Prospective, Open-Label Study, to Evaluate The Impact on Skin Quality Attributes by Juvederm® Volite Injection on Healthy Volunteers
Phase: NA
Conditions: Healthy Adults, Skin Enhancement
Sponsor: Allergan

NCT04206293 
 
Study ID: CMO-MA-FAS-0617 
 
 
Title:  Prospective, Open-Label Study, to Evaluate The Impact on Skin Quality Attributes by 
Juvederm® Volite Injection on Healthy Volunteers 
 
Protocol Date: 21Aug2019 

  
 
 
PRM03-F-227_V1_EN  
Clinical investigational plan for MD 
 
 
 
PROSPECTIVE, OPEN-LABEL STUDY, TO EVALUATE THE IMPACT ON 
SKIN QUALITY ATTRIBUTES BY JUVEDERM® VOLITE INJECTION ON 
HEALTHY VOLUNTEERS 
 
 
Clinical Investigational Plan for Medical Device according to ISO standard 14155:2012 and its 
updates 
 
 
Clinical Investigational plan #: 
18E2581PL – CMO-MA-FAS-0617 
ANSM registration #: 
2019-A00317-50 
Device under investigation: 
Juvederm® VOLITE 
Form(s): 
Sterile gel 
Application(s): 
Intradermal injection 
CRO : 
DERMSCAN - Pharmascan  
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE 
FRANCE 
Investigational Centre 
Dermscan Poland Sp. z o.o. 
ul. Matuszewskiego 12 
80-288 GDANSK 
POLAND 
Principal Investigator: 
 
Sponsor: 
Allergan Pharmaceuticals International Limited 
Clonshaugh Industrial Estate 
Coolock 
Dublin 17 
Ireland 
Clinical Investigation Plan date and 
version:  
Final version 1.0 of 21/08/2019 
 
 

Allergan Pharmaceuticals 
International Limited 
Juvéderm® VOLITE 
CIP # 18E2581PL 
Final version 1.0 
Date: 21/08/2019 
 
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TABLE OF CONTENTS 
1- 
GENERAL INFORMATION AND SIGNATURES ...................................................... 5 
1.1 
Introduction ...................................................................................................................... 5 
1.2 
Identification of the clinical investigation plan (CIP) ................................................... 6 
1.3 
Sponsor ............................................................................................................................. 7 
1.4 
Principal Investigator, coordinating investigator and investigation site(s) .............. 7 
1.5 
Overall synopsis of the clinical investigation ............................................................... 9 
2- 
IDENTIFICATION AND DESCRIPTION OF THE DEVICE UNDER INVESTIGATION
 
14 
2.1 
Summary description of the device under investigation and its intended purpose14 
2.2 
Details concerning the manufacturer of the device under investigation ................. 14 
2.3 
Name or number of the model/type ............................................................................. 14 
2.4 
Traceability of the device under investigation............................................................ 14 
2.5 
Intended purpose of the device in the proposed clinical investigation ................... 14 
2.6 
Population and indications for which the device under investigation is intended. 15 
2.7 
Description of the device under investigation ............................................................ 15 
2.8 
Summary of the training and experience needed to use the device under 
investigation ................................................................................................................... 15 
2.9 
Description of the specific medical or surgical procedures involved in the use of 
the device under investigation ..................................................................................... 15 
3- 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ............17 
3.1 
Summary of the results of the relevant pre-clinical testing/ assessment carried out 
to justify the use of the device under investigation in human subjects .................. 17 
3.2 
Clinical data .................................................................................................................... 17 
4- 
RISKS AND BENEFITS OF THE DEVICE UNDER INVESTIGATION AND CLINICAL 
INVESTIGATION ..............................................................................................................18 
4.1 
Anticipated clinical benefits ......................................................................................... 18 
4.2 
Anticipated adverse device effects .............................................................................. 18 
4.3 
Residual risks associated with the device under investigation................................ 18 
4.4 
Risks associated with participation in the clinical investigation.............................. 19 
4.5 
Potential Interactions with concomitant medical treatments .................................... 19 
4.6 
Steps that will be taken to control or mitigate the risks ............................................ 19 
4.7 
Risk-to-benefit rationale ................................................................................................ 19 
5- 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION .............20 
5.1 
Objective ......................................................................................................................... 20 
5.2 
hypotheses to be accepted or rejected by statistical data ........................................ 20 
5.3 
Claims and intended performance of the device under investigation that are to be 
verified ............................................................................................................................ 20 
5.4 
Risks and anticipated adverse device effects that are to be assessed ................... 20 
6- 
DESIGN OF THE CLINICAL INVESTIGATION ........................................................20 
6.1 
General information ....................................................................................................... 20 
6.2 
Device under investigation ........................................................................................... 23 

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International Limited 
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CIP # 18E2581PL 
Final version 1.0 
Date: 21/08/2019 
 
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6.3 
Studied population ........................................................................................................ 24 
6.4 
Procedures ..................................................................................................................... 27 
6.5 
Monitoring ....................................................................................................................... 40 
7- 
STATISTICAL CONSIDERATIONS .........................................................................41 
7.1 
Statistical design, method and analytical procedures ............................................... 41 
7.2 
Sample size and its statistical justification ................................................................. 43 
7.3 
Level of significance and power of the clinical investigation ................................... 43 
7.4 
Expected drop-out rates ................................................................................................ 43 
7.5 
Statistical pass/fail criteria to be applied .................................................................... 43 
7.6 
Criteria for the termination of the clinical investigation on statistical grounds ..... 43 
7.7 
Deviation(s) from the original statistical plan ............................................................. 43 
7.8 
Treatment of missing, unused or spurious data, including drop-outs and 
withdrawals..................................................................................................................... 43 
8- 
DATA MANAGEMENT .............................................................................................43 
8.1 
Procedures used for data review, database cleaning and issuing/resolving data 
queries ............................................................................................................................ 43 
8.2 
Procedures for verification, validation and securing of electronic clinical data 
systems, if applicable .................................................................................................... 45 
8.3 
Procedures for data retention....................................................................................... 45 
8.4 
Other aspects of clinical quality assurance ................................................................ 45 
9- 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ..................................45 
10- DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ........................................45 
10.1 
Procedures for evaluating subject compliance .......................................................... 46 
10.2 
Procedures for recording, reporting and analysing CIP deviations ......................... 46 
10.3 
Corrective and preventative actions and principal Investigator disqualification 
criteria ............................................................................................................................. 46 
11- DEVICE ACCOUNTABILITY ....................................................................................46 
12- STATEMENTS OF COMPLIANCE ...........................................................................46 
12.1 
Regulatory aspect .......................................................................................................... 46 
12.2 
Ethics Committee ........................................................................................................... 47 
12.3 
Personal data protection ............................................................................................... 47 
12.4 
Insurance ........................................................................................................................ 47 
13- INFORMED CONSENT PROCESS ..........................................................................47 
14- ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES
 
48 
14.1 
Definitions....................................................................................................................... 48 
14.2 
Process for reporting adverse events and device deficiencies ................................ 51 
14.3 
Process for reporting a pregnancy .............................................................................. 52 
14.4 
List of foreseeable adverse events and anticipated adverse device effects ........... 53 
14.5 
Information regarding the Data monitoring committee (DMC) .................................. 53 
15- VULNERABLE POPULATION .................................................................................53 

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CIP # 18E2581PL 
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16- SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION ..............................................................................................................53 
16.1 
Study end ........................................................................................................................ 53 
16.2 
Suspension or premature termination of the clinical investigation ......................... 53 
17- PUBLICATION POLICY ...........................................................................................54 
18- BIBLIOGRAPHY ......................................................................................................54 
18.1 
Ethical aspect ................................................................................................................. 54 
18.2 
Skin Quality and Quality of Life .................................................................................... 54 
18.3 
Justification for Design of Clinical Investigation ....................................................... 54 
18.4 
Residual Risk Associated with Device Under Investigation ..................................... 55 
18.5 
Instrumental devices ..................................................................................................... 55 
 
LIST OF FIGURES 
 
Figure 1- Localization of injection zone, skin quality measurement zone and biopsies ............. 28 
 
LIST OF TABLES 
 
Table 1- Study flow-chart .................................................................................................................... 22 
Table 2- Summary of performance parameters ................................................................................ 30 
Table 3- MoistureMeter D® probes used for the study..................................................................... 31 
Table 4- List of ISR .............................................................................................................................. 39 
 
 

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CIP # 18E2581PL 
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1- GENERAL INFORMATION AND SIGNATURES 
 
1.1 INTRODUCTION 
 
 
The phenotypic changes of the skin provoked by aging are affected by both intrinsic and extrinsic factors 
(Sachs and Voorhees, 2011). Intrinsic factors such as age, sex, and estrogenic status induce changes 
in the composition and appearance of the dermis that are accompanied by a substantial reduction in the 
levels of glycosaminoglycans (including hyaluronic acid [HA]). This reduction, which is directly related 
to age and a decrease in the synthesis of glycosaminoglycans such as HA (Biecker and Schachtschabel, 
2001; Okano et al, 2002), is accelerated by dermal exposure to ultraviolet (UV) radiation. Histological 
studies confirm that the epidermis loses a substantial amount of density, a process accompanied by 
atrophy, decline in several epidermal differentiation indicators, and loss of water retention capacity. This 
process results in tissue dehydration and interphase weakness, which compromise the organization of 
the dermal-epidermal junction. Extrinsic factors, such as UV radiation, wind, extreme temperatures, 
medication, and exposure to abrasive substances, can result in the production of free radicals, which 
induce catabolism of HA and can lead to substantial changes in the extracellular matrix and loss of 
interstitial collagen (Agren et al, 1997). This damage promotes wrinkles and loss of skin tone and 
elasticity. 
 
Over time, the intrinsic and extrinsic factors together affect the structure and function of the components 
of skin, leading to measurable changes in its viscoelastic properties and to visible manifestations of 
aging. Aging or poor skin quality as well as skin conditions that result in facial symptoms such as 
wrinkles, fine lines, blemishes, tone or pigmentation changes, or lesions can have an effect on a 
person’s physical and psychological well-being, and therefore may be regarded as an impaired health 
state (Fried 1998, Sadick 2008, Sommer 2003). The effects of skin conditions and diseases as well as 
poor skin quality and advancing age that alter facial appearance negatively impact one’s self-perception 
and HRQoL (Health-related quality of life). For those not directly affected by poor facial skin quality there 
is a tendency to trivialize its potential impact (Schmid-Ott 2010). 
 
Today, many injectable fillers are used to treat facial aging, correct skin defects, and enhance and pout 
the lips to correct structural or age-related defects such as asymmetry, contour deficiencies, and volume 
loss. In the past decade, many new HA-based dermal products have become available to treat/prevent 
the visible signs of aging, by filling wrinkles and folds. Crosslinking HA with an agent such as butane-
diol-diglycidyl-ether (BDDE) improves duration of treatment effect by reducing susceptibility to 
degradation mechanisms. Different crosslinking technology and HA concentrations result in fillers with 
varying rheological properties and specific indications. 
 
HA filler products can be placed within the superficial, mid, or deep dermis, at the dermal-subcutaneous 
junction, or in the superficial subcutis, depending on the nature of the correction that is necessary and 
the characteristics of the filler being used (Arlette and Trotter, 2008). In recent years, there has been 
increased demand for products that improve attributes of skin quality in addition to treating skin 
depressions. As such, many of these HA rejuvenation products have proven successful within their 
indications of amelioration of the visible signs of cutaneous aging and treatment of cutaneous 
depressions, with limitations linked to duration in situ as many of these products are not crosslinked.   
 
JUVÉDERM VOLITE®, which is included in the JUVÉDERM® range of products, contains 12 mg of HA 
of nonanimal origin crosslinked by BDDE, 3 mg of lidocaine hydrochloride (to reduce patient’s pain 
during treatment) and 1 mL quantity sufficient (QS) phosphate buffer pH 7.2 and is supplied in a cyclic 
olefin copolymer (COC) syringe. JUVÉDERM VOLITE® was designed to treat by filling superficial 
cutaneous depressions such as fine lines and for additional improvement of skin quality. The injection 
depth for JUVÉDERM VOLITE® is specified as intradermal, with the depth of injection being determined 
by healthcare professionals with regard to the desired correction. 
 
Although various materials have been investigated as potential candidate soft-tissue fillers, none have 
produced as consistent and optimal results as HA fillers. HA is capable of providing volume to the 
targeted area, reducing the appearance of cutaneous depressions, and restoring the natural contour of 

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International Limited 
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CIP # 18E2581PL 
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the region to which it is applied. Risks associated with the device have been mitigated by its formulation, 
and potential complications that may arise have been described in the literature and DFU. The success 
of HA dermal fillers for the treatment of superficial skin depressions such as fine lines and for 
improvement of skin hydration and elasticity restoration is reflected in the CE Mark approvals of 
VOLBELLA, JUVÉDERM Hydrate and JUVÉDERM VOLITE® which demonstrate that the benefit of 
usage outweighs the risk of potential complications. 
 
JUVÉDERM VOLITE, a hyaluronic acid gel enhanced with lidocaine, is an injectable implant used for 
treatment, by filling, of superficial cutaneous depressions such as fine lines and for additional 
improvement of skin quality attributes such as hydration and elasticity. The unique formulation of 
JUVÉDERM VOLITE is intended to provide optimized durability versus fillers with similar indications, as 
shown by in vitro and animal testing.   
 
To gain greater knowledge on the impact of JUVÉDERM VOLITE® on skin quality attributes such as 
hydration, elasticity, thickness and density, and cell/tissue responses, various skin measurement 
devices will be used and cutaneous biopsies will be taken on the volar forearm of healthy volunteers, 
who will be followed up to 3 months.  
 
Biopsies collected in the study from injections in the volar forearm will allow to better understand the 
interactions of this particular hyaluronic acid-based filler with cells and tissues and to improve 
understanding of the clinical benefits relating to skin quality attributes assessed in previous studies. The 
improvement of skin quality attributes is not purely an aesthetic goal but, in fact, relates directly to patient 
quality of life. 
Biopsy analysis is as important as the skin measurements and as it is an exploratory study, it was 
decided to include them all under a single objective of the study. This type of study has indeed never 
been done on this product. The risks associated with biopsies are minimized by the fact that it is skin 
biopsies of small diameter (3 mm), generally allowing proper healing. The criteria for inclusion and non-
inclusion will include subjects with limited risk, particularly in terms of poor healing. 
The number of biopsies was decreased to the necessary minimum. 2 biopsies per zone and per time 
point are needed to have enough material for the planned analysis. It was preferred to sample 2 small 
biopsies instead of one larger biopsy to decrease the risks of visible and anaesthetic scars. Two time 
points are important to better understand the kinetics of product action on tissues and cells. A 1 month 
time point was chosen to align with previous studies evaluating the visible effects of this product and a 
3 month time point was selected to evaluate any kinetic effects of the cell and tissue interaction. A non-
treated area is essential to have baseline data to compare the treatment data to. Finally, volar forearms 
have been chosen because this is an area less visually exposed than the usual injection sites (face, 
neck, neckline, hands,…) but structure, thickness and properties of skin forearms are very close to the 
skin of usual injection site areas. 
 
 
1.2 IDENTIFICATION OF THE CLINICAL INVESTIGATION PLAN (CIP) 
 
TITLE OF THE CIP: PROSPECTIVE, OPEN-LABEL STUDY, TO EVALUATE THE 
IMPACT ON SKIN QUALITY ATTRIBUTES BY JUVEDERM® VOLITE INJECTION 
ON HEALTHY VOLUNTEERS 
 
CLINICAL INVESTIGATION #: 18E2581PL 
 
VERSION AND DATE OF THE CIP: FINAL V1.0 OF 21/08/2019 
 
SUMMARY OF THE REVISION HISTORY (IN THE CASE OF AMENDMENTS): NA 
 
 
 
 
 

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CIP # 18E2581PL 
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Date: 21/08/2019 
 
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ABBREVIATION LIST: 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
ANSM 
Agence Nationale de Sécurité Sanitaire des Produits de Santé = French Competent 
Authority 
ARS 
Agence régionale de santé (regional health agency) 
CIP 
Clinical Investigational Plan 
CNIL 
Commission Nationale Informatique et Libertés 
CRA 
Clinical Research Assistant 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSP 
Code de la Santé Publique 
D 
Day 
DFU 
Directions For Use 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
GCP  
Good Clinical Practice 
HA 
Hyaluronic Acid 
HIV 
Human Immunodeficiency Virus 
95% CI 
95% confidence interval 
I.C.H 
International Conference on Harmonisation  
ISE 
Instant Skin Elasticity 
ISR 
Injection Site Reaction 
ITT 
Intent To Treat 
MD 
Medical device 
OCT 
Optical Coherence Tomography 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Event 
SOP 
Standard Operating Procedure 
UV 
UltraViolet 
TMF 
Trial Master File 
 

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1.5 OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION 
 
ANSM registration #: 
2019-A00317-50 
Clinical investigation plan #: 
18E2581PL – CMO-MA-FAS-0617 
Title of the Clinical 
Investigation: 
PROSPECTIVE, OPEN-LABEL STUDY, TO EVALUATE THE IMPACT 
ON SKIN QUALITY ATTRIBUTES BY JUVEDERM® VOLITE 
INJECTION ON HEALTHY VOLUNTEERS 
Sponsor: 
Allergan Pharmaceuticals International Limited 
Clonshaugh Industrial Estate 
Coolock 
Dublin 17 
Ireland 
Investigation category: 
This study will be considered as an interventional research involving 
human beings. 
Objectives: 
To evaluate the impact on skin quality attributes, including physical 
measurements 
 
 
 following administration of Juvéderm® VOLITE in the 
volar forearms of healthy volunteers. 
Design: 
Prospective, single-center, open study 
Planned Sample Size: 
11 subjects included for 10 subjects analyzed 
Number of centres: 
One center 
Inclusion criteria: 
1. Healthy subject 
2. Sex: male and female 
3. Age: between 30 and 50 years old at the time of the written 
consent. 
4. Subjects with Fitzpatrick skin type II or III. 
5. Subject willing to receive Juvéderm® VOLITE in the forearms 
and agrees to complete all study required procedures, 
including having 6 cutaneous punch biopsies taken in the 
forearms and blood drawn (HIV, B and C hepatitis analysis at 
screening). 
9. Written informed consent and data privacy consent obtained. 
 
 

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Exclusion criteria: 
In terms of population: 
1. Pregnant or nursing woman or planning a pregnancy during the study. 
4. Subject participating to another research on human beings or being 
in an exclusion period for a previous study. 
5. Intensive exposure to sunlight or UV-rays within the previous month 
and foreseen during the study. 
6. Subject having other resorbable filling product injections, a laser 
treatment, an ultrasound-based treatment, radiation treatment, a 
dermabrasion, a surgery, a deep chemical peeling or other ablative 
procedure on the studied zones within the past 12 months prior to 
study start. 
7. Subject with subcutaneous retaining structure on the studied zones 
(meshing, threads, gold strand). 
8. Subject having received injections of permanent or semi-permanent 
filling products in the studied zones. 

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Related to previous or ongoing treatment 
24. Subject under anti-coagulant treatment or treatment liable to interfere 
with the healing process or hemostasis, during the previous month 
and during the study. 
25. Subject receiving or is planning to receive anti-inflammatory drugs 
(oral/injectable corticosteroids or NSAIDs, e.g., aspirin, ibuprofen), or 
other substances known to increase coagulation time (herbal 
supplements with garlic or ginkgo biloba, etc) for 10 days prior to 
study treatment and 3 days after. 
26. Subject under immunosuppressive therapy. 
Device under investigation: 
Name / code: 
 
Galenic form: 
 
Dosage: 
 
 
 
Administration route: 
 
Juvéderm® VOLITE 
 
Sterile gel in disposable syringe 
 
On Day 0 (D0) the specialist injector will treat the study area with an 
appropriate volume based on his/her clinical experience and according 
to Instructions for Use. 
 
Intra-dermal injection in forearms 
 

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Evaluation criteria/Endpoints: 
Performance exploratory Endpoints 
 
Changes in skin quality parameters, one and three months after 
Juvéderm® VOLITE injection in the forearms, in comparison with before 
treatment (D0). Evaluated skin parameters and instruments used are 
summarized in the table below: 
 
Instrument 
Measurement of interest 
MoistureMeter D® 0.5 mm 
Hydration (epidermis + dermis) 
MoistureMeter D® 1.5mm 
Hydration (epidermis + dermis) 
Corneometer® 
Hydration (superficial layers of 
epidermis) 
Cutometer® 
Elasticity 
Elastimeter® 
Elasticity 
Skin Scanner® 
Skin thickness and density 
Vivosight OCT® 
Skin roughness, density and 
vascularity 
Glossymeter® 
Brightness 
Spectrophotometer® 
Colour 
Mexameter® 
Melanin content 
Safety Endpoints 
- Injection Site Reactions (ISRs) evaluated by the investigator at each 
time point after injection. 
- Collection of adverse events and incidents at all visits including 
severity, action taken, and relationship to device. 
 
Study Procedures: 
Screening visit: informed consent, medical examination, medical 
background and previous treatment, subject selection, blood sampling. 

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Statistical methods: 
All the variables will be described using adapted statistics according to 
their type (quantitative data or qualitative data). 
Where appropriate, statistical tests will be performed, to assess the 
change from baseline. Skin quality parameter changes will be evaluated 
with a mixed ANOVA model for repeated measures. 
Foreseen study duration: 
Foreseen First Subject First Visit: Q3 2019 
Foreseen Last Subject Last Visit: Q2 2020 
Clinical investigation global duration: 10 months 
Duration by subject: 9 months + screening period 
 
 

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2- IDENTIFICATION AND DESCRIPTION OF THE DEVICE UNDER INVESTIGATION   
2.1 SUMMARY DESCRIPTION OF THE DEVICE UNDER INVESTIGATION AND ITS 
INTENDED PURPOSE  
 
Juvéderm® VOLITE is a class III resorbable injectable medical device with CE marking since 2016. It is 
a sterile pyrogen-free physiological solution of cross-linked hyaluronic acid which is not of animal origin. 
This injectable implant is used for the treatment, by filling, of superficial cutaneous depressions such as 
fine lines and for additional improvement of skin quality attributes such as hydration and elasticity. The 
presence of lidocaine in the product is meant to reduce the patient’s pain during treatment. 
 
 
2.2 DETAILS 
CONCERNING 
THE 
MANUFACTURER 
OF 
THE 
DEVICE 
UNDER 
INVESTIGATION 
 
Manufacturer: 
 
ALLERGAN  
Route de Promery  
Zone Artisanale de Pré-Mairy  
74370 PRINGY-FRANCE 
 
2.3 NAME OR NUMBER OF THE MODEL/TYPE 
 
Juvéderm® VOLITE 
 
2.4 TRACEABILITY OF THE DEVICE UNDER INVESTIGATION 
 
Each device is assigned a batch number to insure its traceability from its production to its destruction. 
In the device packaging, 2 traceability labels mentioning the device name, batch number and expiry 
date are present. One of these labels should be stuck in subject medical file. 
 
Moreover, each device will be labelled with a specific label for the investigational study. 
The labelling of the devices for the clinical study will be realized by Dermscan. 
Here is an example of the label which will be pasted on each device packaging (blister and box), in 
Polish language: 
 
2.5 INTENDED PURPOSE OF THE DEVICE IN THE PROPOSED CLINICAL INVESTIGATION 
 
Improvement of skin quality attributes. 
 
 

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2.6 POPULATION AND INDICATIONS FOR WHICH THE DEVICE UNDER INVESTIGATION 
IS INTENDED 
 
In the proposed clinical study, the device under investigation is intended to be administered to healthy 
subjects aged between 30 and 50 years old. This age group has been chosen to have homogeneous 
mature skins, able to be improved by hyaluronic acid injection. 
 
 
2.7 DESCRIPTION OF THE DEVICE UNDER INVESTIGATION 
 
Tested device 
Juvéderm® VOLITE 
 
Formula 
Hyaluronic Acid Gel                       12 mg 
Lidocaine hydrochloride                   3 mg 
Phosphate buffer pH 7.2 q.s.   1 ml (or g) 
Galenic form 
Sterile pyrogen-free physiological gel of cross-linked hyaluronic 
acid 
Route/ mode of 
administration 
Intra-dermal injection 
Packaging 
The gel is presented in a graduated, pre-filled, disposable 
syringe of 1 ml. 
Each box contains two 1 mL Juvéderm® VOLITE syringes, 4 
single-use 32G1/2” sterile needles to be used only for injecting 
Juvéderm® VOLITE, an instruction leaflet and a set of labels in 
order to ensure traceability. 
Blinding procedure 
Commercial packaging will be used 
Storage 
At room temperature (below 25°C) 
Intended purpose 
✓ Juvéderm® VOLITE is an injectable implant used for the 
treatment, by filling, of superficial cutaneous depressions such 
as fine lines and for additional improvement of skin quality 
attributes such as hydration and elasticity. 
✓ The presence of lidocaine is meant to reduce the patient’s 
pain during treatment. 
 
 
2.8 SUMMARY OF THE TRAINING AND EXPERIENCE NEEDED TO USE THE DEVICE 
UNDER INVESTIGATION 
 
The device under investigation must only be used by authorised practitioners, trained in injecting 
implants, after fully familiarizing themselves with the device, its complete instruction leaflet and CIP.   
 
2.9 DESCRIPTION OF THE SPECIFIC MEDICAL OR SURGICAL PROCEDURES INVOLVED 
IN THE USE OF THE DEVICE UNDER INVESTIGATION 
 
1. The area to be treated should be disinfected thoroughly prior to the injection. Hyaluronic acid is 
known to be incompatible with quaternary ammonium salts such as benzalkonium chloride. Juvéderm® 
VOLITE should therefore never be placed in contact with these substances or with medical-surgical 
instrumentation which has been treated with this type of substance. There is no known interaction with 
other local anaesthetics. 
2. Remove tip cap by pulling it straight off the syringe as shown in fig. 1 below. Then firmly push the 
needle provided in the box (fig. 2) into the syringe, screwing it gently clockwise. Twist once more until it 
is fully locked and has the needle cap in the position shown in fig. 3. If the needle cap is positioned as 
shown in fig. 4, it is incorrectly attached. 
3. Next, remove the protective cap by holding the body of the syringe in one hand, the protective cap 
in the other, as shown in fig. 5, and pulling the two hands in opposite directions. 
4. Prior to injecting, depress the plunger rod until the product flows out of the needle. Inject slowly and 
apply the least amount of pressure necessary. 

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Recommendations: 
 
✓ If the needle is blocked, do not increase the pressure on the plunger rod. Instead, stop the injection 
and replace the needle. Failure to comply with these precautions could cause a disengagement of 
the needle and/or product leakage at luer-lock level. 
✓ After needle insertion and before injection, it is recommended to withdraw slightly the plunger to 
aspirate and verify the needle is not intravascular. 
✓ If immediate blanching occurs at any time during the injection, the injection should be stopped and 
appropriate action taken such as massaging the area until its return to a normal color. 
✓ The degree and duration of the correction depend on the character of the defect treated, the tissue 
stress at the implant site, the depth of the implant in the tissue and the injection technique. The 
amount injected will depend on the areas which are to be corrected based on the experience of the 
medical practitioner. 
✓ Do not overcorrect as injection of an excessive volume can be at the origin of some side effects such 
as tissue necrosis and oedema. 
✓ It is important to massage the area treated after the injection in order to ensure that the material has 
been uniformly distributed. 

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3- JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION  
3.1 SUMMARY OF THE RESULTS OF THE RELEVANT PRE-CLINICAL TESTING/ 
ASSESSMENT CARRIED OUT TO JUSTIFY THE USE OF THE DEVICE UNDER 
INVESTIGATION IN HUMAN SUBJECTS 
 
The device is already on the market and has the CE marking since 2016. 
 
 
3.2 CLINICAL DATA  
 
 
The safety of JUVÉDERM VOLITE XC is supported by preclinical biocompatibility data, which show that 
it is nontoxic, noncytotoxic, nongenotoxic, nonirritant, nonsensitizing, noncarcinogenic, and 
nonpyrogenic. 
 
A prospective, single-arm European postapproval study (V12 001) was conducted at a single center (6 
injecting physicians from 6 countries) to assess the safety and effectiveness of JUVÉDERM VOLITE 
without lidocaine in treating fine lines and skin roughness in the face and neck. Treatment was 
administered on both sides of the face (cheek and forehead) and neck (if desired) for fine lines and the 
improvement of skin roughness. For 131 treated subjects, a total of 261 cheeks, 120 foreheads, and 96 
necks were treated. Touch-up treatments were provided for 31 subjects (23.7%) and 46 cheeks (17.6%), 
and repeat treatments at 9 months were provided for 62 subjects (47.3%) and 124 cheeks (47.5%). 
Among treated cheeks with scores of moderate or severe at baseline on the Allergan Fine Lines Scale 
(AFLS), the AFLS responder rate was 89.4% at Month 1, 66.7% at Month 4, 40.5% at Month 6, 15.6% 
at Month 9, and 94.3% at 1 month after repeat treatment. The responder rate on the Allergan Cheek 
Smoothness Scale (ACSS; (formerly known as the Allergan Skin Roughness Scale) was 96.2% at Month 
1, 76.3% at Month 4, 34.9% at Month 6, 15.8% at Month 9, and 87.1% at 1 month after repeat treatment. 
A statistically significant improvement (p < 0.001) in subject satisfaction with skin based on the FACE Q 
Satisfaction with Skin questionnaire was observed at all timepoints. The V12 001 study served as the 
basis for the present study’s injection volumes and treatment characteristics (see Section 6.2) as well 
as a study follow-up duration of 3 months based on the product’s responder rate and observed clinical 
duration. 
 
Existing studies have primarily evaluated the physical and visual changes (e.g. reduction of wrinkles, 
changes in hydration, etc.) following HA filler treatment (see European post-approval study V12 001 
above). Additional effects due to the physical interaction of cells and tissue with the implanted filler are 
not well understood, except through a limited number of animal studies (Wang et al., 2007; Paliwal et 
al., 2014; Mochizuki et al., 2018; Fan et al., 2019) and clinical studies evaluating primarily changes in 
collagen production (Turlier et al., 2013; Wanick et al., 2016).  Changes to gene and protein expression 
of extracellular matrix proteins and cytokines/growth factors beyond collagen can have a significant 
impact on clinical outcomes beyond just evaluating the ability to correct wrinkles but have not been 
evaluated clinically.  Further understanding of these effects requires biopsies and can lead to improved 
understanding of the clinical benefits for patients, especially related to improvements in skin quality. 
 
 
 

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4- RISKS AND BENEFITS OF THE DEVICE UNDER INVESTIGATION AND CLINICAL 
INVESTIGATION 
4.1 ANTICIPATED CLINICAL BENEFITS 
 
Volite is indicated for treatment, by filling, of superficial cutaneous depressions such as fine lines and 
for additional improvement of skin quality attributes such as hydration and elasticity. This study is 
designed to further evaluate improvements to skin quality attributes that may have an impact on potential 
clinical benefits for patients receiving Volite to address skin quality and early signs of aging. No direct 
clinical benefit is expected for healthy subjects participating in the study, as the product injection will 
only be done on a small zone of volar forearms. However, locally, an improvement of skin quality, such 
as moisturization or elasticity may be observed. This study will help to add further understanding of the 
benefits of treatment for patients. 
 
4.2 ANTICIPATED ADVERSE DEVICE EFFECTS 
 
As described in the product leaflet: 
 
Potential side effects associated with implantation of this product, may occur immediately or may be 
delayed. These include, but are not limited to: 
 
Potential immediate side effects 
Potential delayed side effects 
Inflammatory reactions (redness, oedema, 
erythema, etc.) which may be associated with 
itching and/or pain on pressure and/or 
paresthesia, occurring after the injection. These 
reactions may last for a week 
In rare cases, abcesses or granuloma after 
hyaluronic acid injection have been reported. 
Haematomas. 
Delayed hypersensitivity after hyaluronic acid 
and/or lidocaine injections have also been 
reported. 
Induration or nodules at the injection site. 
 
Staining or discoloration of the injection site 
might be observed, especially when HA dermal 
filler is injected too superficially and/or in thin 
skin (Tyndall effect). 
 
Immediate hypersensitivity after hyaluronic acid 
and/or lidocaine injections have also been 
reported. 
 
 
4.3 RESIDUAL RISKS ASSOCIATED WITH THE DEVICE UNDER INVESTIGATION 
 
As with any skin injection, risks can be posed by the injection procedure itself, the anesthetic agent, and 
injection of JUVÉDERM VOLITE XC injectable gel. Risks related to the injection procedure include 
redness, itching, pain, tenderness, swelling, bruising, and lumps and bumps, which are common to 
dermal filler injection procedures in general and typically resolve within 1 month (De Boulle et al., 2015; 
Signorini et al., 2016; Heydenrych et al., 2018). The use of a small gauge needle to deliver JUVÉDERM 
VOLITE XC used in this study is intended to minimize tissue trauma. In rare instances, adverse events 
(e.g. abcesses, nodules, swelling) may occur weeks to months following implantation. Materiovigilance 
data of the last three years (since the product launch) show a 0.004% rate of inflammatory nodules 
reported after injection of Juvederm® VOLITE, without any case of confirmed granuloma by biopsy. The 
ability to reverse (dissolve) hyaluronic acid fillers and defined consensus treatment algorithms minimize 
the long-term impact of these events (Alam et al., 2008, De Boulle et al., 2015; Signorini et al., 2016; 
Heydenrych et al., 2018). The inclusion of 0.3% lidocaine in the formulation is meant to reduce pain 
during the injection, and this needs to be taken into account when administering concomitant additional 
anesthetics as well as in relation to subjects’ medical history (ie, allergy to lidocaine). Risks associated 

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with the anesthetic agent include allergic reactions that may manifest as an anaphylactic reaction, skin 
rash, redness, itching, hives, burning, stinging, swelling, tenderness, and transient loss of skin color.  
 
4.4 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL INVESTIGATION 
 
Blood sampling: 
Subjects may experience a brief uncomfortable pricking sensation from the introduction of a needle into 
their forearm vein and hematoma at the puncture point. There is also a small risk of fainting during the 
sampling and a risk of infection or nervous lesion (motor or sensitive disability). 
 
 
 
 
 
  
 
Scarring: 
The subject may experience visible scarring as a consequence of the biopsies. The subject will have to 
not expose the biopsies zones to the sun or UV light, in order to minimize the chance of scarring, during 
at least three months. 
 
4.5 POTENTIAL INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
 
As described in the product leaflet: 
 
- 
Juvéderm® VOLITE should not be used simultaneously with laser treatment, deep chemical peels or 
dermabrasion. For surface peels, it is recommended not to inject the product if the inflammatory 
reaction generated is significant. 
- 
It is recommended not to inject into a site which has been treated with a permanent implant. 
- 
No clinical data is available regarding the efficiency and tolerance of Juvéderm® VOLITE injections 
in patients having a history of, or currently suffering from, autoimmune disease or autoimmune 
deficiency or being under immunosuppressive therapy. 
- 
Patients on anti-coagulation medication or using substances that can prolong bleeding (warfarin, 
acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, or other substances known to increase 
coagulation time such as herbal supplements with garlic or ginkgo biloba, etc.) must be warned of 
the potential increased risks of bleeding and haematomas during injection. 
 
These treatments are part of exclusion criteria of the study. Such subjects will not be included. 
 
 
4.6 STEPS THAT WILL BE TAKEN TO CONTROL OR MITIGATE THE RISKS  
 
The risks are mitigated by using qualified clinical injectors who have training and experience in 
intradermal procedures, implants, and biopsies and have access to modern medical facilities to conduct 
those procedures. Only one site will participate in this study. In addition, risks are mitigated by including 
only those subjects that meet the study entry criteria. Consequently, careful definitions of specific 
eligibility criteria, study procedures and instructions for use, appropriate selection, qualification and 
training of the investigator, and subject follow-up procedures have been designed as to further contribute 
to reduce risks as far as possible for the subject and residual risk acceptance. 
 
 
4.7 RISK-TO-BENEFIT RATIONALE 
 
Based on pre-clinical and clinical data already obtained on the product before its commercialization, as 
well a materiovigilance feedback, no specific risk is expected after intra-dermal injection of Juvéderm® 
VOLITE in forearms by a qualified and trained injector. 
 

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No specific benefit is anticipated for healthy subjects participating in the study. 
 
5- OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
5.1 OBJECTIVE 
 
To evaluate the impact on skin quality attributes, including physical measurements 
 
, following administration of Juvéderm® VOLITE 
in the volar forearms of healthy volunteers. 
 
5.2 HYPOTHESES TO BE ACCEPTED OR REJECTED BY STATISTICAL DATA  
 
Not applicable. Exploratory study. 
 
5.3 CLAIMS AND INTENDED PERFORMANCE OF THE DEVICE UNDER INVESTIGATION 
THAT ARE TO BE VERIFIED 
 
Improvement of skin quality attributes such as hydration and elasticity and good tolerance. 
 
5.4 RISKS AND ANTICIPATED ADVERSE DEVICE EFFECTS THAT ARE TO BE 
ASSESSED 
 
The anticipated adverse device effects that are to be assessed are the one described in § 4.2. 
 
6- DESIGN OF THE CLINICAL INVESTIGATION 
6.1 GENERAL INFORMATION 
6.1.1 
Study design 
 
The study will be: 
 prospective, 
 open-label, single arm  
 intra-individual, 
 single centre, 
 on healthy subjects 
 
6.1.2 
Foreseen study dates 
 
Foreseen First Subject First Visit: Q3 2019 
Foreseen Last Subject Last Visit: Q2 2020 
Global duration of the study: 10 months 
Global duration by subject: 9 months + screening period 
 
6.1.3 
Sample size 
11 subjects will be included to expect at least 10 subjects analyzed. 
 

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6.1.4 
Description of the measures to be taken to minimize or avoid bias 
A repositioning mask of the injection zone will be made for the injected area and measurement zones 
in order to find back the exact same area at each time point.  
 
6.1.5 
Primary and secondary endpoints  
 
6.1.5.1 
Performance/Exploratory Endpoints 
 
Changes in skin quality parameters, as listed in the table below, one and three months after 
Juvéderm® VOLITE injection in the forearms, in comparison with before treatment (D0). Evaluated 
skin parameters and instruments used are summarized in the table below: 
 
Instrument 
Measurement of interest 
MoistureMeter D® 0.5 mm 
Hydration (epidermis + dermis) 
MoistureMeter D® 1.5mm 
Hydration (epidermis + dermis) 
Corneometer® 
Hydration (superficial layers of epidermis) 
Cutometer® 
Elasticity 
Elastimeter® 
Elasticity 
Skin Scanner® 
Skin thickness and density 
Vivosight OCT® 
Skin roughness, density and vascularity 
Glossymeter® 
Brightness 
Spectrophotometer® 
Colour 
Mexameter® 
Melanin content 
 
6.1.5.2 
Safety Endpoints 
 
- Injection Site Reactions (ISRs) evaluated by the investigator at each time point after injection. 
- Collection of adverse events and incidents at all visits including severity, action taken, and 
relationship to device. 
 
 
 

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6.1.6 
Flow chart 
Table 1- Study flow-chart 

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6.1.7 
Equipment to be used for assessing, recording and analysing variables and 
arrangements for monitoring maintenance and calibration 
 
6.2 DEVICE UNDER INVESTIGATION 
6.2.1 
Description of the exposure to the device 
 
Juvéderm® VOLITE will be injected on D0, on a zone of 8 cm x 4 cm (32 cm2) of the volar left forearm.  
 
6.2.1.1 
Dosage 
 
The study area will be treated by the specialist injector per the DFU (approximately 0.01 mL intradermal 
microboluses, spread 0.5 - 1 cm apart, over a 4 x 8 cm area) into the left forearm. A maximum of 1 ml 
will be injected on the zone treated. 
 
 
6.2.1.2 
Instructions for use 
 
Juvéderm® VOLITE will be injected as per the current European DFU (Directions For Use). 
The 32G1/2” needles present with the product will be used for the injection. 
Superficial intra dermal injections of micro aliquots (or microbolus) without papular formation will be 
performed. 
A massage is necessary post injection and a basic cream for the massage can be used. 
6.2.2 
Justification of the choice of comparator(s)  
 
Not applicable, non-comparative study. 
6.2.3 
Other medical device or medication to be used during the clinical investigation 

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6.2.4 
Concomitant treatments 
6.2.4.1 
Collection of concomitant treatments 
 
Any concomitant medication at selection of the subject into the study must be reported on the source 
document and in the study Case Report Form (CRF) at the initial visit and will be taken into consideration 
by the Investigator deeming study eligibility. 
Any modification on these medications during the study must be reported on the source document and 
in the study CRF. 
Use of any concomitant medication will be recorded in the CRF with the following information: 
• Indication for use of the treatment; 
• Name of the drug, and unit strength; 
• Dose administered; 
• Route of administration; 
• Duration of treatment (start and stop date). 
 
6.2.4.2 
Rescue treatment(s) 
In case of adverse reaction affecting subject well-being, the investigator is authorized to prescribe to the 
subject a rescue treatment/medication. 
The adverse event will be recorded in the subject’s CRF and source document, including details on 
rescue medication.  
 
6.3 STUDIED POPULATION 
 
6.3.1 
Inclusion criteria for subject selection 
 
1. 
Healthy subject 
2. 
Sex: male and female 
3. 
Age: between 30 and 50 years old at the time of the written consent. 
4. 
Subjects with Fitzpatrick skin type II or III. 
5. 
Subject willing to receive Juvéderm® VOLITE in the forearms and agrees to complete all study 
required procedures, including having 6 cutaneous punch biopsies taken in the forearms and 
blood drawn (HIV, B and C hepatitis analysis at screening). 
9. 
Written informed consent and data privacy consent obtained. 
 
 
 

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6.3.2 
Exclusion criteria for subject selection 
 
In terms of population: 
1. 
Pregnant or nursing woman or planning a pregnancy during the study. 
4. 
Subject participating to another research on human beings or being in an exclusion period for a 
previous study. 
5. 
Intensive exposure to sunlight or UV-rays within the previous month and foreseen during the 
study. 
6. 
Subject having other resorbable filling product injections, a laser treatment, an ultrasound-based 
treatment, radiation treatment, a dermabrasion, a surgery, a deep chemical peeling or other 
ablative procedure on the studied zones within the past 12 months prior to study start. 
7. 
Subject with subcutaneous retaining structure on the studied zones (meshing, threads, gold 
strand). 
8. 
Subject having received injections of permanent or semi-permanent filling products in the 
studied zones. 

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Related to previous or ongoing treatment: 
24. Subject under anti-coagulant treatment or treatment liable to interfere with the healing process 
or hemostasis, during the previous month and during the study. 
25. Subject receiving or is planning to receive anti-inflammatory drugs (oral/injectable 
corticosteroids or NSAIDs, e.g., aspirin, ibuprofen), or other substances known to increase 
coagulation time (herbal supplements with garlic or ginkgo biloba, etc) for 10 days prior to study 
treatment and 3 days after. 
26. Subject under immunosuppressive therapy. 
6.3.3 
Withdrawal criteria 
Any deviation to the CIP that can affect: 
- 
the primary evaluation criterion, 
- 
the adherence of the subjects to the study schedule, 
- 
the adherence relative to the products use,  
- 
the inclusion / exclusion criteria, 
can be considered as an exclusion criterion. Before any exclusion of the subject from the study, each 
case will be discussed with the Sponsor who will make the final decision if the subject must be excluded 
from the study. 
6.3.4 
Restrictions and recommendations 
 
Recommendations after injection: 
• Subjects are recommended not to use cosmetic products on the zone injected during 16 hours. 
• Subjects are recommended to avoid intensive exposure to sunlight or UV rays, temperatures below 
0°C, as well as any sauna or hammam sessions during the 2 weeks following the injection treatment. 
• To limit bleeding and bruising, subjects are recommended not to use aspirin, anti-inflammatories and 
anti-coagulants during 1 week after injection. 
Restrictions: 
• Subjects must not take part in any other clinical study on human beings.  
• Subjects must continue using their usual cleansing and care products on the studied zones for the 
whole study period.  
• Subjects must not apply any care product to the studied area 24 hours before each visit to the site.  
• Subjects must keep their dietary habits. 
 
 
 

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6.3.5 
Recruitment procedure 
 
Subjects will be recruited by phone from Dermscan data base according to inclusion and exclusion study 
criteria. This data base is constituted from registration files of people wishing to participate in clinical 
studies at Dermscan. 
Advertisement will be placed in Dermscan website and reception.  
 
6.3.6 
Subjects identification  
 
Each subject having signed a consent form will be assigned a “screening subject number” according to 
6.3.7 
ID card 
 
6.4 PROCEDURES 
6.4.1 
Study schedule 

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6.4.2 
Description of performance procedures 
 
6.4.2.1 
Summary of performance assessments 
 
Table 2- Summary of performance parameters 
 
Instrument 
Measurement of interest 
Parameters studied 
MoistureMeter D® 0.5 mm 
Hydration (epidermis+ dermis) 
Hydration rate (TDC) 
MoistureMeter D® 1.5mm 
Hydration (epidermis + dermis) 
Hydration rate (TDC) 
Corneometer® 
Hydration (superficial layers of 
epidermis) 
Hydration rate (A.U.) 
Cutometer® 
Elasticity 
Uf (R0), Ur, Ua (R8),  Uf – Ua 
(R1), Ua/Uf (R2), Ur/Ue (R5), 
Uv/Ue (R6), Ur/Uf (R7) (mm), 
Q1, Q2, Q3 
Elastimeter® 
Elasticity 
ISE (N/m) 
Skin Scanner® 
Skin thickness and density 
% of non-echogenic surface 
(skin density), skin thickness 
(mm) 
Vivosight OCT® 
Skin roughness, density and 
vascularity 
For roughness: Ra, Rq, Re, Sp, 
Sv, Sz 
For density: A-scan in mm and 
AU 
For vascularity: unitless 
Glossymeter® 
Brightness 
Brightness Index (GU) 
Spectrophotometer® 
Colour 
L*, a*, b* (A.U.), ITA°(°) 
Mexameter® 
Melanin content 
Melanin Index (A.U.) 
 
 

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6.4.2.2 
MoistureMeter D® 
 
MoistureMeter D® (Delfin Technologies) allows to measure water content of biological tissues. 
6.4.2.3 
Corneometer® 
 
Epidermis hydration measurements will be performed 
 
 

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6.4.2.4 
Cutometer® 
 
 Cutometer® 
 
6.4.2.5 
Elastimeter® 
 
The ElastiMeter® (Delfin Technologies) 
 
 
 
 

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6.4.2.6 
SkinScanner® 
 
Measurements are performed directly in vivo, using the high frequency echograph DUB® SkinScanner 
(TPM). 
6.4.2.7 
Vivosight OCT® 
The Vivosight Dx is a Multi-Beam Optical Coherence Tomography (OCT) system indicated for use in 
the two-dimensional, cross-sectional, real-time imaging of external tissues of the human body. 
 

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6.4.2.8 
Glossymeter® 
 
The Skin-Glossymeter® GL200 (Courage & Khazaka) measures both the fraction of light being 
reflected directly from the sample (skin) and the scattered fraction of reflected light. 
 
 

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6.4.2.9 
Spectrophotometer® 
 
Skin colorimetric measurement will be done with a MINOLTA CM700-d Spectrophotometer®, 
 
 
 

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6.4.2.10 Mexameter® 
 
Mexameter® MX18 is a Courage and Khazaka device, 
 
6.4.2.11 Serology checking 
 
A blood sample will be taken before subject inclusion in order to ascertain volunteer serologic status for 
Hepatitis B and C, and HIV to ensure the safety of the biological samples taken during the course of the 
study. 

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6.4.2.12 Cutaneous biopsies 
 

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6.4.3 
Description of safety parameters 
6.4.3.1 
Local tolerance  
 
Immediately after injection, one and three months after injection, the investigator will evaluate the local 
tolerance of the tested device with the following 4-point numerical rating scale (NRS): 
 
Table 4- List of ISR 
Parameter 
None 
Mild 
Moderate 
Severe 
Redness / Erythema 
0 
1 
2 
3 
Pain / Tenderness 
0 
1 
2 
3 
Induration 
0 
1 
2 
3 
Swelling / Oedema 
0 
1 
2 
3 
Lumps / Bumps 
0 
1 
2 
3 
Bruising / Hematoma 
0 
1 
2 
3 
Itching 
0 
1 
2 
3 
Discoloration/ 
pigmentation 
0 
1 
2 
3 
 
Each local reaction will be described by the intensity as follows: 
 
 
Qualification 
Definition 
0 
None 
 
1 
Mild 
Discomfort noted, but no disruption to normal daily activities. 
No treatment considered 
2 
Moderate 
Discomfort sufficient to reduce or affect normal daily activities; 
treatment may be needed. 
3 
Severe 
Inability to work or to carry out normal daily activities; treatment 
is required. 
 
Moreover, the subjects will be given a daily-log in order to grade each ISR described above, each day 
during 28 days after injection. The ISR will not be reported in the Adverse Event Form except if still 
present at D28, if they require a medical treatment of if judged abnormal by the investigator.  
 
6.4.3.2 
General tolerance  
Collection of adverse events by the investigator. 
 
6.4.4 
Description of activities performed by Sponsor representatives 
 
The Sponsor has delegated the following activities to the CRO (Dermscan): 
 
- 
Submission of the study files to the EC and regulatory authorities 
- 
Monitoring 
- 
Data management 
- 
Statistical analysis and clinical investigation report writing. 
- 
Management and transportation of biopsies 
 
6.4.5 
Any known or foreseeable factors that may compromise the outcome of the clinical 
investigation or the interpretation of results 
None.  
 
 
 

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6.5 MONITORING 
 
The monitoring of the study will be done by a CRA, ofDermscan France. The monitor has the 
responsibility to familiarise the investigator(s) and the centre staff involved in the study with all study 
procedures if necessary. The monitor has the responsibility of reviewing the ongoing study with the 
investigator(s) to verify adherence to the CIP and to deal with data queries as well as any problems that 
arise during the conduct of the study. After each visit, a monitoring report will be sent to the sponsor. 
 
6.5.1 
Monitoring visits 
6.5.2 
Access to source data  
In accordance with good clinical practices and the standards of the data protection law, data obtained during 
a research involving human beings must be treated confidentially to guarantee the subjects’ privacy.  
 
The investigator agrees that, subject to local regulations and ethical considerations, the Sponsor 
representatives’ designee and/or and any regulatory agency have direct access to all study records, CRFs, 
corresponding subject/patient medical records, study drug dispensing records and study drug storage area, 
and any other documents considered source documentation. The investigator also agrees to assist the 
representative, if required. 
 

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7- STATISTICAL CONSIDERATIONS 
The statistical analysis will be performed by Dermscan Biostatistician. 
 
 
7.1 STATISTICAL DESIGN, METHOD AND ANALYTICAL PROCEDURES  
 
7.1.1 
Intermediary analysis 
 
An intermediary analysis will be planned after D94 visit for safety and performance endpoints. 
The final analysis will be done at the study end with the last safety data. 
 
7.1.2 
Analysis population 
 
The following analysis populations will be studied and will be considered for the statistical analysis: 
 
- 
Safety population: any subject having used the tested device.  
- 
FAS (Full Analysis Set): Any subject included in the study with at least a post-basal value. 
 
The analysis of the safety/tolerance parameters will be performed on the “safety” population. The 
analysis of the performance parameters will be performed on the FAS. 
 
7.1.3 
Descriptive statistics 
 
Descriptive statistics will be presented for each parameter. Categorical variables will be summarized 
with frequency and relative frequency. Continuous variables will be summarized by number of subjects, 
mean, median, standard deviation, minimum, and maximum. Where appropriate, 2-sided 95% CIs for 
population mean, or population proportion, will be provided as part of the descriptive summary.  
7.1.4 
Patient accountability 
 
A flow diagram will be drawn with the number of patients enrolled, the number and % of screen failures 
and reason for exclusion, the number and % of patients receiving the medical device, the number and 
% of patients dropping out before and reason for dropping out, and the number and % of patients 
completing the study. 
 
7.1.5 
Demographic data and other baseline characteristics 
 
The studied population will be described on the demographic and injection parameters recorded at the 
screening and inclusion visits. The listing of medical history and prior medications will also be provided. 
 
7.1.6 
Performance endpoints 
 
7.1.6.1 
Skin quality measurements 
 
Descriptive statistics will be provided on both primary endpoint (one month change) and secondary 
endpoints (comparison zones for both one- and three months changes). Considering primary criterion 
of change between baseline and one month, descriptive statistics is a requirement while ANOVA model 
is served as exploratory analysis. 
 

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All parameters listed in Table 2 of paragraph 6.2.4.1 (
) will be 
analysed using a mixed ANOVA model for repeated measures (MIXED procedure of SAS®) fitted to 
raw data.  
 
The following factors will be included in the model: 
• 
Zone as fixed (2 levels: treated and control) 
• 
Time as fixed (3 levels: D0, D28 and D84) 
• 
Zone by time interaction 
 
To capture the correlation between data obtained from a same subject, an unstructured variance -
covariance matrix (UN@UN) is set. 
 
The specific contrasts of interest will be built (LS-Means statement) to: 
➢ Assess the change from baseline value (D0) on D28 and D84 within each zone 
➢ To compare the zones for the change (D28-D0) and (D84-D0) 
 
The underlying assumptions (residual normality and homoscedasticity) will be analyzed with Shapiro-
Wilk test and graphs to judge the model validity. In case of strong deviation, a data transformation or a 
non-parametric approach (Wilcoxon signed rank test) will be carried out. 
 
 
7.1.7 
Safety Endpoints 
 
For each parameter of ISR evaluation, the score distribution will be summarized in frequency and 
percentage by time point. 
 
In addition, for each parameter of ISR evaluation, the proportion of the subjects presenting the sign will 
be also computed and summarized in frequency and percentage.  
 
The individual listing of AE will be provided. 
AEs, ADEs, SAEs and SADEs will be summarized by presenting the number and percentage of patients 
having any sign or symptom. AEs will be classified by System Organ Class (SOCs) and Preferred Term 
(PTs) using MedDRA. 
 
 
 
 

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7.2 SAMPLE SIZE AND ITS STATISTICAL JUSTIFICATION 
 
This study is an exploratory study, no formal sample size calculation has been performed. 
11 subjects will be included to have at least 10 subjects analysed (10% of drop-out rate expected). 
 
 
7.3 LEVEL OF SIGNIFICANCE AND POWER OF THE CLINICAL INVESTIGATION 
 
All statistical tests will be assessed at  = 5% level of significance in a bilateral approach.  
 
7.4 EXPECTED DROP-OUT RATES 
 
It is considered as acceptable to lose a maximum of 10% of subjects in the final analysis population. 
 
 
7.5 STATISTICAL PASS/FAIL CRITERIA TO BE APPLIED  
 
Not applicable, exploratory study. 
 
7.6 CRITERIA FOR THE TERMINATION OF THE CLINICAL INVESTIGATION ON 
STATISTICAL GROUNDS  
 
As no interim statistical analysis has been planned, no statistical criteria for the termination of the clinical 
investigation has been defined. 
 
7.7 DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN 
 
Any modification to the statistical analysis plan due to a substantial modification of the CIP will be 
documented as an amendment and will be described in the final study report if applicable. 
 
 
7.8 TREATMENT OF MISSING, UNUSED OR SPURIOUS DATA, INCLUDING DROP-OUTS 
AND WITHDRAWALS 
 
No strategy for taking in charge missing data has been defined. Data that are not valid or missing will 
be considered and treated as missing data. 
 
 
8- DATA MANAGEMENT 
8.1 PROCEDURES 
USED 
FOR 
DATA 
REVIEW, 
DATABASE 
CLEANING 
AND 
ISSUING/RESOLVING DATA QUERIES 
 
8.1.1 
Identification of source data 
 
The data related to the subject characteristics, to their actual or previous medical state and to the safety 
of the device will be notified in the subject’s source document and the Case Report Form (CRF).  
 
The data relative to the device efficacy will only be collected in the CRF and/or directly in specific 
software and will be considered as source data. 
 
 
 

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8.1.2 
Data collection  
 
All data for this study will be recorded on CRF or directly recorded within data capture software for 
measurement instruments.  
8.1.3 
Data entry 
8.1.4 
Data coding 
 
Not applicable. 
8.1.5 
Data Review 
8.1.6 
Preparation of the Database and Locking 

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8.1.7 
Data unblinding 
Not applicable, open study. 
 
8.1.8 
Final Report 
 
A final report according to ISO 14155:2012 will be written by the Project Manager. A draft will be sent to the 
Sponsor for validation. This final report will be signed by the principal investigator, the Project Manager, the 
Biostatistician and the Sponsor. 
 
8.2 PROCEDURES FOR VERIFICATION, VALIDATION AND SECURING OF ELECTRONIC 
CLINICAL DATA SYSTEMS, IF APPLICABLE 
 
Verification, validation and securing of electronic clinical data systems is done according to Dermscan 
Standard Operating Procedure (SOP). No e-CRF will be used for the study. 
 
8.3 PROCEDURES FOR DATA RETENTION  
 
The Sponsor must archive the CIP, documentation, approvals and all other essential documents related 
to the study, including certificates that satisfactory audit and inspection procedures have been carried 
out, for 30 years. Dermscan will archive all documents concerning the study as detailed below: 
- 
All documents must be archived in a secure place and treated as confidential material. 
- 
Paper documents relating to this study are stored maximum during one year on site before to 
be transmitted for archiving to an approved service provider. 
- 
Data will be archived securely as digital and paper version for 15 years from the date of dispatch 
of the final report’s acceptance.  
 
At the end of this period of 30 years, the study archives will be destroyed unless otherwise stipulated in 
writing by the Sponsor. 
 
8.4 OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE 
 
In order to ensure the conformity of the studies entrusted to Good Clinical Practices and regulatory 
requirements, DERMSCAN has implemented a quality management system which has been certified 
ISO 9001:2008. 
9- AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
The Sponsor or the Investigator might modify the CIP for ethical, medical or scientific reasons.  
No change can be implemented at investigational sites, unless to eliminate an immediate hazard to study 
subjects, without having obtained the favourable opinion of the Sponsor. 
 
These changes will be documented in the Trial Master File (TMF) and communicated to investigational 
centres as soon as possible. 
 
If applicable, changes will be submitted as substantial or non-substantial modification (according to its nature) 
to EC. 
 
10- DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
 
The Investigators are not allowed to deviate from the CIP, excepted under emergency circumstances, 
to protect the rights, safety and well-being of the subjects. In this case, such deviations shall be 
documented and reported to the Sponsor and the EC as soon as possible. 
 

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10.1 PROCEDURES FOR EVALUATING SUBJECT COMPLIANCE 
 
The device under investigation will not be dispensed to the subject but will be injected at D0 at the study 
centre. 
Subjects will be given a daily log to report any adverse event or concomitant treatment. 
 
10.2 PROCEDURES FOR RECORDING, REPORTING AND ANALYSING CIP DEVIATIONS 
 
All CIP deviations will be managed according to Dermscan Standard Operating Procedure (SOP). 
 
Deviations to the CIP should be classified as: 
• 
Minor if they don't impact the rights, safety or well-being of the subjects. They do not increase 
the risk or do not diminish the benefit for the subject and/or do not have a significant effect on 
the integrity of the data collected,  
• 
Major (or CIP violations) if they affect the rights, safety or well-being of participants. They 
increase the risk or diminish the benefit for the subject and/or have a significant effect on the 
integrity of the data in the study.  
 
If the deviation is reported/observed during the study, the sponsor/the investigator may decide to drop-
out the subject of the study or not.  
If the deviation is detected after the study end, the case will be discussed during the « data review » 
which occurs before data analysis. 
 
 
10.3 CORRECTIVE AND PREVENTATIVE ACTIONS AND PRINCIPAL INVESTIGATOR 
DISQUALIFICATION CRITERIA 
 
If major deviations from the investigator is observed during the study, the CRA/study monitor will warn 
the investigator of the importance to respect the CIP. An investigator who continuously violates the CIP 
despite CRA warnings could be excluded from the investigation after agreement of the Sponsor. 
 
11- DEVICE ACCOUNTABILITY 
The device will be used only under conditions defined in this CIP and only for included subjects. 
 
The CRO must keep an updated dispensation form which contains the subject number, the number of 
Medical Device (MD) injected to each subject, with the corresponding dates. This will be collected on a 
specific form. 
 
All MD supplies (empty containers, as well as partly used and unused MD) must be available for 
inspection at every monitoring visit. The study monitor should verify the investigational site’s devices 
accountability records against record of administrated doses in the CRF. All MD (wasted and unused) 
must be returned by the Investigator to the Sponsor at the end of the study. 
 
12- STATEMENTS OF COMPLIANCE 
 
12.1 REGULATORY ASPECT 
 
The study will be performed on healthy subjects, in accordance with: 
• 
the study CIP,  
• 
the Good Clinical Practices (GCP), 
• 
the ISO 14155:2012 standard and its updates, and any regional or national regulations, 

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• 
the ethical principles that have their origin in the Declaration of Helsinki and its later 
modifications. 
• 
the polish law  
 
 
 
12.2 ETHICS COMMITTEE 
 
It is the responsibility of the Sponsor or its legal representative to submit a copy of the CIP and detailed 
subject information sheet and consent form to an ethics committee in order to obtain independent approval 
to conduct the study. Ethics committee approval must be obtained before the study is started. The Ethics 
Committee submission is delegated by the Sponsor to the CRO Dermscan. 
The approval of the ethics committee must be sent in writing, to the Sponsor or its legal representative and 
then to the investigator. The Ethics Committee approval letter must mention the Ethics Committee members 
and their function. Any additional requirements imposed by the EC must be followed, if appropriate. 
 
12.3 PERSONAL DATA PROTECTION 
 
In this study, DERMSCAN processes personal data of subjects on behalf of the Sponsor, in accordance 
with the rules on the protection of personal data and, in particular, the Regulation (EU) 2016/679 of the 
European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard 
to the processing of personal data and on the free movement of such data,. For this purpose, 
DERMSCAN limits the collection and use of personal data to that which is needed for analysis and 
control purposes, by insuring their security and integrity and by guaranteeing their confidentiality. 
DERMSCAN makes sure beforehand and throughout the duration of the data-processing: 
- 
of the compliance with the obligations of the applicable data protection law,  
- 
to inform subjects of their personal data-processing and obtain their consent on it,  
- 
to implement and maintain appropriate technical and organisational measures. 
 
An identification code is attributed to each subject for the purpose to keep his/her identity confidential. 
This code consists of: the first letter of the subject's first name and the first letter of his/her last name. 
 
According to Article 14 of GDPR, the concerned subject must be informed of the identity and the contact 
details of the Controller and, where applicable, of the controller's representative.  
 
 
 
12.4 INSURANCE 
 
The Sponsor has subscribed an insurance contract to cover the financial consequences of the liability of all 
investigators, the Sponsor itself and anyone involved in the study. 
 
The collaboration agreements are established by the Sponsor/service provider, as defined in the 
requirements specification.  
The copy of the insurance certificate is presented separately in the EC submission file. 
13- INFORMED CONSENT PROCESS 
Voluntary written informed consent form must be obtained from each subject prior to perform any study 
related procedures in compliance with the recommendations of the Declaration of Helsinki. Subject should not 
be screened or enrolled before the subject has signed an approved informed consent form, written in a 
language that is understandable to the subject. 
Each subject should be given both verbal and written information describing the nature and duration of the 
clinical study. The informed consent form should be signed and personally dated in two originals by the 
subject and the person who conducted the informed consent discussion. The investigator, or the attending 
physician, will explain the nature, purpose and risks of the study. The subject will be informed that he has 
the right to withdraw at any time from the study, without giving reasons. The informed consent process should 

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take place under conditions where the subject has adequate time to consider the risks and benefits 
associated with her participation in the study.  
The investigator is responsible for assuring the appropriate content of the informed consent form and that 
informed consent is obtained from each subject in accordance with all applicable regulations. The informed 
consent form will be reviewed and approved by the Sponsor.  
Each subject should receive one original of the signed and dated written informed consent form and any 
other information provided to the subject. 
The second original of the signed and dated informed consent form should be retained in the investigator’s 
file. The investigator should maintain a log of all subjects who sign the informed consent form.  
No copy will be given to the Sponsor. 
 
14- ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
14.1 DEFINITIONS 
 
Table below presents categorization of adverse events: 
 
 
ADVERSE 
EVENTS 
Non-device-related 
Device- or procedure-related 
Non-serious 
Adverse Event (AE)a 
Adverse Device Effect (ADE) 
Serious 
 
Serious 
Adverse 
Event (SAE)b 
Serious Adverse Device Effect (SADE) 
Anticipated 
Unanticipated 
Anticipated Serious 
Adverse Device Effect 
(ASADE) 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
a      Includes all categories 
b      Includes all categories that are serious 
 
14.1.1 Adverse event (AE)  
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the medical 
device. 
 
NOTE 1: This definition includes events related to the medical device or the comparator. 
 
NOTE 2: This definition includes events related to the procedures involved. 
 
NOTE 3: For users or other persons, this definition is restricted to events related to medical devices. 
14.1.2 Adverse device effect (ADE)  
 
Adverse event related to the use of a medical device.  
 

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NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation, or any malfunction of the medical device. 
 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the l 
medical device. 
14.1.3  Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance. 
 
NOTE 1: Device deficiencies include malfunctions, use errors and inadequate labelling. 
  
14.1.4 Serious adverse event (SAE)  
 
A serious adverse event is defined as an adverse event that led to: 
a) death (death is the result and not the event), 
b)  serious deterioration in the health of the subject, that either resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) foetal distress, foetal death, or a congenital abnormality or birth defect. 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event. 
 
14.1.5 Serious adverse device effect (SADE)  
 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
14.1.6 Unanticipated Serious Adverse Device Effect (USADE)  
 
Any serious adverse device effect whose nature, incidence, severity, or outcome have not been 
identified in the current version of the risk analysis report.” 
NOTE: anticipated serious adverse device effect (ASADE) is an effect whose nature, incidence, severity 
or outcome have been identified in the risk analysis report. 
 
14.1.7 Severity definition 
The severity of adverse events/reactions can be graded on a three-point scale: 
 
* 
Mild: discomfort noted, but no disruption to normal daily activities. 

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* 
Moderate: discomfort sufficient to reduce or affect normal daily activities. 
* 
Severe: inability to work or to carry out normal daily activities. 
 
14.1.8 Relationship to the medical device(s) 
The Investigator must determine the relationship (if any) between an adverse event and the device or 
CIP.  
For the purpose of harmonizing reports, each AE will be classified according to five different levels of 
causality. The Sponsor and the Investigators will use the following definitions to assess the relationship 
of the serious adverse event to the investigational medical device1 or procedures (MEDDEV 2.7/3 
revision 3, May 2015).  
 
Not related: relationship to the device or procedures can be excluded when:  
- 
the event is not a known side effect2 of the product category the device belongs to or of similar 
devices and procedures;  
- 
the event has no temporal relationship with the use of the device or the procedures;  
- 
the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible;  
- 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious event;  
- 
the event involves a body-site or an organ not expected to be affected by the device or 
procedure;  
- 
the serious event 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);  
- 
the event does not depend on a false result given by the device used for diagnosis3, when 
applicable; 
- 
harms to the subject are not clearly due to use error;  
- 
 In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained.  
 
Possible the relationship with the use of the device is weak but cannot be ruled out completely. 
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible.  
 
Probable the relationship with the use of the  device seems relevant and/or the event cannot reasonably 
be explained by another cause, but additional information may be obtained. 
 
Causal relationship: the serious event is associated with the device or with procedures beyond 
reasonable doubt when:  
• 
the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;  
 
1 Investigational device: any device object of the clinical investigation, including the comparators. 
2 When the event is not a known side effect of the product category the device belongs to or of similar devices  
and procedures, generally is considered “not related”. Yet, the unexpected effect shall not be excluded from  
evaluation and reporting. 
3If an investigational device gives an incorrect diagnosis, the patient might, for example, receive an unnecessary 
treatment and incur all the risks that accompany that treatment, or might be incorrectly diagnosed with a serious 
disease. In other cases, the patient might not receive an effective treatment (thereby missing out on the benefits 
that treatment would confer), or might not be diagnosed with the correct disease or condition. 

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• 
the event has a temporal relationship with device use/application or procedures;  
• 
the event involves a body-site or organ that  
o 
the device or procedures are applied to;  
o 
the device or procedures have an effect on;  
• 
the serious event follows a known response pattern to the medical device (if the response 
pattern is previously known);  
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible);  
• 
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;  
• 
harm to the subject is due to error in use; the event depends on a false result given by the 
device used for diagnosis2, when applicable;  
• 
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
 
The Sponsor and the Investigators will distinguish between the adverse events related to the device and 
those related to the procedures (any procedure specific to the clinical investigation). An adverse event 
can be related both to procedures and the device. Complications of procedures are considered not 
related if the said procedures would have been applied to the patients also in the absence of device 
use/application. In some particular cases the event may be not adequately assessed because 
information is insufficient or contradictory and/or the data cannot be verified or supplemented. The 
Sponsor and the Investigators will make the maximum effort to define and categorize the event and 
avoid these situations. 
 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse (device) 
events. The occurrence of unanticipated events related to the use of the device (USADE) could suggest 
that the clinical investigation places subjects at increased risk of harm than was to be expected 
beforehand. 
 
14.2 PROCESS FOR REPORTING ADVERSE EVENTS AND DEVICE DEFICIENCIES 
14.2.1 Documentation 
 
All adverse events shall be documented in a timely manner throughout the clinical investigation in the 
source document and in the “adverse event documentation” form in the CRF.  
Investigators are responsible for documenting adverse events in the table provided for this purpose. 
All AE reports should contain:  
• 
a brief description of the event, localization, 
• 
date and time of onset, 
• 
severity of symptoms,  
• 
treatment required,  
• 
relationship with device and CIP procedures, 
• 
action taken with the device,  
• 
outcome,  
• 
date of resolution, 
• 
duration of the event, 
• 
and whether the event is classified as serious. 
 
This information is reported at the end of the study in the clinical report.  
 
All device deficiencies shall be documented throughout the clinical investigation and appropriately 
managed by the Sponsor. 
Device deficiencies that did not lead to an adverse event but could have led to a medical occurrence: 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 

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shall be reported as specified below. 
 
14.2.2 Reporting by the Investigator 
 
The declaration of Serious Adverse Event (Events, Reactions, or suspicion of Serious Adverse 
Reactions) is a legal requirement. Timelines for reporting adverse events to the Sponsor are described 
in the table below: 
 
Reporting by the Investigator 
What to 
report? 
• All AEs will be reported to Allergan Product Surveillance Department. 
• all SAEs (except for those recorded in the CIP or the investigator’s brochure as not 
requiring an immediate notification) 
• the results of abnormal analyses defined in the CIP as determining factors for the 
evaluation of the safety of individuals participating in the research 
To whom? 
• For SAE, to Vigilance/Materiovigilance Department at Allergan: 
• For AE, to Product Surveillance Department at Allergan: 
 
How to 
report? 
 
1- First notification:  
SAEs immediately upon awareness by telephone, fax, or e-mail. 
 
2- Completed form sending:  
the first notification is confirmed by sending the completed SAE form and AE 
documentation form by fax or e-mail with an acknowledgement of receipt, within 48 
hours of knowledge by the investigator.   
The AEs will be notified within 72 hours of knowledge by the investigator.  
 
3- Additional follow-up reports:  
send by fax or e-mail. 
 
Note: As a part of monitoring of serious adverse events, if necessary, this first 
notification will be followed by additional detailed written reports. In notifications, 
individuals participating in research are identified by a code number. 
 
14.2.3 Reporting by the Sponsor 
 
Sponsor will submit any post market vigilance reports as required. 
 
 
14.3 PROCESS FOR REPORTING A PREGNANCY 
 
The occurrence of a pregnancy (reported or diagnosed) after screening but before inclusion (first use of 
the device) in the study is not reported to the Sponsor unless severity criteria (like SAE related to CIP 
procedures). If the pregnancy is confirmed, the studied device must not be administered and the subject 
immediately withdrawn from the study. 
 

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The Investigator must immediately notify the Sponsor of the pregnancy using specific form and reports 
the withdrawn from the study in the CRF (study end). 
Women who become pregnant during the study will be followed until the outcome of the pregnancy is 
known and reported to the Sponsor (baby health). 
 
 
14.4 LIST OF FORESEEABLE ADVERSE EVENTS AND ANTICIPATED ADVERSE DEVICE 
EFFECTS 
 
The anticipated adverse device effects and foreseeable adverse events are described in section 4.2.  
 
14.5 INFORMATION REGARDING THE DATA MONITORING COMMITTEE (DMC) 
 
For the purposes of this study, no data monitoring committee will be formed, because: 
- 
studied population is not considered to be high-risk population: healthy subjects, young (< 50 
years old) and female subjects of childbearing potential should use a medically accepted 
contraceptive regimen, 
- 
medical device contains known components and is available on the market. 
- 
lastly, study duration is short enough (94 days). 
 
15- VULNERABLE POPULATION 
 
Not applicable. The population studied during the clinical investigation is not considered as a vulnerable 
population. 
 
16- SUSPENSION 
OR 
PREMATURE 
TERMINATION 
OF 
THE 
CLINICAL 
INVESTIGATION 
 
16.1 STUDY END  
 
The study end is defined as the last subject last visit.  
 
16.2 SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION 
 
16.2.1 Criteria and modalities for suspension or premature termination of the whole clinical 
investigation  
Urgent security measures in case of a new fact, which involves the premature termination of the study, 
might occur.  
They are followed, according to the case, by a study end declaration or by a substantial modification 
request. The opinion request is submitted in a 15 days delay after the implementation of urgent security 
measures to the Ethics Committee and to the Competent Authority if applicable.  
16.2.2 Criteria for access and to breaking the blinding/masking code 
 
Not applicable. 
 
16.2.3 Requirements for subjects follow-up 
 

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Subjects participating in the study are informed of the urgent security measures by the Investigator. A 
first information is made by phone, followed by a written document sent by email or post mail with receipt 
confirmation. A visit with the Investigator is then planned as soon as possible.   
 
17- PUBLICATION POLICY 
The Sponsor reserves the right to review all the manuscript(s) and abstract(s) before their submission 
for publication or presentation. Publication of data will be at the discretion of the Sponsor. 
 
This is not intended to restrict or hinder publication or presentation, but to allow the Sponsor to protect 
proprietary information and to provide comments based on information that may not yet be available to 
the Investigator(s). 
 
18- BIBLIOGRAPHY 
 
 
18.1 ETHICAL ASPECT 
 
1. 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI/ Ethical Principles for 
Medical Research Involving Human Subjects- Helsinki Declaration (1964) and its successive 
updates 
 
2. 
EN ISO 14155:2012 Clinical investigation of medical devices for human subjects - Good clinical 
practice 
 
3. 
Loi Jardé 2012-300 du 5 mars 2012 relative aux recherches impliquant la personne humaine 
 
4. 
LOI "INFORMATIQUE ET LIBERTES"/ Loi n°78-17 du 6 janvier 1978 relative à l’informatique, 
aux fichiers et aux libertés mise à jour par la loi n°2004-801 du 6 août 2004 concernant la 
protection des personnes pour la déclaration à la CNIL 
 
18.2 SKIN QUALITY AND QUALITY OF LIFE 
 
1. 
FRIED RG., CASH TF. / Cutaneous and psychosocial benefits of alpha hydroxyl acid use. 
Perceptual Motor Skills 1998;86:137-138. 
 
2. 
SADICK NS. / The impact of cosmetic interventions on quality of life. Derm Online J 
2008;14(8):2. Available at http://escholarship.org/uc/item/7s4656k6. 
 
3. 
SCHMID-OTT G, STEEN T. / Skin Disorders and Quality of Life. In: JH Stone, M Blouin, eds. 
International 
Encyclopedia 
of 
Rehabilitation. 
2010. 
Available 
at: 
www.cirrie.buffalo.edu/encyclopedia/en/article/152.  Accessed: 10 May 2016. 
 
4. 
SOMMER B., ZSCHOCKE I., BERGFELD D., SATTLER G., AUGUSTIN M. / Satisfaction of 
patients after treatment with botulinum toxin for dynamic facial lines. Dermatol Surg 
2003;29(5):456-60. 
 
18.3 JUSTIFICATION FOR DESIGN OF CLINICAL INVESTIGATION 
 
1. 
FAN Y., CHOI TH., CHUNG JH., JEON YK., KIM S. / Hyaluronic acid-cross-linked filler 
stimulates collagen type 1 and elastic fiber synthesis in skin through the TGF-β/Smad 
signaling pathway in a nude mouse model. J Plast Reconstr Aesthet Surg 2019; S1748-
6815(19)30152-4. [Epub ahead of print] 

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2. 
MOCHIZUKI M,, AOI N., GONDA K., HIRABAYASHI S., KOMURO Y. / Evaluation of the In 
Vivo Kinetics and Biostimulatory Effects of Subcutaneously Injected Hyaluronic Acid Filler. 
Plast Reconstr Surg 2018;142(1):112-121.  
 
3. 
PALIWAL S., FAGIEN S., SUN X., HOLT T., KIM T., HEE CK., VAN EPPS D., MESSINA DJ. / 
Skin extracellular matrix stimulation following injection of a hyaluronic acid-based dermal 
filler in a rat model. Plast Reconstr Surg 2014;134(6):1224-33.  
 
4. 
WANG F., GARZA LA., KANG S, et al. / In vivo stimulation of de novo collagen production 
caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. 
Arch Dermatol. 2007;143:155–163. 
5. 
FRANCA WANICK FB., ALMEIDA ISSA MC., LUIZ RR., SOARES FILHO PJ., OLEG B. Skin 
Remodeling Using Hyaluronic Acid Filler Injections in Photo-Aged Faces. Dermatol Surg 
201642(3):352-9.  
 
6. 
TURLIER V., DELALLEAU A., CASAS C., ROUQUIER A., BIANCHI P., ALVAREZ S., JOSSE 
G., BRIANT A., DAHAN S., SAINT-MARTORY C., THEUNIS J., BENSAFI-BENAOUDA A., 
DEGOUY A., SCHMITT AM., REDOULES D. / Association between collagen production and 
mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic 
acid filler. A randomised, placebo-controlled study. J Dermatol Sci. 2013;69(3):187-94. 
 
 
18.4 RESIDUAL RISK ASSOCIATED WITH DEVICE UNDER INVESTIGATION 
 
1. 
ALAM M, GLADSTONE H, KRAMER EM, MURPHY JP Jr., et al. / ASDS guidelines of care: 
injectable fillers. Dermatol Surg 2008;34(Suppl 1):S115–S48. 
 
2. 
DE BOULLE K., HEYDENRYCH I., CONSENSUS GROUP / Patient factors influencing dermal 
filler complications: prevention, assessment, and treatmentClinical – Clin Cosmet Investig 
Dermatol, 8 : 205–214, 2015. 
 
3. 
HEYDENRYCH I., KAPOOR KM., DE BOULLE K., GOODMAN G., SWIFT A., KUMAR N., 
RAHMAN E. / A 10-point plan for avoiding hyaluronic acid dermal filler-related complications 
during facial aesthetic procedures and algorithms for management - Clin Cosmet Investig 
Dermatol, 11 : 603–611, 2018. 
 
4. 
SIGNORINI M., LIEW S., SUNDARAM H., DE BOULLE K., GOODMAN GJ., MONHEIT G., 
WU Y., TRINDADE DE ALMEIDA AR., SWIFT A., VIEIRA BRAZ A., GLOBAL AESTHETICS 
CONSENSUS GROUP / Global Aesthetics Consensus: Avoidance and Management of 
Complications from Hyaluronic Acid Fillers—Evidence- and Opinion-Based Review and 
Consensus Recommendations - Plast. Reconstr. Surg. 137: 961e, 2016. 
 
18.5 INSTRUMENTAL DEVICES 
 
18.5.1 Moisturemeter D® 
 
1. 
ALANEN E., LAHTINEN T. and NUUTINEN J. / Penetration of electromagnetic fields of open-
ended coaxial probe between 1 MHz and 1GHz in dielectric skin measurements - Phys Med 
Biol, 44(7): N169-176, 1999. 
 
 
2. 
LAHTINEN T., NUUTINEN J. and ALANEN E. / Dielectric properties of the skin - In: Radio 
Frequency Radiation Dosimetry, Editors: B. J. Klauenberg and D. Miklavcic. Kluwer Academic 
Publishers, the Netherlands, 2000. 
 
3. 
MAYROVITZ H. N and LUIS M. / Spatial variations in forearm skin tissue dielectric constant. - 
Skin Res Technol, 16: 438-443, 2010.  

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4. 
MAYROVITZ H. N, BERNAL M., BRLIT F and DESFOR R. / Biophysical measures of skin tissue 
water: variations within and among anatomical sites and correlations between measures. - Skin 
Res Technol, 0: 1-8, 2012.  
18.5.2 Corneometer® 
 
1. 
BERARDESCA E. / EEMCO guidance for the assessment of stratum corneum hydration: 
electrical methods. - Skin Research and Technology. 1997; 3: 126 - 132. 
 
2. 
KHAZAKA D. / Assessing hydration of the skin: a practical approach to the measurement with 
the corneometer CM 825. - Proceed. Personal Care Ingredients Asia. 1998; 67-72. 
 
3. 
HEINRICH U. and al. / Multicentre comparison of skin hydration in terms of physical-, 
physiological- and product-dependent parameters by the capacitive method (Corneometer CM 
825) - Int. Journal of Cosmetic Science, April 2003, Volume 25, Numbers 1-2, pp. 45-53. 
 
4. 
CLARYS P., CLIJSEN R. and BAREL A. O. / Hydration measurements of the stratum corneum: 
comparison between the capacitance method (digital version of the Corneometer CM 825®) 
and the impedance method (Skicon-200EX®). - Skin Research and Technology. 2011, 0: 1-8 
 
5. 
CLARYS P., CLIJSEN R. and BAREL A. O. / Influence of probe application pressure on in vitro 
and in vivo capacitance (Corneometer CM 825®) and conductance (Skicon 200 EX®) 
measurements. - Skin Research and Technology. 2011, 1: 1-6 
18.5.3 Glossymeter® 
 
1. 
MONADERM / Skin Glossymeter GL200: measuring gloss on skin, lips, nails and hair. 
 
2. 
Ezerskaia A; and al. / High sensitivity optical measurement of skin gloss. – Biomedical optics 
express. 2017; vol. 8 ; n°9 : 3981 - 3992. 
18.5.4 Spectrophotometer® 
 
1. 
WEATHRALL I.L., COOMBS B.D. / Skin color measurements in terms of CIELAB color space 
values. - Journal of Investigative Dermatology. 1992; 99: 468-473. 
 
2. 
PIERARD G. E. / EEMCO Guidance for the assessment of skin colour – J. eur. Acad. Venereol. 
1998, 10 : 1-11. 
 
3. 
DE RIGAL J. and al. / The effect of age on skin color and color heterogeneity in four ethnic 
groups. Skin Research and Technology. 2010, 16: 168-178. 
18.5.5 Mexameter® 
 
1. 
HA J.H, JO NS, LEE H.K, LEE B.G, PARK W.J, PACIFIC CORP. The depigmentation effect of 
a new material extracted from paper mulberry and its comparison by the tree colorimeter 
instruments. 19th IFSCC Congress, October 1996, SYDNEY 1996. 
 
2. 
COURAGE & KHAZAKA Mexameter - General information’s and note of use - MONADERM - 
June 1999. 
18.5.6 Cutometer® 
 
1. 
DOBREV H. / Use of cutometer to assess epidermal hydration. - Skin Research and 
Technology. 2000; 6: 239-244. 
 

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2. 
SMALLS L. K., RANDALL WICKETT R., VISSCHER M. O. / Effect of dermal thickness, tissue 
composition, and body site on skin biomechanical properties. - Skin Research and Technology. 
2006; 12: 43-49. 
 
3. 
RYU H. S., JOO Y.H., KIM S. O., PARK K. C., YOUN S. W. / Influence of age and regional 
differences on skin elasticity as measured by the Cutometer®. - Skin Research and Technology. 
2008; 14: 354-358. 
 
4. 
BAREL A. O., CLYSEN R. and CLARYS P. / Evaluation of the elastic properties of the skin 
using the suction method (Cutometer). Which parameters to use for claims in anti-aging 
treatments? – ISBS Barcelona, 2009. 
 
5. 
LUEBBERDING S., KRUEGER N. and KERSCHER M. / Mechanical properties of human skin 
in vivo: a comparative evaluation in 300 men and women. – Skin Research and Technology. 
2014; 20: 127-135. 
18.5.7 Elastimeter® 
1. 
MAYROVITZ H.N. and coll. / Skin indentation firmness and tissue dielectric constant assessed 
in face, neck, and arm skin of young healthy women. – Skin Res. Technol. 2017; 23: 112-120 
 
2. 
MAYROVITZ H.N., WONG J., MADELINE F. / Age and hydration dependence of jowl and 
forearm skin firmness in young and mature women. – J Cosmet. Dermatol. 2017;1-9 
 
3. 
VIREN T. and coll. / Accuracy and reliability of a hand-held in vivo skin indentation device to 
assess skin elasticity. – Int. J. Cosmetic Sci. 2018; 40: 134-140  
18.5.8 Dermascan® 
 
1. 
BANGHA E., ELSNER P. / Evaluation of topical antipsoriatic treatment by chromametry 
visiometry and 20-MHz ultrasound in the psoriasis plaque test. - Skin Pharmacology. 1996; 9: 
298-306. 
 
2. 
NIVERT C., COURTOT T., CHADOUTAUD B., PUSEL B., ZANA K.,  CANAZZI F., JOFFRE F. 
/ Etude comparative de l'échographie, le scanner et l'IRM dans l'évaluation des états 
cellulitiques. - Cosmétologie. 1995; 2: 38-41. 
 
3. 
SEIDENARI S., PAGNONI A., DI NARDO A., GIANNETTI A. / Echographic evaluation with 
image analysis of normal skin: variations according to age and sex. - Skin Pharmacology. 1994; 
7: 201-209.