that up 
to 440 units (à 1 mL) of the IMD may be used during this clinical investigation. 
Documentation of receipt, dispensing/use in individual subjects, and return of IMD must be maintained 
by the investigator or his/her designee. Appropriate forms will be provided by the Sponsor or their 
representative to facilitate IMD accountability.  
At the end of the clinical investigation, all remaining supplies, including empty boxes of IMD that have 
been used, must be returned to the Sponsor for accurate destruction and accounting of the IMD.  
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Empty or used syringes will not be returned to the Sponsor, but will be destroyed by the investigation 
site, in line with their routine procedure for medical waste disposal. Used needles should be disposed 
immediately after the use as per routine procedure for medical waste disposal at the site.  
According to the underlying monitoring plan (see also section 6.7) the monitor will regularly check 
study documentation and inventory of IMDs held by the investigator to verify accountability of all 
devices used. 
 
Handling of deficient investigational medical devices 
6.2.8
Any IMD alleged to be deficient must not be used by the investigator and must be returned to the 
Sponsor. Instructions in section 14.8 must be followed.  
6.3 
Subjects 
 
Number of subjects and duration of the clinical investigation 
6.3.1
Approximately 110 subjects with moderate to severe volume deficiency of lips (defined as grade 1 
grade 3 within LFS) will be enrolled and treated with the IMD.  
Each subject will participate in the study for up to 18 months. Taking into account the anticipated 
recruitment period of 2-3 months, the total expected duration of the clinical investigation will be about 
21 months. 
 
Recruitment strategy 
6.3.2
The recruitment over the study will be competitive and will be stopped as soon as 110 subjects are 
enrolled in the study.  
The study subjects will be recruited by the investigator, among subjects who attend the investigation 
site seeking the corrective treatment of volume deficiency  of their lips.  
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. 
 
Inclusion criteria 
6.3.3
A subject must meet ALL of the following criteria to be ELIGIBLE for the study: 
1. Adult female or male subjects 18 years of age at Screening/Baseline visit (Visit 1) 
2. Presence of approximately symmetrical “very thin” lips (minimal red lip shows) to “moderately 
thick” lips (moderate red lip shows) as assessed with the LFS (severity grade of 1 to 3 on both 
lips) as determined by the investigator at Visit 1 
3. For females of childbearing potential only: negative urine pregnancy test at Visit 1, and must agree 
to use an highly effective method of contraception for the duration of the clinical investigation (see 
section 6.3.7 for details) 
4. Healthy skin in the treatment area and free of diseases that could interfere in evaluation of 
treatment 
5. Willingness to abstain from any cosmetic or surgical procedures in the treatment area for the 
duration of the clinical investigation 
6. Willingness to take part in this clinical investigation documented by a personally signed/dated 
informed consent. 
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Exclusion criteria 
6.3.4
A subject who meets ANY of the following criteria is NOT ELIGIBLE for the study and must 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)History of mental disorders or emotional 
instability 
2. History of allergic reaction or hypersensitivity to hyaluronic acid, lidocaine or any amide-based 
anaesthetic  
3. Prior surgery, scars or tattoo to the upper or lower lip or lip line; surgery and tattooing are 
prohibited until end of clinical investigation 
4. Tooth gap, overbite, beard longer three-day beard, or excessive facial hair that could interfere in 
evaluation of treatment as judged by the investigator 
5. Presence of any abnormal lip structure, such as a scar or lump or severe lip asymmetry, as judged 
by the investigator  
6. Previous tissue augmenting therapy in the lip area (including lips, oral commissures, nasolabial 
folds, marionette and perioral lines) with HA or collagen filler, or laser treatment, chemical peeling, 
dermabrasion or mesotherapy within 12 months before Visit 1 and until end of clinical investigation 
7. Previous permanent implant or treatment with non-HA or non-collagen filler in the lip area 
(including lips, oral commissures, nasolabial folds, marionette and perioral lines) and until end of 
the investigation 
8. Previous toxin treatment in the lip area (including lips, oral commissures, nasolabial folds, 
marionette and perioral lines) within 9 months before Visit 1 and until end of clinical investigation 
9. Presence of cutaneous lesions, inflammatory and/or infectious processes (e.g. acne, herpes, etc.) 
or proliferative lesions in the treatment area 
10. Known human immune deficiency virus-positive individuals 
11. History of allergies against aesthetic filling products and recurrent (3 times a year) herpes simplex 
in the treated area  
12. Tendency to hypertrophic scars, keloid formation and/or pigmentation disorders  
13. History or presence of any autoimmune or connective tissue disease, or current treatment with 
immune therapy 
14. Uncontrolled systemic diseases (such as diabetes mellitus) 
15. Use of anticoagulant, antiplatelet or thrombolytic medication (e.g. acetylsalicylic acid) from 10 days 
pre- to three days post IMD injections  
16. Planned dental/oral surgery or modification (bridge-work, implants) within two weeks prior to initial 
IMD injection and to a minimum of four weeks post IMD injections 
17. Any medical condition which, in the investigator’s opinion, prohibits the inclusion in the study 
18. Current or previous (within 30 days of enrolment) treatment with another investigational drug 
and/or medical device or participation in another clinical study 
19. Previous enrolment in this clinical investigation 
20. Any dependent relationship of the subject with the investigator, investigation site or Sponsor (e.g. 
employees or relatives) 
21. 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) 
 
 
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Withdrawal criteria and procedures 
6.3.5
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. Pregnancy 
5. 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. If the subject is unreachable, a corresponding note should be 
provided in the subject´s medical record. 
Reasons, circumstances and findings related to early withdrawal should be fully described in the 
subject's medical records and 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 Month 18 visit (Visit 6; also see section 6.5.6). In the event that the 
withdrawal is caused by an AE, the procedures stated in section 14.6 must be followed. 
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening/baseline failure” or “dropout” as specified in section 6.3.10.  
 
Replacement of subjects 
6.3.6
Subjects withdrawn from the investigation or lost for follow-up will not be replaced. No re-screening is 
allowed. 
 
Life-style and other restrictions  
6.3.7
Contraception 
The safety of Saypha® FILLER Lidocaine administration in pregnancy has not been established. Non-
clinical studies on reproductive and developmental toxicity of Saypha® FILLER Lidocaine have not 
been conducted. No studies on the effect of Saypha® FILLER Lidocaine on lactation have been 
conducted. So women of childbearing potential participation should not be pregnant and should use 
highly effective contraception or avoid unprotected sexual intercourse throughout the clinical 
investigation. Any pregnancy occurring in study subjects during the investigation (i.e., from date of ICF 
signature until the last scheduled visit) should be reported as AE and followed-up as described in 
section 14. 
Note 1: A woman is considered to be of childbearing potential (WOCBP) if fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. 
Note 2: Highly effective methods of birth control include: combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion), vasectomized partner (provided that 
is the sole sexual partner of the subject and that the vasectomized partner has received medical assessment of 
the surgical success.) or sexual abstinence (if in line with the preferred and usual lifestyle of the subject and 
defined as refraining from heterosexual intercourse during the entire period of the trial.  
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Other restrictions 
The following restrictions apply to all subjects: 
 
Make-up should not be applied for 12 hours after each IMD injection; 
 
Prolonged exposure to sunlight or ultraviolet (UV) radiation must be avoided for one week after 
each IMD injection; lip 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 each IMD injection 
(exception: a light massage may be applied after injection of the device for uniform distribution of 
the filler by the investigator – see section 6.2.2);  
 
Use of saunas or Turkish baths is prohibited for one week after each IMD injection. 
 
Beard longer three-day beard, or excessive facial hair that could interfere in evaluation of 
treatment as judged by the investigator (see ExC#5) 
 
Prohibited medication and aesthetic treatments 
6.3.8
The following medications and treatments are prohibited prior to start of the investigation and during 
the entire investigation, if not stated otherwise below (also refer to the respective ExC in section 6.3.4): 
 
Prior surgery or tattoo to the upper or lower lip or lip line (see ExC#4) 
 
Previous tissue augmenting therapy in the lip area (including lips, oral commissures, nasolabial 
folds, marionette and perioral lines) with HA or collagen filler, or laser treatment, chemical peeling, 
dermabrasion or mesotherapy within 12 months before Visit 1 (see ExC#7) 
 
Previous permanent implant or treatment with non-HA or non-collagen filler in the lip area 
(including lips, oral commissures, nasolabial folds, marionette and perioral lines) (see ExC#8) 
 
Previous toxin treatment in the lip area (including lips, oral commissures, nasolabial folds, 
marionette and perioral lines) within 9 months before Visit 1 (see ExC#9) 
 
History or presence of any autoimmune or connective tissue disease, or current treatment with 
immune therapy (see ExC#14) 
 
Anticoagulant, antiplatelet, or thrombolytic drugs (e.g. acetylsalicylic acid) from ten days pre- until 
three days after each injection of the device (see ExC#16)  
 
Planned dental/oral surgery or modification (bridge-work, implants) within two weeks prior to initial 
IMD injection and to a minimum of four weeks post IMD injections (see ExC#17) 
 
Current or previous (within 30 days of enrolment) treatment with another investigational drug 
and/or medical device or participation in another clinical study (see ExC#19) 
 
If no aesthetic effect is present anymore new injections for lip augmentation might be placed after 
3 months in general (see section 6.4.12).  
 
According to IB (see section 8.1.5) sensitive skin may be pre-treated using a local anaesthetic 
patch or cream. However, a pre-treatment with local anaesthetics is not allowed in this 
investigation to not falsify the pain assessment (as collected via Numerical Pain Rating Scale; see 
section 6.4.8). 
 
Medical care upon termination of the clinical investigation 
6.3.9
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. 
In case no aesthetic effect is present anymore new injections might be placed at previously injected 
locations after 3 months in general (see section 6.4.12). 
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 Screening/Baseline failures and dropouts 
6.3.10
Data for screening/baseline failures (eligible subjects who did not receive investigational device for 
whatever reason) will be documented in appropriate forms (e.g., Subject Screening/Enrolment Log). 
Screening data for these subjects will be kept in the Investigator’s File. The type of data to be entered 
in the eCRF, if any, will be defined in the eCRF Completion Guidelines.  
Subjects who prematurely discontinue the investigation after receiving at least one dose of the IMD will 
be defined as dropouts.  
 Subject identification, privacy and confidentiality 
6.3.11
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 
format of the codes will be defined in the eCRF Completion Guidelines. 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 medical record. 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 8.4. 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. 
Clinical photography and assessment of the independent photographic reviewer and use of 
photographs for publication purposes  
Besides assessment by the investigator on site, lip fullness will additionally be assessed by an 
independent photographic reviewer using photographs (see section 6.4.7). Subject's eyes will not 
appear on the photographs, i.e., only anonymized pictures will be sent to the independent 
photographic reviewer. Should there be attributes visible on the photographs that could identify a 
subject (e.g., characteristic scars, tattoos), the photographs will be anonymized for that purpose (i.e., 
the identifying features will be obscured by a black bar). The same applies to photographs used for 
publication purposes. However, subjects will be explicitly informed about this matter when obtaining 
written informed consent.  
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 and in section 6.5. 
It is the investigator’s obligation to assure documentation of all relevant data in the subject’s medical 
record, such as medical history and concomitant diseases, date of enrolment into the clinical 
investigation, visit dates, results of examinations, application of the IMD, and AEs. 
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Demographic data 
6.4.1
Information on subject’s year of birth, gender and race will be collected. In addition, the smoking habits 
(current, former, never smoked, unknown) will be collected. In case the subject is a current smoker 
(less than 3 months smoking cessation), the average number of cigarettes or other tobacco products 
per day must be recorded.  
All demographic data will be documented in the subject´s medical record and in the eCRF. 
 
Medical history and aesthetic procedures history 
6.4.2
Medical history will be collected at Day 0 (Visit 1) prior to application of the IMD, from subject interview 
and medical records (if available). Special attention should be paid to diseases and conditions relevant 
for exclusion criteria with particular reference to facial aesthetic or surgical procedures.  
Any medical condition that is present at Screening/Baseline prior to start of application of the IMD 
should be considered as medical history.  
Medical history findings will be documented in the subject´s medical record and in the eCRF by 
diagnosis and time of diagnosing (start date and end date, if applicable). 
If such condition, however, deteriorates after the IMD administration, at any time during the 
investigation, it should be documented as an AE (see Section 14). 
 
Prior and concomitant medication and non-drug therapies 
6.4.3
Prior medication and procedures (e.g. surgeries or aesthetic procedures) are as all medication taken 
or procedures performed within ten days (whether continuing or not) prior to Visit 1 (Day 0).  
Concomitant medication / procedure is defined as all medication taken or procedures performed from 
Visit 1 (including medication taken immediately pre-injection and post-injection of the IMD) until the 
final visit (Visit 5 or 6, if applicable).  
At each visit the subject will 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 IMD. 
Prior and concomitant medication and non-pharmacological procedure applied (e.g. surgeries or 
aesthetic procedures) will be documented in the subject’s medical record and in the eCRF classified 
by drug generic name / trade name or active substance (in case that no generic name is available). 
Prohibited concomitant medications and non-pharmacological procedure (e.g. surgeries or aesthetic 
procedures) are listed in section 6.3.7. 
 
Pregnancy test 
6.4.4
In females of childbearing potential, including women who are postmenopausal for less than twelve 
months, a urine pregnancy test will be performed using a dipstick test with sensitivity of ≤20 mLU of 
human chorionic gonadotropin per mL. The result will be recorded in the subject’s medical record and 
the eCRF. 
 
Photography 
6.4.5
Photographs of the subject´s lips will be taken by the investigator or their designee using a digital 
camera before the application of the medical device at Visit 1 (Day 0) and at each follow-up visit 
except Week 3 visit.  
A standardized procedure, which will be described in a photography manual, will be applied to ensure 
consistency of the background, camera settings, lighting, and subject position between the visits and 
across the sites. An excessive or distracting makeup (especially of the lips) has to be removed.  
A review of all photographs will be performed by an independent photography reviewer who will 
evaluate the severity of volume deficiency as described in section 6.4.7.  
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The photographs will also be used for the investigator´s and subject´s assessment of aesthetic 
improvement using the Global Aesthetic Improvement Scale (GAIS) (see section 6.4.9). 
 
Injection volume, injection technique and injection equipment 
6.4.6
The actual injection volume (initial and touch-up) required for an optimal augmentation of lips with 
Saypha® FILLER Lidocaine will be documented separately for upper and lower lips in the subject´s 
medical record and the in eCRF. The volume injected into each lip will be read off the syringe by the 
investigator. The actual volume injected will be read of the device by the investigator and recorded in 
the eCRF, together with information on injection technique (i.e., retrograde technique or bolus 
technique), the injection equipment used (i.e., needle or cannula), area of application, date, and exact 
start time and end time of injection. 
 
Lip Fullness Scale (LFS) - Grading of lip  volume deficiency 
6.4.7
Lip Fullness Scale (LFS) is a validated 5-point rating scale ranging from Grade 1 (minimal) to Grade 
5 (very significant) as outlined in Table 5. The upper and lower lip will be separately graded, and the 
assigned grades will be recorded in the subject’s record and the eCRF. 
Table 5. Croma - Lip Fullness Scale (LFS) 
Croma LFS - 
grade  
1 (Minimal) 
2 (Slight) 
3 (Moderately 
thick) 
4 (Thick) 
5 (Full) 
Description 
Minimal red lip 
shows  
Flat contour. 
Slight red lip 
shows 
May have minimal 
lip pout or nearly 
flat contour 
 
Moderate red lip 
shows 
May have slight lip 
pout 
 
Significant red lip 
shows 
May have 
moderate or 
significant lip pout 
or may be curved. 
Very significant 
red lip shows  
May have 
significant/very 
significant lip pout 
or may be very 
curved 
Visual guide 
 
Investigator 
The severity of volume deficiency of the lips will be evaluated by the investigator according to the LFS.  
At the Visit 1 (Day 0) the LFS grading will be performed before the IMD treatment, and the grade 
assigned at this visit will represent the baseline value for derivation of the responder status. Subjects 
can be included only if Inclusion criterion #2 is met (refer to 6.3.3).  
The LFS grading results of the investigator will be recorded in the subject´s medical record and in the 
eCRF.  
 
 
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Independent photographic reviewer 
The severity of volume deficiency will additionally be assessed by an independent photographic 
reviewer using LFS on photographs.  
This assessment is performed after the photo has been uploaded. The independent photographic 
reviewer will be dislocated from the investigation sites and will not discuss any findings with the 
investigators during the trial. Further details will be described in a separate manual.  
 
Numeric Pain Rating Scale (NPRS) - Pain assessment 
6.4.8
After initial administration and touch-up treatment of the IMD, 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 
imaginable.17 
Pain intensity will be assessed twice, immediately after injection, and approximately 15 minutes 
thereafter, by asking the subject one of the following questions, as appropriate: 
 
“How would you rate the pain you have felt during the treatment, if “0” is no pain at all, and “10” is 
the worst pain you can imagine?” 
 
“How would you rate the pain you have felt during recovery from the treatment, if “0” is no pain at 
all, and “10” is the worst pain you can imagine?” 
Subject’s response will be recorded on the Pain Assessment Form. The subject will be provided with 
the appropriate questionnaire in local language.  
Completed subject’s Pain Assessment Form will be considered as source documents and archived in 
the subject’s medical record. The results will be transferred into 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 
according to the procedures described in section 14.  
 
Global Aesthetic Improvement Scale (GAIS) - “Aesthetic improvement” 
6.4.9
The aesthetic improvement after correction of hypotroph lips will be independently evaluated by the 
investigator and the subject using the Global Aesthetic Improvement Scale (GAIS)20, a widely-used 
instrument presented in Table 6. The upper and lower lip will be graded separately. 
Table 6. Global Aesthetic Improvement Scale (GAIS) 
Category 
Description 
Very much improved 
Optimal aesthetic result for the implant in this patient. 
Much improved 
Marked improvement in appearance from the initial condition, but not completely optimal for this 
patient. A Touch-up would slightly improve the result.  
Improved 
Obvious improvement in appearance from the initial condition, but a Touch-up or retreatment is 
indicated. 
No change 
The appearance is essentially the same as the original condition. 
Worse 
The appearance is worse than the original condition. 
Investigator 
The investigator will perform live assessment and will evaluate the aesthetic improvement against 
subject’s photographs obtained at the Visit 1 (Day 0). Results will be recorded in the subject´s medical 
record and in the eCRF.  
 
 
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Subject 
For subject’s assessment, the subject will get the GAIS Questionnaire Form and review the 
photographs taken at the current and the Baseline visit. The subject will be asked to evaluate the 
aesthetic improvement by comparing the appearance on current photographs against Visit 1 (Day 0).  
The assessment will be done at the beginning of the visit (but after clinical photography was 
conducted) to avoid potential influence of investigator’s comments on subject’s perception of 
improvement. The investigator´s answer should not be disclosed to the subject prior to his/her 
assessment to avoid potential influence. 
The subject will be provided with the appropriate questionnaire in local language.  
Completed subject’s GAIS Questionnaire Forms will be considered as source documents and archived 
in the subject’s medical record. The results will be transferred into the eCRF.  
 FACE-QTM Questionnaire – “Satisfaction with overall outcome” 
6.4.10
Subject’s satisfaction with the treatment will be assessed using the FACE-QTM Questionnaire 
“Satisfaction with Outcome” (Patient experience scale: Outcome) in order to evaluate the performance 
of the device and consistency in alignment with subject expectation. 
The questionnaire is a validated instrument for evaluation of subject´s satisfaction with the overall 
outcome of the treatment.21 It comprises 6 positively worded items that ask the subjects to indicate 
how they feel about the result of their most recent facial aesthetic procedure.  
Four response options are provided (i.e., definitely agree, somewhat agree, somewhat disagree, and 
definitely disagree). For each statement, the subject may circle only one answer. The upper and lower 
lip will NOT be graded separately. The scale is described in Table 7 below. 
The subject will be provided with the appropriate questionnaire in local language.  
The assessment should preferably be conducted at the beginning of the visit to avoid potential 
influence of subject’s perception of improvement by investigator’s comments. 
Completed questionnaires will be considered as a source documents and archived in the subject’s 
medical records. The results will be transferred into the eCRF.  
 
 
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 FACE-QTM Questionnaire – “Satisfaction with lips” 
6.4.11
Subject’s satisfaction with lips will be evaluated using the respective FACE-QTM Questionnaire 
(Appearance appraisal scale: Lips).  
The questionnaire is a validated instrument for evaluation of subject´s satisfaction with lips. It 
comprises 10 items.This scale measures the appearance of the lips with items that ask about size, 
shape and fullness, as well as how their lips suit their face and how the lips look when smiling.  
Four response options are provided (i.e., answers very dissatisfied, somewhat dissatisfied, somewhat 
satisfied, very satisfied). For each statement, the subject may circle only one answer. The upper and 
lower lip will NOT be graded separately.The scale is described in Table 8 below. 
 
The subject will be provided with the appropriate questionnaire in local language.  
The assessment should preferably be conducted at the beginning of the visit to avoid potential 
influence of subject’s perception of improvement by investigator’s comments. 
Completed questionnaires will be considered as a source documents and archived in the subject’s 
medical records. The results will be transferred into the eCRF.  
 Assessment of aesthetic effect 
6.4.12
At each follow-up visit, the investigator will evaluate the aesthetic effect. The presence of an aesthetic 
effect at a given visit relative to baseline will be recorded as either „YES“ or „NO“ in the subject´s 
medical record and in the eCRF.  
The duration of the clinical investigation is planned for 18 months at a maximum and depends on the 
assessment of the aesthetic effect. In case it is observed by the investigator that no aesthetic effect is 
any more visible the study can be terminated at Month 12 (Visit 5) for the respective subject.  
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If no aesthetic effect is present anymore new injections for lip augmentation might be placed at 
previously injected locations after 3 months in general.  
 Safety monitoring 
6.4.13
The safety of the subjects will be monitored throughout the investigation, from Visit 1 (Day 0) 
beginning immediately after start of initial treatment until the final visit (Visit 5 or 6, if applicable).  
At visits IMD will be applied, special focus will be paid on potential AEs occuring within 15 min after 
each IMD application.  
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. Special focus should be on inflammatory 
reactions persisting for more than one week or any other occurring secondary effect.  
Device deficiencies will be documented as well at each IMD treatment.  
The procedure for collection, recording and reporting of AEs and device deficiencies is described in 
section 14. 
6.5 
Schedule of procedures 
The “schedule of procedures and assessments” in Table 1 gives an overview of study procedures 
during study conduct. The following sections tabulate the procedures to be performed by visit.  
 
Visit 1 -Screening / Baseline Visit - Day 0  
6.5.1
 
Assessments prior to IMD administration:  
o 
Provide subject information / Obtain written informed consent (see section 13) 
o 
Assign the subject number (see eCRF Completion Guidelines) 
o 
Collect demographic data (see section 6.4.1) 
o 
Record medical history (including information on prior facial aesthetic or surgical 
procedures) (see section 6.4.2) 
o 
Record prior and concomitant medication and procedures (see section 6.4.3)  
o 
Review and evaluate inclusion/exclusion criteria (see section 6.3.3 and 6.3.41) 
including wash out periods for prohibited treatment (see section 6.3.7)  
o 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) 
o 
Instruct female subjects of childbearing potential about highly effective methods of 
contraception (see section 6.3.7) 
o 
Perform photography (see section 6.4.5) 
o 
Lips fullness assessment (LFS) – investigator (see section 6.4.7) 
o 
Lips fullness assessment (LFS) – independent photographic reviewer; Note: This 
assessment is performed after the photo has been uploaded (see section 6.4.7).  
 
IMD administration:  
o 
see Section 6.2 for detailed instructions for injection  
o 
Document information on injection (see section 6.4.6) 
o 
Place the one peel-off label of the outer carton box in the subject´s medical record and 
provide the other label to the subject to ensure traceability of the device (see 
section 2.5) 
 
Pain assessment (during treatment) using the NPRS by subject immediately after IMD 
administration (see section 6.4.8) 
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 
Pain assessment (during recovery from treatment) using the NPRS by subject 15 min after 
administration of the IMD (see section 6.4.8) 
 
Record AEs from beginning of the first IMD administration procedure onwards (see section 14):  
o 
The subject should be kept at the investigation site and observed for at least 15 min 
after IMD administration in order to identify potential AEs post-administration 
o 
Special focus should be laid on inflammatory reactions persisting for more than one 
week or any other occurring secondary effect (see section 6.4.13).  
 
Advise the subject prior to discharge to follow restrictions specified in section 6.3.7 and to inform 
the investigator especially about inflammatory reactions persisting for more than one week or any 
other occurring secondary effect (see section 6.4.13). 
 
Record any device deficiencies (see section 14.8) 
 
Visit 1a - Telephone Visit - Day 1 (24h after 1st injection) 
6.5.2
 
Ask for any changes in AEs and new AEs (see section 14)  
 
Ask for changes in concomitant medication and procedures (see section 6.4.3) 
In case of an AE an unscheduled on-site visit should be performed (see section 6.5.7).  
 
Visit 2 – Week 3 (after Visit 1) ± 2 days 
6.5.3
 
Record any new AE or changes of AEs (see section 14) with special focus on inflammatory 
reactions persisting for more than one week or any other occurring secondary effect (see section 
6.4.13).  
 
Record changes in concomitant medication and procedures (see section 6.4.3) 
Optional Touch-up IMD administration (see Section 6.2):  
The touch-up treatment is optional and will be conducted at investigator's discretion, if full correction 
was not achieved after initial IMD treatment (i.e., at Visit 1). If the investigator decides to conduct a 
touch-up treatment, the following assessments must be conducted for the respective subjects:  
 
Document information on injection (see section 6.4.6) 
 
Place the one peel-off label of the outer carton box in the subject´s medical record (see section 
2.5) 
 
Pain assessment (during treatment) using the NPRS by subject immediately after IMD 
administration (see section 6.4.8) 
 
Pain assessment (during recovery from treatment) using the NPRS by subject 15 min after 
administration of the IMD (see section 6.4.8) 
 
The subject should be kept at the investigation site and observed for at least 15 min after IMD 
administration in order to identify potential AEs post-administration 
 
Re-advise the subject prior to discharge to follow restrictions specified in section 6.3.7 and to 
inform the investigator especially about inflammatory reactions persisting for more than one week 
or any other occurring secondary effect (see section 6.4.13). 
 
Record any device deficiencies (see section 14.8) 
 
Visit 2a - Telephone Visit - Day 1 (24h after touch-up) – only in case of touch-up 
6.5.4
treatment 
 
Ask for any changes in AEs and new AEs (see section 14)  
 
Ask for changes in concomitant medication and procedures (see section 6.4.3) 
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In case of an AE an unscheduled on-site visit should be performed (see section 6.5.7).  
 
Visit 3 to 6 – Week 6 to Month 18 (after Visit 1)  
6.5.5
Through the follow-up phase of the investigation the following visits will be performed: 
 
Visit 3 – Week 6 (± 5 d) after Visit 1 
 
Visit 4 – Month 6 / Week 26 (± 7 d) after Visit 1 
 
Visit 5 – Month 12 / Week 52 (± 7 d) after Visit 1 
 
Visit 6 – Month 18 / Week 76 (± 7 d) after Visit 1 – optional  
 
The following assessment will be performed through these follow-up visits:  
 
Record any new AE or changes of AEs (see section 14) 
 
Record changes in concomitant medication and procedures (see section 6.4.3) 
 
Women of child-bearing potential: Urine dipstick pregnancy test (see section 6.4.4) 
 
Lips fullness assessment (LFS) – investigator (see section 6.4.7) 
 
Lips fullness assessment (LFS) – independent photographic reviewer; Note: This assessment is 
performed after the photo has been uploaded (see section 6.4.7).  
 
GAIS assessment – investigator (see section 6.4.8) 
 
GAIS assessment – subject (see section 6.4.8) 
 
FACE-QTM – Satisfaction with overall outcome of treatment (see section 6.4.10) 
 
FACE-QTM – Satisfaction with lips (see section 6.4.11) 
 
Assessment of aesthetic effect (see section 6.4.12). In case it is observed by the investigator that 
no aesthetic effect is any more visible the study can be terminated at Month 12 (Visit 5) for the 
respective subject; otherwise a visit for optional Month 18 (Visit 6) should be scheduled. 
 
Early Termination Visit 
6.5.6
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 6.5.5).  
For safety reasons, the following assessments are recommended to be completed at a minimum:  
 
Record any new AE or changes of AEs (see section 14) 
 
Record changes in concomitant medication and procedures (see section 6.4.3) 
 
Lips fullness assessment (LFS) – investigator (see section 6.4.7) 
 
Unscheduled Visit  
6.5.7
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. Special 
focus should be on inflammatory reactions persisting for more than one week or any other occurring 
secondary effect. The investigator should treat these side effects appropriately.19   
In case the unscheduled visit results in early termination of the subject, the assessments for the Early 
Termination Visit should be performed (see section 6.5.6). Details of the event are to be recorded in 
the subject’s records and in the eCRF.  
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6.6 
Factors that may compromise the outcome 
There are no foreseeable factors that may significantly compromise the outcome. Subject eligibility 
criteria and prohibition of concomitant medications and aesthetic procedures that may affect the 
outcome are carefully defined.  
A substantial body weight change could possibly affect the results in individual subjects. Since this is 
an interventional post-market investigation, designed to mimic a real-life situation, this random and 
relatively rare event that can either improve or deteriorate the outcome will not be controlled.  
It is possible that women will prevail in the study population, but this reflects common clinical practice. 
6.7 
Monitoring plan 
The conduct of this clinical investigation will be monitored by the Sponsor’s representative, who will 
appoint one or more monitors. 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, the eCRF and other investigation-related documents and forms with the investigator and their 
staff, and verify that all prerequisites for the initiation are met. No subject should be enrolled into the 
investigation before this site initiation visit.  
During the investigation, further monitoring visits will be performed according to ISO 14155:2011, the 
applicable standard operating procedures, and local regulations. At each visit the monitor will check 
the progress of enrolment, will review source data for adherence to the CIP, review eCRFs against 
source data for completeness, accuracy and consistency, and will also check if the IMD have been 
stored, dispensed and accounted for according to respective specifications.  
The monitor will inform the investigator or their authorized designee on any error in the eCRF and will 
ensure that appropriate data corrections or clarifications are made in appropriate manner. In case of 
any other observed default, the monitor will inform the investigator and, when appropriate, the Sponsor 
as well. The monitor will discuss and agree with the investigator suitable corrective actions, and will 
follow-up their implementation.  
Upon completion of the investigation, the monitor will ensure that all investigator’s records are 
accurate and complete, all documents needed for the Sponsor’s files are retrieved, the remaining 
investigation supplies, including the IMD, are disposed of, and that all previously identified issues have 
been resolved. 
The investigator and their institution must permit the monitoring of the investigation, and must provide 
the monitor a direct access to those portions of the subject’s medical records, which directly concern 
this clinical investigation. Furthermore, key personnel at the site involved in the investigation must be 
available to assist the monitor during the monitoring visits. 
6.8 
Audits 
The investigator will permit study related audits, EC review, and regulatory inspections, providing 
direct access to source data / documents. 
Audits of the clinical investigation may be conducted by the Sponsor or external organizations 
designated by the Sponsor to evaluate compliance with the CIP, written procedures, ISO 14155:2011 
and the applicable regulatory requirements.  
A visit may be arranged by the Sponsor or Sponsor’s representative in order to audit the investigation 
site and the investigation documents, which originate there. The auditor(s) will usually be accompanied 
by the monitor or the project manager. The investigator will be informed about the outcome of the 
audit. 
In addition, inspections by health authority representatives, including foreign authorities, are possible 
at any time. The investigator should notify the Sponsor and/or Sponsor’s representative
 
of any such inspection immediately. 
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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 
Confidence Interval calculation has been performed for the primary performance endpoint “The 
proportion of subjects ('responders') with the lip volume improved by ≥1 point versus baseline value at 
6 weeks after initial treatment based on the investigator live assessment using a validated Lip Fullness 
Scale (LFS)”. A responder is defined having at least ≥ 1 grade improvement compared to baseline 
values on the 5 point-validate lip fullness scale” (see section 6.1.1). 
Approximately 110 subjects with moderate to severe volume deficiency of lips will be enrolled in order 
to obtain performance and safety data.  
This sample size is arbitrarily selected and is considered sufficient to provide robust estimations on 
performance and safety parameters in the overall study population and in the subgroups regarding 
IMD manufacturing site. With a sample size of 100 a two-sided 95% confidence interval for a single 
proportion using the large sample normal approximation will extend by 0.059 in the overall population 
and 0.083 in the two manufacturing site subgroups  from the observed proportion for an expected 
proportion of 0.900 (i.e., responder rate of 90%; calculated with nQuery Advanced 8.2.1.0). In order to 
cover subjects’ drop-out or lost to follow-up the sample size will be increased by 10%. 110 subjects will 
be enrolled (with 55 subjects per manufacturing site). Thus, a robust estimation of the success rate at 
week 6 can be derived. 
7.2 
Analysed data sets 
Safety Analysis Set (SAF)  
The Safety Analysis Set (SAF) consists of all subjects who received at least one administration of the 
investigational medical device (IMD).  
Full Analysis Set (FAS)  
The Full Analysis Set (FAS) comprises all subjects who received at least one administration of the IMD 
and who had at least one post-treatment evaluation of the LFS. 
Per-Protocol Set (PPS): 
The Per-Protocol Set (PPS) includes all subjects of the FAS who have no major protocol deviations. 
Subjects with major protocol deviations will be excluded from the PPS. For this purpose, protocol 
deviations that could interfere with the objectives of the study, use of prohibited concomitant 
medications/procedures or deviation of the inclusion/exclusion criteria etc. will be assessed as ‘minor’ 
or ‘major’ in collaboration with the sponsor in the Data Review Meeting (DRM). The criteria for this 
assessment will be defined before analysis in the SAP. Listings will be prepared to assess the 
eligibility of all subjects during the DRM.  
All safety analyses will be based on the SAF. The primary data set for effectiveness analysis will be 
the FAS and PPS. Certain sensitivity analyses may be also done in the PPS.  
7.3 
Methods of analysis 
All statistical analyses will be done using descriptive statistics. All summary tables and subject data 
listings will be prepared by visit if applicable.  
Summary statistics (mean, standard deviation, minimum, first quartile, median, third quartile, and 
maximum) will be provided for continuous variables, and the number and percentage of each category 
will be provided for categorical data. If applicable and unless otherwise specified statistical tests will be 
non-parametric and 2-sided at 0.05 level of significance.  
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Two-sided 95% confidence intervals for the percentages of responders and mean LFS improvement at 
various time points will be given and proportions for the LFS improvements of ≥1 point will be 
calculated. Individual LFS grades per visit will be calculated as the mean of grades assigned to the 
upper lip and lower lip, respectively. 
All statistical analyses including will be outlined in detail in the SAP including all aspects of the interim 
analysis (IA), tables, figures and subject data listings. Any changes in the original statistical 
methodology will be documented in the SAP as well. 
All data collected will be presented in subject data listings. 
 
Interim analysis  
7.3.1
An interim analysis (IA) assessing the safety and effectiveness will be performed after all subjects 
have completed the follow-up visit at Month 6 (Visit 4). Summary tables and subject data listings will 
be provided for the SAF and the FAS and all variables that are outlined in detail in the IA section of the 
final SAP. The SAP has to be finalized prior to the IA database lock. The IA database will be cleaned 
and a data base lock prior to export for data analysis will be done. The interim analysis will be done on 
the ‘overall population’ (see section 7.3.10 for more information). 
 
Final analysis 
7.3.2
Final analysis will be done after completion of the investigation by all subjects. All primary, secondary 
and safety endpoints will be tabulated by visit, if applicable, and summarized using descriptive 
statistics only. The final analysis will be done for the ‘overall population’ and for several defined 
subgroups (see section 7.3.10 for more information).  
 
Subject disposition  
7.3.3
Summary tables will be provided for the following subject characteristics: 
 
Number of subjects, both screened and received at least one administration of IMD, included in 
the study. 
 
Number of subjects by visit.  
 
Number of subjects included in the SAF, FAS and PPS. 
 
Number of subjects withdrawn from the study and the reason for withdrawal 
Subjects who prematurely discontinue the investigation after receiving at least one dose of the IMD will 
be defined as dropouts, see section 6.3.10. 
 
Demographics and baseline characteristics  
7.3.4
Summary statistics for demographic and baseline characteristics, including age, gender, race, and 
other relevant study entry criteria will be prepared for the SAF. 
 
Medical and aesthetic procedures history  
7.3.5
Medical history and aesthetic procedures history will be encoded using the Medical Dictionary for 
Regulatory Activities (MedDRA) system. These data will be presented for the SAF using frequency 
tables. 
 
Prior and concomitant medication and non-pharmacological procedures 
7.3.6
Prior and concomitant medication / non-pharmacological procedures will be coded using the World 
Health Organization (WHO) Drug Dictionary. All recorded medication for the SAF will be presented in 
subject data listings according to anatomical area, therapeutic area and preferred term. 
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Performance endpoints 
7.3.7
As two lips of each subject will be considered, there are two measurements per subject for LFS. 
Differences between the lips are expected, thus both measurements will be separately used for 
analyses.  
Individual LFS grades per visit will be calculated separately to the upper and the lower lip, respectively. 
The absolute LFS change versus baseline will be computed by subtracting the value obtained on Day 
0 from that of the corresponding visit. Absolute LFS change from baseline will be summarized by the 
visit using descriptive statistics. In addition, the proportion of the LFS change values ≥1 and its 95% 
confidence interval will be calculated. 
Individual GAIS grades, subjects’ satisfaction with the overall outcome of the treatment, subject’s 
satisfaction with augmentation of lips, the pain ratings, investigator´s evaluation of aesthetic effect and 
the injection volume (initial and touch-up) will be summarized and tabulated by visit using descriptive 
statistics. 
 
Safety endpoints 
7.3.8
AEs will be coded by the 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.  
Urine pregnancy tests will be listed only. All other safety data will be statistically summarized for all 
subjects dosed (SAF). 
 
Multicentre trial 
7.3.9
This study will take place in up to three investigation sites, however, due to the limited number of 
subjects no site stratification is planned. 
 Analysis of subgroups 
7.3.10
Besides the ‘overall population’ (including all subjects enrolled in the investigation), which includes all 
enrolled subjects, the following subgroups will descriptively be analyzed:  
 
IMD from manufacturing sites: ‘HQ’ and ‘C1’ 
In this study, IMD from two different manufacturing sites (‘C1’ and ‘HQ’) will be used and 
subjects will be randomly assigned in a 1:1 ratio to ‘IMD-C1’ or ‘IMD-HQ’, respectively.  
This subgroup analysis will compare both IMDs (‘IMD-HQ’ or ‘IMD-C1’) and separately analyze 
the results for the ‘IMD-C1’ and ‘IMD-HQ’ subgroups. 
 
Injection technique: ‘retrograde technique’ and ‘bolus technique’ 
It is planned to descriptively analyze the performance of the IMD separated by injection 
technique.  
The corresponding subgroup analysis will separately analyze the results for subjects treated 
with the two different injections techniques.     
 
Injection equipment: ‘27G ½″ needle’ versus cannula (‘25G x 50mm cannula’ or ‘22G x 
70mm cannula’) 
It is planned to analyze the performance of the IMD separately for the injection equipment used 
(27G ½″ needle versus cannula (25G x 50mm cannula or 22G x 70mm cannula)). Therefore it is 
planned to treat a minimum of 30 subjects either with needle or cannula (25G x 50mm cannula 
or 22G x 70mm cannula). 
The corresponding subgroup analysis will separately analyze the results for subjects treated by 
means of the different injection equipment. 
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All subgroup analyses are planned to be performed for the primary performance endpoint and the 
main secondary performance endpoints.  
The following secondary performance endpoints are planned to be analyzed:  
 
The percentage of responders, based on the investigator live assessment at 6, 12 and optional 
18 months after the initial treatment using the validated LFS. 
 
The percentage of responders based on the independent photographic reviewer´s assessments 
before initial treatment and at Week 6, Month 6, 12 and optional Month 18 after initial treatment, 
based on photographs and using the validated LFS. 
 
The percentage of subjects with an improvement relative to baseline photographs, (subjects who 
have been rated as “very much improved” or “much improved” or “improved”), based on the 
investigator assessment at Week 6, Month 6, 12 and optional Month 18 after initial treatment using 
the 5-point GAIS. 
 
The percentage of subjects with an improvement relative to baseline photographs (subjects who 
have been rated as “very much improved” or “much improved” or “improved”), based on subject 
assessment at Week 6, Month 6, 12 and optional Month 18 after initial treatment, using the 5-point 
GAIS.  
 
Subject’s perception of pain after initial and touch-up treatment with Saypha® FILLER Lidocaine 
using the 11-point Numeric Pain Rating Scale (NPRS), where 0 is no pain and 10 is the worst pain 
imaginable.  
7.4 
Subject data listings 
All recorded data will be presented in subject data listings. 
7.5 
Missing data 
Adverse events with unknown onset times will be counted as post IMD administration AEs. AEs with 
missing relationship to IMD will be counted as related AEs (ADEs). 
In addition, there will be no imputation of missing values. All data will be analyzed as they appear in 
the data base. 
7.6 
Software used for statistical analysis 
The SAS software version 9.4 or higher will be used for the statistical analysis and for the reporting of 
this study. 
7.7 
Deviations from the planned statistical analysis 
Any deviations from the planned statistical analysis have to be discussed in the final study report and 
should be defined in the SAP. If the deviation has any impact on the effectiveness analysis, the 
deviation has to be specified in an amendment to the CIP. 
8 Data handling and data management  
8.1 
Source documents and other records maintained by the investigator 
It is the investigators’ obligation to assure documentation of all relevant data in the subject’s medical 
record, such as the dates of informed consent and enrolment into the clinical investigation, medical 
history, prior and concomitant medications, visit dates, clinical observations including AEs (incl. 
reporting and follow-up of AEs), results of all assessments including clinical photographs, information 
related to medical device application, and the date of subject’s exit from the investigation, including the 
reason. 
Any form completed by the subject is also considered as a source document and must be kept in the 
subject’s medical record.  
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In addition, the investigator must maintain all other essential documents pertaining to the clinical 
investigation as defined by ISO 14155:2011 and applicable regulatory requirements. 
8.2 
Case report forms 
A CRF will be completed for each subject enrolled in the investigation who received the investigational 
device. Data on each subject enrolled in the investigation will be recorded pseudonymously in the 
web-based validated electronic CRF (eCRF), which is designed to accommodate the specific features 
of the clinical investigation design and complies with regulatory requirements on electronic data 
transfer.  
The investigator and their authorized designees only are allowed to make entries in the eCRF. This will 
be regulated by appropriate read and write access. Completed eCRFs will be electronically signed by 
the investigator or their authorized designee.  
For the formal interim analysis (see section 8.3), the addition of a second eSignature page will be for 
the Investigator agreeing and confirming that all clinical data recorded through the Month 6 visit is 
correct and accurate. This page will be associated only with the Screening/Baseline through Month 6 
pages (but not with the pages documenting AEs, medical history, prior and concomitant medications 
and procedures; the ability of the last visits to be entered will not be restricted). Once signed, no 
changes can be made without stripping the eSignature. 
Any subsequent change, deletion or addition will be recorded by an audit trail system, which will 
require re-signing of the eCRF by the Investigator or their authorized designee. The investigator must 
assure that all data are entered promptly, completely, and accurately according to the eCRF 
instructions, and is ultimately responsible for conformance of eCRF entries with source documents. 
8.3 
Data management procedures 
All data management activities will be conducted by the Sponsor's representative following their 
standard operating procedures. They will build the database and handle the data cleaning process, 
including logical checks, medical checks, and query process. Details on data handling and data 
cleaning will be described in the Data Management Plan (DMP).  
Procedures for verification, validation and securing of electronic clinical data systems  
The database application development occurs on a validated clinical data management system. The 
validation requirement for a database is satisfied through the following components:  
 
The data entry screen testing and edit check testing serve as evidence of a database that 
performs for its intended use of capturing and cleaning of clinical data.  
 
The User Acceptance Testing Plan serves as the summary of the testing documenting the 
validation process, findings and resolutions. 
 
All validation is performed on the project development/test environment of the database which is 
an exact replica of the production database, reserved primarily for testing. 
Procedures for Data Cleaning  
Computerized validated check programs on completeness, correctness, plausibility (such as range 
checks, cross-checks, edit checks) will verify the data according to the listing of all planned 
programmed data integrity checks, the Database Design Validation Specification (DDVS). All identified 
discrepancies will be queried and addressed to the investigator. The investigator or their designee 
must carefully answer any query issued by Data Management.  
Upon completion of data collection and all data cleaning activities, i.e., when the database is 
considered complete and accurate, it is considered soft locked and reviewed by the Sponsor together 
with the clinical investigation team during the Data Review Meeting. The database will be hard locked 
after Sponsor’s approval. All changes will be tracked by audit trail. Once hard locked the final clean 
datasets will be exported for final statistical analysis.  
 
 
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Interim analysis 
An interim analysis (IA) assessing the safety and effectiveness will be performed after all subjects  
have completed the follow-up visit at Month 6 (Visit 4). For the interim analysis the database will be 
cleaned and a data base lock prior to export for data analysis will be done.  
8.4 
Data retention 
The investigator shall retain all clinical investigation records (including all individual subject-related 
documents (e.g., subject´s questionnaires and ICF), device-related records, investigation-related 
correspondence, and all other documents contained in the Investigator’s File) 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, or the time period 
specified in the contract between the Sponsor and the investigator, whichever is longer. In any case, 
the investigator must contact the Sponsor in writing prior to destruction of any records pertaining to the 
clinical investigation, to get confirmation that these no longer need to be retained. In addition, the 
Sponsor should be informed in writing if the investigator plans to leave the site or chooses to store the 
records at a different physical address than the site address, to ensure traceability of the records and 
appropriate arrangements for the transfer of custody. 
The medical records of subjects taking part in the investigation must be retained in accordance with 
local legislation and the maximum period permitted by the hospital, institution or private practice. 
8.5 
Report of the clinical investigation 
Following completion of the clinical investigation, the results will be evaluated, and the Clinical 
Investigation Report (CIR) 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 relevant authorities as appropriate, within the 
timeframes defined per national regulation or to the Ethics committee (EC).  
After the interim analysis an interim Report will be generated. 
9 Amendments to the clinical investigation plan (CIP) 
Any change of this CIP can only be made in form of a written amendment. Such amendment must be 
discussed, agreed upon and signed by the Sponsor and the investigator 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, change of the principal 
investigator 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 with impact on procedures to be performed, risk-benefit ratio for the subject and/or the 
well-being of the subjects require additional informed consent, which must 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 favourable opinion of the EC if the rights, safety and well-being of human subjects need 
to be protected. Such deviations will be documented and reported to the Sponsor and the EC as soon 
as possible in accordance with national regulations. 
All CIP deviations will be listed and their impact on evaluability of respective subjects will be discussed 
in a data review meeting prior to the hard data base lock. 
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11 Device accountability 
Investigational medical device accountability is described in section 6.2.7. 
12 Statements of compliance 
This clinical investigation will be conducted in compliance with this 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 EU regulations and national medical device laws. 
By acting in accordance with this CIP, the investigators and the investigation site personnel fulfil the 
requirements of the International Standard ISO 14155:2011. 
The clinical investigation will not commence until a favorable opinion from the respective ECH 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. 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. They also must be informed that the quality of their medical care will not be adversely 
affected if they decline to participate in the investigation or in case of subsequent consent withdrawal. 
Before consenting, the subject must be left with ample time to consider and ask questions.  
The subject must then sign and date the Informed Consent Form (ICF) prior to the conduct of any 
investigation-related procedures. The consent taker (the investigator or, according to local laws, their 
designee) must sign and date the ICF as well.  
The investigator will document in the subject´s medical record and the eCRF that s/he has informed 
the subject and that the subject and the investigator have signed the ICF. A signed and dated copy of 
the ICF will be given to the subject for their records. The other copy of the signed and dated ICF will 
remain in the Investigator´s File.  
If subject’s participation in the investigation or decision to participate in the investigation is or may be 
affected by amendment to the CIP (e.g. a change in any procedure), the ICF must be amended 
accordingly, and the subject must sign the amended ICF indicating that they re-consent to participate 
in the clinical investigation. 
                                                     
H The Ethics Committee (EC) is an independent body whose responsibility it is to review clinical investigations in order to protect 
the rights, safety and well-being of human subjects participating in a clinical investigation. For the purposes of this CIP, “ethics 
committee” is synonymous with “research ethics committee”, “independent ethics committee” or “institutional review board”. The 
regulatory requirements pertaining to ethics committees or similar institutions vary by country or region (also see 
ISO14155:2011, section 3.18). 
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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 IMD. 
 
For subjects taking part in the clinical investigation 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 IMD. 
Adverse Device Effect (ADE): is an AE related to the use of the IMD. 
 
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 IMD. 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 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; 
 
Foetal distress, foetal death, a congenital abnormality or birth defect. 
Planned hospitalization for pre-existing condition or a procedure required by the CIP without a serious 
Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the consequences 
characteristic of an SAE. 
Unanticipated Serious Adverse Device Effect (USADE) is defined as an SADE which by its nature, 
incidence, severity or outcome has not been identified in the current version of the Investigator´s 
Brochure (IB). 
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 observation and by asking the subject about the occurrence of 
AEs. Care should be taken not to introduce bias when eliciting AE information from the subject. 
Open-ended and non-leading verbal questioning is the preferred method and appropriate questions 
include: 
 
“How are you feeling?” 
 
“Have you had any medical problems since your last visit/contact?” 
 
“Have you taken any new medication since your last visit/contact?” 
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In order to identify potential AEs post-administration of IMD (initial treatment and touch-up treatment) a 
safety evaluation 15 minutes after the IMD administration needs to take place (see section 6.4.13).  
To avoid over-reporting of pain, a non-leading question „How do you feel?“ should be asked prior to 
pain assessment via NPRS at Visit 1 and – if applicable – at Visit 2 (see section 6.4.8). Spontaneously 
reported pain, or pain graded ≥4 during or after treatment will be recorded as an AE according to the 
procedures described in section.  
In addition, the subjects will be instructed to immediately contact the investigator/investigation site in 
case of occurrence of any untoward event between visits and an unscheduled visit will be performed 
(see section 6.5.7). Special focus should be on inflammatory reactions persisting for more than one 
week or any other occurring secondary effect. The investigator should treat these side effects 
appropriately.19  
Throughout the entire investigation the investigator should also verify results of all assessments with 
respect to possible AEs.  
14.3 AE/SAE documentation 
For each AE the following must be reported:  
 
Description of the event (event term) 
 
Seriousness  
 
Start date, including start time for events occurring on the day of IMD administration 
 
Intensity 
 
Action taken (none, medical and/or surgical) 
 
Outcome 
 
End date (if applicable) 
 
The relationship to the IMD and procedure, respectively 
The information will be documented in subject´s medical record and in the eCRF. 
Each AE has to be documented, even if the investigator feels that it is not connected with the IMD or 
procedure.  
The AE will be described in precise, standard medical terminology. The investigator will attempt to 
establish a diagnosis of the event based on signs, symptoms, and/or other clinical information 
(including affected body site(s)). In such cases, the diagnosis will be documented as the AE and not 
the individual signs/symptoms. In case of any local reaction the exact location (e.g., upper or lower 
lips) should be clearly noted. 
Each AE should be reported separately. The investigator will record all AEs in subject´s (medical) 
record and on the ”Adverse Events” page of the eCRF. For SAEs, the “Serious Adverse Event 
Reporting Form” must also be completed. Complete description of all AEs should be also available in 
source documents of the subject.  
Adverse events will be documented beginning immediately after start of initial treatment until the last 
visit. Events occurring after provision of informed consent and prior to start of application of the IMD 
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. If such condition, however, 
deteriorates after the IMD administration, at any time during the investigation, it should be reported as 
an AE.  
If the intensity or seriousness of an AE changes over time, the most severe intensity or seriousness of 
the AE will be recorded and included in the analysis. No separate AEs will be recorded for each 
intensity level.  
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Changes in causality assessment should also be clearly documented. AEs related to the IMD as well 
as to investiation procedure must be documented. Any medication and non-pharmacological 
procedure necessary for the therapy of an AE must be recorded on the respective page of the eCRF. 
Adverse events in users or other persons 
 
For any AE in users or other persons the Adverse Event (AE) Documentation Form for Users / 
Other Persons must be completed according to the Instructions for Completion.  
 
If the AE fulfills one of the criteria for seriousness the SAE Report Form must be completed, 
additionally and reporting responsibilities have to be fulfilled (see section 14.5).  
 
If the AE is related to a device deficiency, the corresponding Device Deficiency Form has to be 
completed, too (see section 14.8).  
14.4 AE assessment 
All AEs will be assessed in terms of seriousness, intensity, relationship to the IMD or clinical 
investigation procedures, and outcome. 
 Seriousness 
14.4.1
The seriousness of an AE is assessed by comparing AE features against the SAE definition provided 
in section 14.1. 
 Intensity 
14.4.2
The intensity of an AE 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. 
 Causality  
14.4.3
The investigator is obligated to estimate the relationship between each AE/SAE and the IMD or clinical 
investigation procedure. Clinical judgement should be used and relevant documents like Instructions 
for Use or Investigators Brochure 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 levels: 22 
Definite: 
The AE/SAE is associated with the IMD 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 IMD 
use/application or procedures; involves a body-site or organ that the IMD or 
procedures are applied to or have an effect on; follows a known response pattern 
to the IMD (if the response pattern is previously known); the discontinuation of 
IMD 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 IMD seems relevant and/or the event cannot 
be reasonably explained by another cause, but additional information may be 
obtained. 
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Possible: 
The relationship with the use of the IMD 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 IMD 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 IMD 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 IMD or 
the procedures; does not follow a known response pattern to the IMD (if the 
response pattern is previously known) and is biologically implausible; the 
discontinuation of IMD 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 IMD 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. 
For the final analysis all AEs assessed with the relationship “unrelated” or “unlikely” will be classified 
as “not related” and AEs assessed with “possible”, “probable” or “definite” will be classified as 
“related”. 
 Outcome assessment 
14.4.4
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. 
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 Sponsor’s representative within 24 hours of 
awareness of the event via Email. Contact details are as follows: 
  
  
 
 
 
 
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This also applies to any significant AE, which in the investigator’s opinion could affect the safety of the 
subjects taking part in the investigation or the conduct of the investigation. 
Information about an SAE will be collected and recorded on the SAE Reporting 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 until the SAE has resolved or, in the case of permanent 
impairment, until the SAE has stabilized. Any pregnancy must be notified to the contact given above 
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. 
The Sponsor’s representative will inform the Sponsor about any SAEs without undue delay after 
receipt of the respective SAE report from the investigator.  
At the end of the clinical investigation, a reconciliation of all reported SAEs will take place and be 
enclosed as a list in the Clinical Investigation Report.  
Reporting to ECs and regulatory authorities will follow pertinent national legislation. 
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 subject’s last day of the clinical investigation at the site, whichever 
occurs first. 
Any pregnancy must be followed-up until the pregnancy outcome. If it is still on-going at the end of the 
clinical investigation, follow-up will be continued outside of the context of clinical investigation and 
pregnancy outcome (including pregnancy duration and health status of a newborn or cause of 
premature termination, as applicable) will be reported to the Sponsor. 
All SAEs judged to be related to the IMD (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.  
14.8 Device deficiency reporting requirements 
All IMD deficiencies will be recorded on a Device Deficiency Reporting Form.  
Device deficiencies should be reported by the investigator to the Sponsor’s representative within 
24 hours after the site became aware of the deficiency using the same contact as for SAEs (see 
section 14.5). 
The Sponsor’s representative will forward the Device Deficiency Reporting Form 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 (see section 
14.4) and reporting procedures (see section 14.5) must be adhered to as well. 
14.9 Data monitoring committee 
Not applicable. 
15 Vulnerable populations 
Vulnerable populations will not be included in this clinical investigation. 
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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 within a time 
period specified in the contract between the sponsor and the investigator 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 within a time period specified in the contract between the 
sponsor and the investigator after receipt of the manuscript or abstract.  
18 Bibliography 
1. 
Sjerobabski-Masnec I, Situm M. Skin aging. Acta clinica Croatica. 2010;49(4):515-8. 
2. 
Luthra A. Shaping Lips with Fillers. J Cutan Aesthet Surg. 2015;8(3):139–42. 
3. 
Macierzynska A, Pierzchala E, Placek W. Volumetric techniques: three-dimensional midface 
modeling. Postepy dermatologii i alergologii. 2014;31(6):388-91. 
4. 
DeFatta RJ, Williams EF, 3rd. Evolution of midface rejuvenation. Archives of facial plastic 
surgery. 2009;11(1):6-12. 
5. 
Sadick NS. The impact of cosmetic interventions on quality of life. Dermatol Online J. 
2008;14(8):2. 
6. 
Gold M. What's New in Fillers in 2010? The Journal of clinical and aesthetic dermatology. 
2010;3(8):36-45. 
7. 
Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher GJ, et al. In vivo stimulation of de novo 
collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged 
human skin. Archives of dermatology. 2007;143(2):155-63. 
8. 
De Boulle K, Glogau R, Kono T, Nathan M, Tezel A, Roca-Martinez JX, et al. A review of the 
metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. Dermatologic 
surgery : official publication for American Society for Dermatologic Surgery [et al]. 2013;39(12):1758-
66. 
9. 
Goldman A, Wollina U. Facial rejuvenation for middle-aged women: a combined approach with 
minimally invasive procedures. Clinical interventions in aging. 2010;5:293-9. 
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10. 
Cummins TR. Setting up for the block: the mechanism underlying lidocaine's use-dependent 
inhibition of sodium channels. The Journal of physiology. 2007;582(Pt 1):11-. 
11. 
CROMA-PHARMA GmBH: Investigator’s brochure, PRINCESS® FILLER LIDOCAINE / 
SAYPHA® FILLER LIDOCAINE.Version 4.0 dated May-2019. 
12. 
Achar S, Kundu S. Principles of office anesthesia: part I. Infiltrative anesthesia. American family 
physician. 2002;66(1):91-4. 
13. 
Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia progress. 
2006;53(3):98-108; quiz 9-10. 
14. 
Ballin AC, Cazzaniga A, Brandt FS. Long-term efficacy, safety and durability of Juvederm(R) XC. 
Clinical, cosmetic and investigational dermatology. 2013;6:183-9. 
15. 
Smith L, Cockerham K. Hyaluronic acid dermal fillers: can adjunctive lidocaine improve patient 
satisfaction without decreasing efficacy or duration? Patient preference and adherence. 2011;5:133-9. 
16. 
CROMA-PHARMA GmbH: Instructions for use, Saypha® FILLER Lidocaine.08-2018. 
17. 
Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Hals EK, et al. 
Assessment of pain. British journal of anaesthesia. 2008;101(1):17-24. 
18. 
Alam M, Gladstone H, Kramer EM, Murphy JP, Jr., Nouri K, Neuhaus IM, et al. ASDS guidelines 
of care: injectable fillers. Dermatologic surgery : official publication for American Society for 
Dermatologic Surgery [et al]. 2008;34 Suppl 1:S115-48. 
19. 
Urdiales-Galvez F, Delgado NE, Figueiredo V, Lajo-Plaza JV, Mira M, Moreno A, et al. 
Treatment of Soft Tissue Filler Complications: Expert Consensus Recommendations. Aesthetic plastic 
surgery. 2018;42(2):498-510. 
20. 
Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, 
multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of 
nasolabial folds. Dermatologic surgery : official publication for American Society for Dermatologic 
Surgery [et al]. 2003;29(6):588-95. 
21. 
Klassen AF, Cano SJ, Schwitzer JA, Scott AM, Pusic AL. FACE-Q scales for health-related 
quality of life, early life impact, satisfaction with outcomes, and decision to have treatment: 
development and validation. Plastic and reconstructive surgery. 2015;135(2):375-86. 
22. 
MEDDEV 2.7/3 rev. 3. Guidelines on medical devices. Clinical investigations: Serious adverse 
event reporting under directives 90/385/EEC and 93/42/EEC. European Commission. . May 2015. 
23. 
Beer K, Glogau RG, Dover JS, Shamban A, Handiwala L, Olin JT, et al. A randomized, 
evaluator-blinded, controlled study of effectiveness and safety of small particle hyaluronic acid plus 
lidocaine for lip augmentation and perioral rhytides. Dermatologic surgery : official publication for 
American Society for Dermatologic Surgery [et al]. 2015;41 Suppl 1:S127-36. 
 
 
 
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19 Protocol Amendments 
19.1 Protocol Amendment 1 
The changes and corresponding rationales are described within a separate document.  
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