A Randomized, Multi-center, Evaluator-blinded, No-treatment Controlled Study to Evaluate the Effectiveness and Safety of Restylane Defyne for Correction of Chin Retrusion
Phase: NA
Conditions: Chin Retrusion
Sponsor: Galderma R&D

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A randomized, multi-center, evaluator-blinded, no-treatment controlled study to evaluate 
the effectiveness and safety of Restylane Defyne for correction of Chin Retrusion
Study product:
Restylane Defyne
Clinical Trial Number (CTN):
43CH1627
Sponsor:
Q-Med AB
Seminariegatan 21
SE-752 28 Uppsala, Sweden
Telephone: +46 18 474 90 00
Facsimile:  +46 18 474 90 01
Confidentiality Statement
This study protocol contains confidential information belonging to Q-Med AB. Except as may 
be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold 
such information in confidence and neither disclose it to any third parties (except where
required by applicable law) nor use it for any other purpose than in relation to the clinical 
study described herein.
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Summary of Changes in Clinical Study Protocol 43CH1627 from Version 2.0 to Version 3.0
Added text is written in bold and deleted text is written as strikethrough.
Section in 
protocol
Rational for changes
Description of changes
Synopsis-
Countries 
involved, 
number of 
sites/country, 
number of 
subjects
According to the 
suggestion of the 
leading site EC, 
Group A was deleted. 
Group A:
Up to 20 subjects (the first two eligible subjects per 
Treating Investigator, each site will have 2 Treating 
Investigators as maximum) will be enrolled as group A. 
These subjects will all receive treatment with Restylane 
Defyne.
Group B:
Evaluator treatment-blinded group with aApproximately 
148 subjects will be randomized in a 3:1 ratio to 
Treatment Group or no-treatment Control Group, i.e., 
111 subjects assigned to the Treatment Group and 37 
subjects assigned to the Control Group.
Synopsis-
Study design
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
And Clarification
This is a randomized, evaluator-blinded, no-treatment 
controlled study in subjects with Chin Retrusion. 
Subjects will be screened for eligibility within 21 days 
prior to Baseline. The first 2 eligible subjects for each 
Treating Investigator will receive treatment as Group A.
Before start of enrolment into Group B the injection 
technique will be evaluated by the Sponsor’s Medical 
Expert and the Treating Investigator. The evaluation will 
be performed when the subjects in Group A for each 
Treating Investigator have received their first treatment 
at the baseline visit. During the evaluation it will be 
ensured that an appropriate injection technique has been 
used. An evaluation form will be completed by the 
Treating Investigator and sent to Sponsor´s Medical 
Expert for assessment. If treatments are found to be 
correctly performed, no further training is needed, there 
are no outstanding questions regarding the injection 
technique and no other corrective actions are identified 
the enrolment in Group B can start for that Treating 
Investigator. The evaluation and decision to proceed with 
enrolment in Group B will be documented in writing. 
Eligible Ssubjects in group B will be randomized either to 
the Treatment Group or the Control Group in a 3:1 ratio.
Summaries of the results for Group A and B will be done 
separately in the study report.
Treatment 
Each subject assigned to Group A or the Treatment Group 
in Group B will receive an initial treatment on Day 1. 
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Subjects assigned to the Control Group in Group B will 
not receive treatment at baseline but will return for 
routine follow-up for 18 months. At month 6 visit after 
randomization, subjects in Control Group will be offered 
a treatment and, at the following visit, an optional touch-
up treatment.
Evaluation of effectiveness
Chin Retrusion will be assessed using a separate Four-
Point GCRS with photo guides by the Treating Investigator 
at each visit; and by the Blinded Evaluator at screening, 
baseline, 3, 6, 9 and 12 months after last treatment in 
Group A and Treatment Group, 
Synopsis-
Duration of 
treatment and 
follow-up
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
The total duration for each subject will be approximately 
14 months for Group A and Treatment Group, 20 months 
for Control Group.
Synopsis-
Statistical 
Methods
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
All summaries will be done separately for Group A and B. 
For statistical inference, only Group B will be used.
4.1 General 
Outline
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
And Clarification
This is a randomized, evaluator-blinded, no-treatment 
controlled study in subjects with Chin Retrusion. 
Subjects will be screened for eligibility within 21 days 
prior to Baseline. The first 2 eligible subjects for each 
Treating Investigator will receive treatment as Group A.
Before start of enrolment into Group B the injection 
technique will be evaluated by the Sponsor’s Medical 
Expert and the Treating Investigator. The evaluation will 
be performed when the subjects in Group A for each 
Treating Investigator have received their first treatment 
at the baseline visit. During the evaluation it will be 
ensured that an appropriate injection technique has been 
used. An evaluation form will be completed by the 
Treating Investigator and sent to Sponsor´s Medical 
Expert for assessment. If treatments are found to be 
correctly performed, no further training is needed, there 
are no outstanding questions regarding the injection 
technique and no other corrective actions are identified 
the enrolment in Group B can start for that Treating 
Investigator. The evaluation and decision to proceed with 
enrolment in Group B will be documented in writing. 
Eligible Ssubjects in group B will be randomized either to 
the Treatment Group or the Control Group in a 3:1 ratio.
Summaries of the results for Group A and B will be done 
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separately in the study report.
Treatment 
Each subject assigned to Group A or the Treatment Group 
in Group B will receive an initial treatment on Day 1. 
Subjects assigned to the Control Group in Group B will 
not receive treatment at baseline but will return for 
routine follow-up for 18 months. At month 6 visit after 
randomization, subjects in Control Group will be offered 
a treatment and, at the following visit, an optional touch-
up treatment.
Evaluation of effectiveness
Chin Retrusion will be assessed using a separate Four-
Point GCRS with photo guides by the Treating Investigator 
at each visit; and by the Blinded Evaluator at screening, 
baseline, 3, 6, 9 and 12 months after last treatment in 
Group A and Treatment Group, 
*Figure 1, the Flow chart was changed accordingly.
4.2 Number of 
Subjects
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
approximately 168 148 subjects will be enrolled.
4.3 Duration 
of Subject 
Participation
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
The total duration for each subject will be approximately 
14 months for Group A and Treatment Group, 20 months 
for Control Group.
4.4.1 
Randomizatio
n
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
Approximately 148 subjects in group B
will be 
randomized in a 3:1 ratio to treatment with Restylane 
Defyne or to no treatment.
Each subject will be assigned a subject number as they 
arrive 
for 
the 
treatment 
visit. 
For 
group 
B,
rRandomization will be assigned via the eCRF system.  
4.4.1 
Randomizatio
n
In the study, subjects 
will be randomized in 
eCRF, no additional 
randomization log is 
needed.
At the time for randomization, the subject’s initials, date 
of 
randomization, 
subject 
number, 
randomized 
treatment, and the signature of the Investigator must be 
documented in a randomization log.
4.7 Schedule 
of events
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
Table 1. Schedule of Events for Group A and Treatment 
Group
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4.7 Schedule 
of events
Typo error correction 
Table 2. 
4.8.1 Visits for 
Treatment 
Group
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
4.8.1 Visits for Group A and Treatment Group
5.4 Screening 
and Subject 
Numbers
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
When the Investigator has confirmed that all inclusion 
criteria and no exclusion criteria are met, each enrolled 
subject will be assigned a subject number by the eCRF. 
For group A,  consisting of a capital letter A, the site 
number, then followed by a consecutive number starting 
with 001 at each site, e.g. A1001, A1002; for group B, 
consisting of the site number followed by a consecutive 
number starting with 001 at each site, e.g. 1001, 1002.
7.2 Galderma 
Chin Retrusion 
Scale (GCRS)
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
The Blinded Evaluator will rate the subject’s Chin 
Retrusion using the GCRS at screening, baseline, 3, 6, 9 
and 12 months after last treatment in Group A and 
Treatment Group;
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
8.2 Laboratory 
assessment
Indirect
bilirubin=total 
bilirubin-direct 
bilirubin, and in some 
labs it is not listed, so 
indirect bilirubin was 
deleted.
Serum chemistry: renal function tests (creatinine and 
BUN); and liver function tests (aspartate amino 
transferase (ASAT), alanine amino transferase (ALAT) 
total bilirubin, and direct bilirubin and indirect bilirubin).
10.1 General
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
A comprehensive Statistical Analysis Plan (SAP) with 
detailed description of all statistical analyses will be 
written and finalized prior to database lock (DBL). All 
summaries will be done separately for Group A and B. For 
group A, only descriptive statistics will be used.
10.2 Analysis 
Populations
According to the 
suggestion of the 
leading site EC, 
Group A was deleted.
Safety
Includes all subjects in Group B who were 
treated 
with 
Restylane 
Defyne
or 
randomized 
to 
no-treatment 
group. 
Subjects are analyzed based on the as 
treated principle.
Full 
Analysis 
Set (FAS)
Includes all subjects in Group B who were 
treated 
with 
Restylane 
Defyne 
or 
randomized 
to 
no-treatment 
group. 
Subjects are analysed according to the 
randomisation assignment.
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Subject 
information 
and informed 
consent form
Updates required: 
Yes  
No  
Electronic case 
report form 
(eCRF)
Updates required:
Yes  
No  
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Study Administrative Structure
Sponsor
Q-Med AB
Seminariegatan 21
SE-752 28  Uppsala, Sweden
Telephone:
+46 18 474 90 00
Facsimile:
+46 18 474 90 01
Medical Expert
Clinical Project Manager
Study Statistician
Further details on all participating Investigators and the complete administrative structure of the study 
are found in the study files. Note that administrative changes are to be documented in the study files 
without requiring a clinical study protocol (CSP) amendment.
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Sponsor Signatures
The CSP is electronically signed in the document management system within the Q-
Med AB quality management system by the representatives listed below.
,   
Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Sponsor’s Medical Expert, Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Clinical Project Manager, Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Study Statistician, Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system 
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Signed Agreement of the Clinical Study Protocol
CTN:                                                      43CH1627
Title of the CSP:
A randomized, multi-center, evaluator-blinded, no-
treatment controlled study to evaluate the effectiveness 
and safety of Restylane Defyne for correction of Chin 
Retrusion
I, the undersigned, have read and understand the protocol specified above, and agree on 
the contents. The study protocol, the Clinical Trial Agreement and the additional 
information given in the Investigator Brochure for Restylane Defyne will serve as a basis for 
co-operation in this study.
Principal Investigator
Printed name 
Signature
Date
Study site
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Synopsis
Title of study:
A randomized, multi-center, evaluator-blinded, no-treatment controlled study to 
evaluate the effectiveness and safety of Restylane Defyne for correction of Chin 
Retrusion
Clinical Trial Number:  
43CH1627
Countries involved, 
number of 
sites/country, number 
of subjects:
The study will be conducted at approximately 5 sites in China. 
Approximately 148 subjects will be randomized in a 3:1 ratio to Treatment Group 
or no-treatment Control Group, i.e., 111 subjects assigned to the Treatment 
Group and 37 subjects assigned to the Control Group.
Objectives:
To evaluate the effectiveness and safety of Restylane Defyne versus a no-
treatment control in the treatment of Chin Retrusion.
Endpoints:
Primary effectiveness endpoint: 
Percentage of responders, defined by at least 1 point improvement from 
baseline on the Galderma Chin Retrusion Scale (GCRS), as measured by the 
Blinded Evaluator at 6 months (after last treatment in Treatment Group, and 
after randomization in Control Group).
Secondary effectiveness endpoints:
Percentage of responders, defined by at least 1 point improvement from 
baseline on the GCRS, as measured by the Blinded Evaluator at 3, 9 and 12 
months after last treatment in Treatment Group, and at 3 months after 
randomization, as well as 3, 6, 9 and 12 months after the last treatment in 
Control Group. 
Percentage of responders, defined by at least 1 point improvement from 
baseline on the GCRS, as measured by the Treating Investigator at each 
follow up visit. 
Safety endpoints:
Incidence, intensity, duration, and onset of adverse events (AEs) collected 
throughout the study.
Study Design:
This is a randomized, evaluator-blinded, no-treatment controlled study in 
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subjects with Chin Retrusion. 
Subjects will be screened for eligibility within 21 days prior to Baseline. Eligible 
subjects will be randomized either to the Treatment Group or the Control Group 
in a 3:1 ratio.
Treatment 
Each subject assigned to the Treatment Group will receive an initial treatment on 
Day 1. A touch-up treatment may be performed 4 weeks after the initial 
treatment if optimal chin augmentation has not been obtained. Optimal chin 
augmentation is defined as the best possible aesthetic result that can be 
obtained for an individual study participant, as agreed upon by the Treating 
Investigator and subject. At least one (>1) grade improvement from baseline on 
the GCRS should be the treatment target.
Subjects assigned to the Control Group will not receive treatment at baseline but 
will return for routine follow-up. At month 6 visit after randomization, subjects in 
Control Group will be offered a treatment and, at the following visit, an optional 
touch-up treatment. 
Evaluation of effectiveness
Chin Retrusion will be assessed using a separate Four-Point GCRS with photo 
guides by the Treating Investigator at each visit; and by the Blinded Evaluator at 
screening, baseline, 3, 6, 9 and 12 months after last treatment in Treatment 
Group, and at screening, baseline, 3 and 6 months after randomization, as well as 
3, 6, 9 and 12 months after last treatment in Control Group. 
Evaluation of safety
Information regarding AEs will be collected continuously during the study. 
Inclusion criteria: 
The subject must meet the following criteria to be eligible for the study:
1.
Signed and dated informed consent to participate in the study.
2.
Men or women aged 18 years of age or older of Chinese origin.
3.
Subjects seeking augmentation therapy for chin retrusion. 
4.
GCRS score of 1 or 2 as assessed by the Blinded Evaluator
Exclusion criteria:
The presence of any of the following exclusion criteria will exclude a subject from
enrolment in the study:
1.
Known/previous allergy or hypersensitivity to any injectable HA gel.
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2.
Known/previous allergy or hypersensitivity to local anaesthetics, e.g. 
lidocaine or other amide-type anaesthetics. 
3.
History of severe or multiple allergies, manifested by anaphylaxis. 
4.
Previous facial surgery, or tissue revitalization treatment with laser or 
light, needling, mesotherapy, radiofrequency, ultrasound, cryotherapy, 
chemical peeling or dermabrasion below the level of the horizontal line 
from subnasale within 6 months before treatment.
5.
Previous surgery (including aesthetic facial surgical therapy or 
liposuction), piercing or tattoo in the area to be treated. 
6.
Previous tissue augmentation therapy or contouring with any permanent 
(non-biodegradable) or semi-permanent filler, autologous fat, lifting 
threads or permanent implant below the level of the horizontal line from 
subnasale. 
7.
Previous use of any hyaluronic acid based or collagen based 
biodegradable facial tissue augmentation therapy in the chin and lips
within 12 months before treatment.
8.
Previous use of any neurotoxin below the level of the horizontal line 
from subnasale within 12 months before treatment.
9.
Presence of any disease or lesions near or at the area to be treated, e.g.
- Inflammation, active or chronic infection (e.g., in mouth, dentals, 
head and neck region);
- Facial psoriasis, eczema, acne, rosacea, perioral dermatitis, herpes 
zoster;
- Scars or deformities;
- Cancer or precancer (e.g. actinic keratosis).
10. History of radiation or cancer/precancer near or in the area to be 
treated.
11. Subjects with temporomandibular joint dysfunction.
12. Subjects with a dental or oral status on visual inspection that in the 
opinion of the Investigator would make the subject unsuitable for 
inclusion, or Subjects with dental, oral or sinus surgery within past 6 
months prior to the treatment visit or planned such surgery, including 
dental implants, during the study period.
13. History of or active collagen diseases such
as systemic lupus 
erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, skin 
or systemic scleroderma.
14. Subjects presenting with porphyria. 
15. Tendency to form keloids, hypertrophic scars, or any other healing 
disorder.
16. History of bleeding disorders or treatment with thrombolytics, 
anticoagulants or inhibitors of platelet aggregation (e.g. aspirin or other 
non-steroid anti-inflammatory drugs (NSAIDs), Omega-3, or vitamin E 
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within 2 weeks before treatment. 
17. Treatment 
with 
chemotherapy, 
immunosuppressive 
agents, 
immunomodulatory therapy (e.g. monoclonal antibodies), systemic 
corticosteroids within 3 months before treatment (inhaled corticoids are 
allowed).
18. Treatment with topical retinoids or corticosteroids on the face below the 
level of the horizontal line from subnasale within 1 month, or systemic 
retinoids within 6 months before treatment.
19. Any medical condition that in the opinion of the Investigator would make 
the subject unsuitable for inclusion.
20. Other condition preventing the subject from entering the study in the 
Investigator’s opinion, e.g. subjects not likely to avoid other facial 
cosmetic treatments, subjects anticipated to be unreliable, unavailable 
or incapable of understanding the study assessments or having 
unrealistic expectations of the treatment result.
21. Women who are pregnant or breast feeding, or Woman of childbearing 
potential who are not practicing adequate contraception or planning to 
become pregnant during the study period. 
22. Subjects planning to accept any other facial plastic surgical or cosmetic 
procedures below the level of the horizontal line from subnasale during 
the study (e.g., laser or chemical resurfacing, needling, facelift, 
radiofrequency etc.).
23. Study site personnel, close relatives of the study site personnel (e.g.
parents, children, siblings, or spouse), employees, or close relatives of 
employees at the Sponsor Company. 
24. Participation in any other clinical study within 30 days before treatment. 
Investigational 
product, 
dose and mode of 
administration:
Restylane Defyne (with lidocaine) consists of stabilized hyaluronic acid of non-
animal origin at a concentration of 20 mg/mL in phosphate buffered saline with 
lidocaine hydrochloride 3 mg/mL. The study product is supplied in 1 mL 
syringes. The contents of the syringe are sterile. Two 27G × ½” ultra-thin wall 
needles are co-packed with the syringe for injection.
Restylane Defyne should be injected in the mid to deep dermis, subcutis or 
supraperiostic zone depending on the area to be treated and the tissue support. 
Restylane Defyne will be administered inferior to the lower lip, including the 
area between the two lines from oral commissure to pre-jowl sulcus. 
The injection technique is at the discretion of the Investigator. Other areas in 
the chin may also be treated to obtain optimal correction. Optimal correction is 
defined as the best possible aesthetic result that can be obtained for an 
individual study subject, as agreed upon by the Treating Investigator and 
subject.
A maximum dosage of 2 mL for Chin Retrusion, and if other areas in the chin are
treated
for optimal correction, another
maximum dosage of 2mL
are
recommended, at each treatment session, i.e., initial treatment or touch-up 
treatment respectively. 
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Reference therapy, 
dose and mode of 
administration:
Not applicable.
Duration of treatment 
and follow-up: 
The total duration for each subject will be approximately 14 months for 
Treatment Group, 20 months for Control Group.
Effectiveness 
Assessment: 
Galderma Chin Retrusion Scale (GCRS):
GCRS is a Four-Point scale that assesses the Chin Retrusion from No Retrusion (0) 
to Severe Retrusion (3) as described below.  The Blinded Evaluator and Treating 
Investigator will rate the subject’s Chin for severity of Retrusion using the GCRS 
at all applicable study visits.  
GCRS
0
No Retrusion: The most anterior portion of the chin is at or near a 
vertical line drawn from the vermillion border of the lower lip.
1
Mild Retrusion: The most anterior portion of the chin is clearly 
recessed, but less than midway, between vertical lines drawn from 
the vermillion border of the lower lip and the oral commissure.
2
Moderate Retrusion: The most anterior portion of the chin is 
recessed approximately midway between vertical lines drawn 
from the vermillion border of the lower lip and the oral 
commissure
3
Severe Retrusion: The most anterior portion of the chin is clearly 
posterior to the midway point between vertical lines drawn from 
the vermillion border of the lower lip and the oral commissure.
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Safety Assessment:
AE will begin to be collected after ICF signed. Each subject will be questioned 
about AEs at each clinical visit following the screening visit. The question asked 
will be “Since your last clinical visit have you had any health problems?” 
Information on AEs can also be obtained from laboratory test report, signs and 
symptoms detected during each examination, observations by the study 
personnel, 
 spontaneous reports from the subjects.
Statistical Methods: 
Primary analysis
The percentage of responders (a responder will be defined as a subject with at 
least 1 point improvement from baseline GCRS ) will be calculated for Treatment 
Group at 6 months after last treatment, and for Control Group at 6 months after 
randomization based on the Blinded Evaluator's assessment.
 In addition, for each group the two-sided 
95% confidence intervals around the estimates of the percentage of responders 
will also be calculated.
Secondary analysis
The percentage of responders based on the GCRS will also be derived at all 
applicable follow-up visits for both the Blinded Evaluator’s assessment and the 
Treating Investigator’s assessment respectively. The response rates and their 95% 
confidence interval will be presented by visit and group. 
Safety
Adverse event incidences will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT).
Sample size
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To account for 15% drop-outs, approximately 111 
will be randomized to the Restylane Defyne Treatment Group and approximately 
37 to the Control Group.
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Abbreviations and definitions of terms 
AE
Adverse Event 
Blinded Evaluator
An evaluator responsible for independent evaluation of treatment 
result(s). The evaluator must not be involved in the treatment of the 
subject.
CFDA
China Food and Drug Administration
Co-ordinating 
Investigator
An Investigator assigned the responsibility for the coordination of 
Investigators at different centers participating in a multicenter study
CSP
Clinical Study Protocol
CTA
Clinical Trial Agreement
CTN
Clinical trial number
CV
Curriculum vitae
Device deficiency
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance (includes malfunctions, use 
errors, and inadequate labelling)
DMP
Data management plan
ECG
Electrocardiograph
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
G
Gauge
GCP
GCRS
Good Clinical Practice
Galderma Chin Retrusion Scale
HA
Hyaluronic acid
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFU
Instructions for Use
Investigational 
product
Medical device being assessed for safety or performance in a study. 
“Investigational product” is the same as “study device”, “investigational 
device”, or “investigational medical device”.
Institution
Any public or private entity or agency or medical or dental facility where 
clinical studies are conducted.
Investigator
The Principal Investigator or other qualified person, i.e. sub-Investigator, 
designated and supervised by the Principal Investigator at a study site to 
perform critical study-related procedures and/or make important study-
related decisions as specified on the delegation log. 
Investigator File
Essential documents relating to a clinical study as defined in GCP 
guidance document and maintained by the Investigator.
LRS
Lemperle Rating Scale
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MedDRA
Medical Dictionary for Regulatory Activities
NSAIDs
Non-steroid anti-inflammatory drugs
PI 
Principal Investigator
PP
Per protocol
QA
Quality assurance
RA
Regulatory authority
PT
Preferred term
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDV
Source data verification
S-HCG
Serum human chorionic gonadotropin
SOC
System organ class 
Sponsor file
Essential documents relating to a clinical study as defined in applicable 
GCP guidance document and maintained by the Sponsor.
Study Site
The department of the hospital that participates in the study.
U-HCG
Urinary human chorionic gonadotropin
VLS
Volume Loss Scale
WHO
World Health Organization
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Table of Contents
STUDY ADMINISTRATIVE STRUCTURE
2
SPONSOR SIGNATURES
8
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
9
SYNOPSIS
10
ABBREVIATIONS AND DEFINITIONS OF TERMS
17
TABLE OF CONTENTS
19
1
ETHICAL CONSIDERATIONS
22
2
BACKGROUND INFORMATION
22
2.1
Indication and population description
22
2.2
Investigational product description
22
2.3
Reference product description
23
2.4
Previous experience
23
2.4.1
Non-Clinical Documentation
23
2.4.2
Clinical Documentation
23
2.5
Study rationale and Justification for design
24
2.6
Risk and benefits
25
3
OBJECTIVE AND ENDPOINTS
26
3.1
Objective of the study
26
3.2
Endpoints of the study
26
3.2.1
Primary effectiveness endpoint:
26
3.2.2
Secondary effectiveness endpoints:
26
3.2.3
Safety endpoints:
26
4
DESIGN OF THE STUDY
26
4.1
General Outline
26
4.2
Number of Subjects
28
4.3
Duration of Subject Participation
28
4.4
Randomization and blinding
28
4.4.1
Randomization
28
4.4.2
Blinding
28
4.4.3
Emergency unblinding
28
4.5
Medical history
28
4.6
Concomitant Medication, Treatment, and Procedure
28
4.7
Schedule of events
30
4.8
Visits
33
4.8.1
Visits for Group A and Treatment Group
33
4.8.2
Visits for Control Group
34
5
SUBJECTS
36
5.1
Subject information and informed consent
36
5.2
Inclusion Criteria
37
5.3
Exclusion Criteria
37
5.4
Screening and Subject Numbers
39
5.5
Withdrawal of Subjects
39
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6
STUDY PRODUCTS
40
6.1
Investigational Product
40
6.2
Reference Product
40
6.3
Additional Products and Material
40
6.4
Packaging, Labelling and Storage
40
6.5
Product accountability
41
6.6
Treatment
41
6.6.1
Treatment Procedure
41
6.6.2
Treatment regimen (dose)
42
6.6.3
Post-treatment Care
43
6.6.4
Post-trial provisions
43
6.6.5
Electronic case report form recordings
43
6.6.6
Treatment compliance
43
7
EFFECTIVENESS ASSESSMENTS
43
7.1
General information
43
7.2
Galderma Chin Retrusion Scale (GCRS)
44
7.5
Photography
45
8
SAFETY ASSESSMENTS
45
8.2
Laboratory assessment 
46
8.3
ECG-screening
46
8.4
Adverse Events
47
8.4.1
Definition of Adverse Events
47
8.4.2
Definition of Serious Adverse Event
47
8.4.3
Recording Instructions
47
8.4.4
Reporting of Adverse Events
49
8.4.5
Reporting of Serious Adverse Events
49
8.4.6
Follow-up of Unresolved Events after study termination and new Events after study termination.
50
8.4.7
Pregnancy
51
8.4.8
Anticipated Adverse Events
51
8.5
Device Deficiencies
52
8.5.1
Definition of Device Deficiency
52
8.5.2
Recording Instructions
52
8.5.3
Reporting Device Deficiency
52
9
DATA HANDLING AND MANAGEMENT
52
9.1
Data management
52
9.2
Electronic case report forms
53
9.2.1
Data entry
53
9.2.2
The query process
54
9.2.3
User identification
54
9.2.4
Audit trail
54
9.3
Source documents
54
9.4
Record keeping and access to source data
55
9.5
Document and data retention
55
10
STATISTICAL METHODS
55
10.1
General
55
10.2
Analysis Populations
56
10.3
Demographics, baseline assessments, and subject characteristics
56
10.4
Effectiveness Analysis
56
10.5
Safety Analysis
57
10.6
Handling of Missing Data
57
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10.7
Interim Analysis
58
10.8
Data monitoring committee
58
10.9
Withdrawals and deviations
58
10.10
Sample Size
58
11
PROTECTION OF PERSONAL DATA
58
12
QUALITY CONTROL AND QUALITY ASSURANCE
59
12.1
Quality control
59
12.2
Quality assurance
59
12.3
Changes to the clinical study protocol
60
13
FINANCING, INDEMNIFICATION, AND INSURANCE
60
14
PUBLICATION POLICY
60
15
SUSPENSION OR PREMATURE TERMINATION
60
16
REFERENCES
62
17
APPENDICES
63
List of Tables
Table 1. Schedule of Events for Group A and Treatment Group .........................................................30
Table 2. Schedule of Events for Control Group....................................................................................31
Table 3.  Galderma Chin Retrusion Scale..............................................................................................44
List of Figures
Figure 1.  Flow Chart……………………………………………………………………………………………………………….……….27
Figure 2.  Treatment Area……………………………………………………………………………………………………….……….42
List of Appendices
Appendix 1
Declaration of Helsinki 
Appendix 2
Photo guide for Galderma Chin Retrusion Scale
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1
Ethical Considerations
1.1 Statement of ethical compliance
The study shall be conducted in compliance with the Clinical Trial Agreement (CTA), the 
Clinical Study Protocol (CSP), applicable Good Clinical Practice (GCP), and applicable regional 
or national regulations. The international standard for clinical study of medical devices for 
human subjects, ISO14155:2011 shall be followed. The International Conference on 
Harmonisation (ICH) guideline for GCP (E6) shall be followed as applicable for medical 
device. The study shall be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki (Appendix 1).
1.2 Application to independent ethics committee and/or regulatory authorities
It is the responsibility of the Principal Investigator (PI) to obtain approval of the 
CSP/CSP amendment(s) from the independent ethics committee (IEC). The study shall not 
begin until the required favourable opinion from the IEC has been obtained. The PI shall file 
all correspondence with the IEC in the Investigator file and copies of IEC approvals shall be 
forwarded to the Sponsor. Any additional requirements imposed by the IEC or regulatory 
authorities (RA) shall be followed. 
The collection, access to, processing, and transfer of protected health information or 
sensitive personal data shall be carried out in accordance with applicable rules and 
regulations.
2
Background Information
2.1
Indication and population description
As a medical device, Restylane Defyne is intended to augment the volume of facial tissues. 
In this study, it is intended for the correction of Chin Retrusion in subjects over the age of 18.
2.2
Investigational product description 
Among the different materials used as raw materials in dermal fillers, sodium hyaluronate,
also denoted hyaluronic acid when found in vivo and hereinafter referred to as HA, is the
most frequently used 1. Hyaluronic acid is a naturally occurring polysaccharide found in all
vertebrates and in some bacteria 1,2. The chemical structure is very simple with repeating
disaccharide units of glucuronic acid and N-acetylglucosamine. As the chemical structure of
HA is identical in all species and tissues, it is non-allergenic.
To minimize the risk for contamination, the HA used in the manufacture of Galderma’s HA
gels is of non-animal source, biosynthesized from Streptococcus species of bacteria. During
manufacturing, cross-links are introduced between the HA chains to obtain a gel network 
and as a result the duration of the gel in the body is several months, as compared to only a 
few days for a solution of native HA. The HA gel is insoluble in water and organic solvents;
however, the gel is highly hydrophilic and swells in water. Hyaluronic acid based fillers
typically exhibit better biocompatibility and fewer adverse reactions than fillers based on
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other materials. The gel, when injected, acts by increasing the tissue volume, thereby
improving tissue structure and support. The gel is gradually degraded over time and
eventually the correction made will subside.
Restylane Defyne is a sterile, biodegradable, transparent gel of non-animal cross-linked HA
containing a concentration of 20 mg HA per mL in a physiological buffer system. Lidocaine
hydrochloride (3 mg/mL) is added to the formulation to diminish the pain resulting from the
injection during the treatment. When the gel is injected and the tissue expands some pain 
can be experienced and it is therefore desirable to have a local anesthetic effect at the site 
of injection.
Restylane Defyne has been regulatory cleared under the brand name Emervel Deep 
lidocaine in more than 50 countries from most continents of the world including the US, 
Europe, Canada, Latin America, Australia, and Asia. The intended use, in the region of origin 
(Europe), is facial tissue augmentation for the correction of severe wrinkles or to redefine 
the shape of the face (cheeks, tear troughs, or lips). The regulatory cleared intended use 
differs between different countries. Depending on the area to be treated and the tissue 
support, the product should be injected in the mid to deep dermis, submucosal layer of the 
lips, subcutis, or supraperiostic zone.
The gel in Restylane Defyne is, produced using the Optimal Balance Technology (OBT).
2.3
Reference product description
Not applicable as no dermal filler intended for Chin retrusion correction is available in China 
at the time of this protocol.
2.4
Previous experience
2.4.1
Non-Clinical Documentation
Products manufactured using the OBT process have been tested and meet all 
biocompatibility requirements specified in the international standard ISO 10993:1 
(Biological Evaluation of Medical Devices; i.e., having no toxic or injurious effects on the 
human body) 3, 4; it is neither cytotoxic nor genotoxic, and it does not give rise to acute 
toxicity, pyrogenicity, skin irritation, or delayed sensitization. 
In in vivo animal studies, the OBT products demonstrated good filler longevity, similar or 
superior to comparator products, and all products were well tolerated with minimal 
microscopic inflammation scores secondary to limited tissue disturbance.
2.4.2
Clinical Documentation
The safety of and performance of Emervel Deep and Restylane Defyne have been evaluated 
in two randomized controlled studies focusing on nasolabial folds, in one open label study 
with full-face treatment with the Emervel range of products and in a large observational 
study.
Restylane Defyne has been evaluated in a 1-year, randomized, evaluator-blinded, active
controlled, multi-center, split-face comparison US study of the two HA fillers Restylane
Defyne and Juvéderm Ultra Plus with the objective to compare efficacy and safety 12. One 
hundred sixty-two (162) subjects with moderate to severe NLFs were treated with Restylane 
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Defyne in one NLF and Juvéderm Ultra Plus in the other. Non-inferiority of Restylane Defyne 
compared with Juvéderm Ultra Plus was demonstrated. Restylane Defyne showed a 
favorable safety profile in subjects with moderate to severe wrinkles and folds, and was 
comparable to Juvéderm Ultra Plus.
Another randomized, evaluator-blinded study in Europe comparing Emervel Deep (identical
to Restylane Defyne but without lidocaine) with Restylane Perlane in 86 subjects,
demonstrated similar safety between the dermal fillers and a superior, albeit of limited
clinical relevance, efficacy of Emervel Deep after NLF correction 13, 14.
The performance and safety of the use of Emervel Deep were evaluated for several other 
indications in an open-label full-face treatment study 6, 15, 16. These indications included 
marionette lines (n=92) and tear troughs (n=15). The performance was demonstrated in 
terms of wrinkle severity improvement and/or aesthetic improvement. In addition, high 
patient satisfaction was recorded. The improvement was demonstrated to last for up to 6 
months for these indications.
In addition, in a large observational study performed in France 8, 1822 patients were treated 
with one or more of the Restylane Emervel Collection of products. As it was a non-
interventional study product choice and injection volumes were at the discretion of the 58
participating physicians. Emervel Deep was used for several treatment areas including 
nasolabial folds, marionette lines, tear trough, lip corners, cheek volume, supramental 
crease, and vertical lip lines. This study investigated mean volumes injected, injection 
techniques used and tolerance. Performance was not evaluated.
Another Emervel filler products, Restylane Volyme,  was evaluated in an 18-month open 
study17 in 60 subjects with at least Grade 2 on the 4-point volume loss scale (VLS) for full 
face and at least 2 indications affected among chin, temporal areas, jawline, cheeks, 
cheekbones, and NLF. Performance was assessed by VLS, Lemperle rating scale (LRS), 
investigator GAIS, and 3-dimensional (3D) imaging. At 18 months, at least a 1-grade 
improvement in VLS was observed for full face (68.3% of subjects), chin (77.8%), temporal 
areas (73.7%), cheeks (66.6%), cheekbones (58.6%), jawline (43.1%), and NLF (71.4%; LRS). 
For all indications, more than 60% of the volume gained at 3 weeks was sustained at 18 
months based on 3D digital imaging. At 18 months, 95.0% of subjects had improved full-face 
GAIS and all subjects were satisfied with their aesthetic outcome. One subject (1.6%) had 
treatment-related adverse events.
Post market surveillance data for Restylane Defyne also support that the AE profile is 
acceptable.
2.5
Study rationale and Justification for design
Chin profile is an important component of the full facial appearance. In Asian people, chin 
retrusion is very common and many people would like to correct it because chin retrusion 
may be considered as unattractive. In clinical practice, surgical techniques, such as 
osteotomy or insertion of implants are commonly used for chin retrusion correction. More 
recently, HA injection for Chin augmentation has been reported in Chinese people18, 19. 
However, no HA filler intended for Chin Retrusion correction has been approved in China.
Although no published data for Restylane Defyne in Chin retrusion treatment, satisfied 
outcome was showed in anectdotal report. Also, pre-clinical testing/previous clinical 
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experience as described in Section 2.4, have demonstrated acceptable performance and 
safety for Restylane Defyne when used for facial tissue augmentation. Therefore, the 
Sponsor consider it justified to conduct a study to investigate Restylane Defyne for the 
treatment of Chin Retrusion. The study will be used as clinical documentation for 
registration of the product in China. No treatment control is chosen as no HA filler intended 
for Chin Retrusion correction is available in China at the time of this protocol.
2.6
Risk and benefits
By January 2017, Restylane Defyne has been regulatory cleared in 50 countries/regions, 
including US, EU, Canada, Australia, Hong Kong, Korea, India, etc. It is considered safe and 
effective for facial tissue augmentation. 
As all other injectable medical devices, Restylane Defyne has the potential to cause 
complications. Most events are related to the injected volume and injection technique,
though some could be associated with properties or constitutes of the gel itself. After the 
injection of Restylane Defyne, some common injection-related reactions might occur. These 
reactions include bruising, erythema, swelling, pain, tenderness, or itching at the implant 
site. Typically, resolution is spontaneous within one week after injection into the skin. The 
intensity and duration of these events are usually considered tolerable by a majority of 
subjects. The study product will be administered in accordance with the instructions in 
section 6.6. 
The primary potential benefit of the study is a perceived improvement in the treated areas. 
However, there is a risk that the subject will not gain the full aesthetic correction of Chin 
Retrusion. There is also a risk for development of palpable lumps or displacement of the 
injected gel. Inflammation or infection have been reported in a few cases after HA filler 
treatment. There may be risk of damaging body structures such as nerves or blood vessels 
connected to the injection site, however these risks are minor. Following facial aesthetic 
treatments isolated rare cases have been reported regarding ischemic events affecting the 
eye leading to visual loss, and the brain resulting in cerebral infarction. Detailed information 
on reported AEs relevant for Restylane Defyne is provided in the IB.
Lidocaine can in rare cases give allergic reactions, and therefore subjects with known allergy 
or hypersensitivity to local anaesthetics should not be included in the study. 
The frequency of post market AE reporting is based on the number of units sold. The
reporting frequency of AEs assessed as related to Restylane Defyne are ranging from seldom 
(approximately 1/1 000 – 1/10 000 events per sold unit) to rare/ isolated cases (i.e., <1/100 
000 events per sold unit).
The risks related to HA filler injections for facial tissue augmentation have been judged to be 
low, based on nonclinical data (Section 2.4.1), experience from clinical studies (Section 2.4.2) 
and post-marketing data. Given the anticipated low level of transient and acceptable AEs in 
connection with the injection, the risk-benefit assessment of the use of Restylane Defyne for 
treatment of Chin retrusion appears to offer a clinical benefit at reasonable risk.
Only study investigators qualified by education and experience, and who are skilled in the 
use of dermal fillers from their clinical practice and involvement in clinical research, will be 
chosen in order to assure proper device implantation and management of study risk.
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3
Objective and Endpoints
3.1
Objective of the study
To evaluate the effectiveness and safety of Restylane Defyne versus a no-treatment 
control in the treatment of Chin Retrusion.
3.2
Endpoints of the study
3.2.1 Primary effectiveness endpoint:
Percentage of responders, defined by at least 1 point improvement from baseline on 
the Galderma Chin Retrusion Scale (GCRS), as measured by the Blinded Evaluator at 6 
months (after last treatment in Treatment Group, and after randomization in Control 
Group).
3.2.2 Secondary effectiveness endpoints:
Percentage of responders, defined by at least 1 point improvement from baseline on 
the GCRS, as measured by the Blinded Evaluator at 3, 9 and 12 months after last 
treatment in Treatment Group, and at 3 months after randomization, as well as 3, 6, 9 
and 12 months after the last treatment in Control Group. 
Percentage of responders, defined by at least 1 point improvement from baseline on 
the GCRS, as measured by the Treating Investigator at each follow up visit. 
3.2.3 Safety endpoints:
Incidence, intensity, duration, and onset of adverse events (AEs) collected throughout 
the study.
4
Design of the Study
4.1
General Outline
This is a randomized, evaluator-blinded, no-treatment controlled study in subjects with Chin 
Retrusion. 
Subjects will be screened for eligibility within 21 days prior to Baseline. Eligible subjects will 
be randomized either to the Treatment Group or the Control Group in a 3:1 ratio.
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Treatment 
Each subject assigned to the Treatment Group will receive an initial treatment on Day 1. A 
touch-up treatment may be performed 4 weeks after the initial treatment if optimal chin 
augmentation has not been obtained. Optimal chin augmentation is defined as the best 
possible aesthetic result that can be obtained for an individual study participant, as agreed 
upon by the Treating Investigator and subject. At least one (>1) grade improvement from 
baseline on the GCRS should be the treatment target.
Subjects assigned to the Control Group will not receive treatment at baseline but will return 
for routine follow-up. At month 6 visit after randomization, subjects in Control Group will be 
offered a treatment and, at the following visit, an optional touch-up treatment. 
Evaluation of effectiveness
Chin Retrusion will be assessed using a separate Four-Point GCRS with photo guides by the 
Treating Investigator at each visit; and by the Blinded Evaluator at screening, baseline, 3, 6, 
9 and 12 months after last treatment in Treatment Group, and at screening, baseline, 3 and 
6 months after randomization, as well as 3, 6, 9 and 12 months after last treatment in 
Control Group. 
Evaluation of safety
Information regarding AEs will be collected continuously during the study. 
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4.2
Number of Subjects
The study will be performed at approximately 5 sites in China and approximately 148 
subjects will be enrolled. 
4.3
Duration of Subject Participation
The total duration for each subject will be approximately 14 months for Treatment Group, 
20 months for Control Group.
4.4
Randomization and blinding
4.4.1 Randomization
Approximately 148 subjects will be randomized in a 3:1 ratio to treatment with Restylane 
Defyne or to no treatment. Before starting the study, a computer generated randomization
list will be prepared under the supervision of a designated statistician. The randomization 
list will be stratified by center.
Each subject will be assigned a subject number as they arrive for the treatment visit. 
Randomization will be assigned via the eCRF system. The treatment information will be 
kept by the Treating Investigator during the study not to be disclosed to the Blinded
Evaluator.
4.4.2 Blinding
Only the evaluator will be blinded to treatment.
The Blinded Evaluator shall not be allowed to retrieve study supplies or to be present during 
opening of the study supplies or injections. The Treating Investigator or the subjects are not 
allowed to discuss treatments with the Blinded Evaluator. All documents with information 
on study products and randomization assignment shall be kept in a separate binder not 
available to the Blinded Evaluator.
4.4.3 Emergency unblinding
Not applicable as the Treating Investigator is unblinded.
4.5
Medical history
History of surgical events and medical conditions that are judged as relevant by the 
Investigator shall be documented in the eCRF using medical terminology.
Any concomitant medications and any relevant medical history (including prior facial 
dermatological procedures performed, and fillers or implants used) or concurrent diseases 
will be asked for.
4.6
Concomitant Medication, Treatment, and Procedure
Except as noted below, concomitant medications or other treatments or procedures may be
utilized when the PI or his/her authorized designee considers it medically necessary.
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Information regarding any use of concomitant medications, including over-the-counter
medications administered during the study is to be recorded in the eCRF. The generic name
or the trade name of all concomitant medication or a description of the procedure and the
reason for its use shall be documented in the eCRF.
The following medications, treatments, and procedures are restricted or prohibited during 
the study:

Thrombolytics, anticoagulants or inhibitors of platelet aggregation (e.g. aspirin or 
other non-steroidal anti-inflammatory drugs [NSAIDs]), Omega-3, or Vitamin E 
should not be used within two weeks before treatment to avoid increased bruising 
or bleeding at injection sites.

Lidocaine should be used with caution in patients receiving other local anesthetics or
agents structurally related to amide-type local anesthetics e.g., certain 
antiarrhythmics, since the systemic toxic effects can be additive.

Concomitant 
treatment 
with 
chemotherapy, 
immunosuppressive 
agents,
immunomodulatory therapy (e.g., monoclonal antibodies) is prohibited.

Long term concomitant treatment with systemic or topical (facial) corticosteroids is
prohibited (inhaled corticoids are allowed). Corticosteroids should be used with
caution and should be adjudged as necessary by the Investigator.

Use of systemic or topical (facial) retinoic acid is prohibited.

Facial tissue augmenting therapy, contouring or revitalization treatment with fillers, 
lifting threads, permanent implant, needling, mesotherapy,
radiofrequency, 
ultrasound, cryotherapy, fat-injection, neurotoxin, laser or light treatment, chemical 
peeling or dermabrasion below the level of the horizontal line from subnasale are 
prohibited.

Planned surgery including aesthetic facial surgical therapy or facial liposuction, sinus
surgery, dental root surgery or dental work, piercing or tattoo in the area to be 
treated is prohibited.

Participation in any other clinical study is prohibited
If a subject has used any of the above prohibited medications or performed any of the 
above prohibited procedures, a protocol deviation will be documented. The subject should 
continue in the study for the scheduled follow-up visits.
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4.7
Schedule of events
Table 2. Schedule of Events for Treatment Group
Treatment Group
Screening a
Baseline a/ 
Initial 
treatment
Optional 
Touch-up b
Follow-up 
Follow-up
Final visit 
/ Early termination 
D-21 to D1
D1
4W(±3d) after 
randomization
4W(±3d) after 
Last treatment 
3M(±1w), 6M(±1w) and 
9M (±2w) after last 
treatment
12M (±2w) after last 
treatment
Informed consent
X
Demography
X
Medical history & concurrent 
diseases
X
X
Concomitant 
medication/procedures
X
X
X
X
X
X
Vital signs
Xc
Laboratory tests
X
Xe
Xf
ECG
X
Pregnancy test
Xh
Xc,i,j
Xd,i
Xi
Inclusion and Exclusion criteria
X
X
Randomization
X
Treatment
X
X
GCRS (Blinded Evaluator) 
X
Xd
X
X
GCRS(Treating Investigator)
X
Xd
Xd
X
X
X
Photography
Xd
Xd
X
X
X
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Device deficiencies
X
X
Assessment of AE
X
X
X
X
X
X
Study termination
X
a)
Screening visit and baseline visit can be combined to one visit if feasible.
b)
This visit is only for subjects who receive touch-up (If no touch-up performed, subjects will conduct the 4w after last treatment visit.
c)
Prior to randomization.
d)
Prior to treatment.
e)
Only performed at 6M.
f)
Only performed at early termination if termination occurs before 6 months visit after last treatment.
g)
Only performed at 
6M.
h)
Serum pregnancy test (S-HCG).
i)
Urine pregnancy test (U-HCG).
j)
Only performed if the screening S-HCG was done 2 weeks before baseline.
Table 2. Schedule of Events for Control Group
Control Group
Activity 
Screening 
a
Baseline 
a
Follow-up
Follow-up
Follow-up 
/Treatment
Optional 
Touch-upb
Follow-up
Follow-up
Final visit
/ Early 
termination 
D-21 to 1
D1
4W(±3d)  after 
randomization
3M (±1w) after 
randomization  
6M(±1w) after 
randomization 
4W(±3d) 
after 6M 
treatment
4W(±3d)
after last 
treatment
3M (±1w), 6M(±1w) 
and 9M (±2w)
after last treatment
12M  (±2w) 
after last 
treatment
Informed consent
X
Demography
X
Medical history & 
concurrent diseases
X
X
Concomitant 
medication/procedures
X
X
X
X
X
X
X
X
X
Vital signs
Xc
Xd
Laboratory tests
X
Xd
Xe
Xf
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ECG
X
Pregnancy test
Xg
Xc,h,i
Xd,h
Xd,h
Xh
Inclusion and Exclusion 
criteria
X
X
Randomization
X
Treatment
X
X
GCRS(Blinded Evaluator) 
X
X
X
Xd
X
X
GCRS (Treating 
Investigator) 
X
X
X
X
Xd
Xd
X
X
X
Photography
X
X
X
Xd
Xd
X
X
X
Device deficiencies
X
X
Assessment of AE
X
X
X
X
X
X
X
X
X
Study termination
X
a)
Screening visit and baseline visit can be combined to one visit if feasible.
b)
This visit is only for subjects who receive touch-up (If no touch-up performed, subjects will conduct the 4w after last treatment visit).
c)
Prior to randomization.
d)
Prior to treatment.
e)
Only performed at 6M after last treatment
f)
Only performed at early termination if termination occurs before 6 months visit after last treatment.
g)
Serum pregnancy test (S-HCG).
h)
Urine pregnancy test (U-HCG).
i)
Only performed if the screening S-HCG was done 2 weeks before baseline.
j)
Only performed at
6M after last treatment.
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4.8
Visits
4.8.1 Visits for Treatment Group
4.8.1.1
Screening (D-21 to D1)

Informed consent

Demography (Initials, Date of birth, Gender and Ethnic origin)

Screening laboratory tests (haematology and serum chemistry)

S-HCG for childbearing potential women

ECG

Inclusion and exclusion criteria

GCRS (by Blinded Evaluator and Treating Investigator)

Medical history/concurrentdiseases including prior facial dermatological procedures 
performed, and fillers or implants used

Concomitant medications/procedures

AE during the visit
4.8.1.2
Baseline (D1)

Medical history/concurrentdiseases

Vital signs (pulse rate, blood pressure, respiratory rate, body temperature)

Inclusion and exclusion criteria

U-HCG for childbearing potential women (Only performed if the screening S-HCG was 
done 2 weeks before baseline)

Photography (before injection)

Randomization 

GCRS (by Blinded Evaluator and Treating Investigator)

Treatment

Concomitant medications /procedures

Device deficiencies

AE since last visit
4.8.1.3
Optional Touch-up 4W (±3d) after randomization (only for subjects who receive
touch-up)

Photography (before injection)

GCRS (by Treating Investigator)

U-HCG for childbearing potential women (before injection)

Treatment 

Concomitant medications/procedures

Device deficiencies

AE since last visit
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4.8.1.4
4W (±3d) after last treatment

Photography

GCRS (by Treating Investigator)

Concomitant medications /procedures

AE since last visit
4.8.1.5
3M (±1w), 6M (±1w) and 9M (±2w) Follow-up after last treatment

Photography

GCRS (by Blinded Evaluator and Treating Investigator)

Concomitant medications /procedures

AE since last visit

Laboratory tests (Only performed at 6M)
4.8.1.6
12M (±2w) after last treatment Final visit or Early termination

Photography 

GCRS (by Blinded Evaluator and Treating Investigator)

U-HCG for childbearing potential women

Concomitant medications/procedures

AE since last visit

Laboratory tests (Only performed at early termination if termination occurs before 6 
months visit after last treatment)

Study termination
4.8.2 Visits for Control Group
4.8.2.1
Screening (D-21 to D1)

Informed consent

Demography (Initials, Date of birth, Gender and Ethnic origin)

Screening laboratory tests (haematology and serum chemistry)

S-HCG for childbearing potential women

ECG

Inclusion and exclusion criteria

GCRS (by Blinded Evaluator and Treating Investigator)

Medical history/concurrentdiseases including prior facial dermatological procedures 
performed, and fillers or implants used

Concomitant medications/procedures

AE during the visit
4.8.2.2
Baseline (D1)

Medical history/concurrentdiseases

Vital signs (pulse rate, blood pressure, respiratory rate, body temperature)

Inclusion and exclusion criteria
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
U-HCG for childbearing potential women (Only performed if the screening S-HCG was 
done 2 weeks before baseline)

Photography 

Randomization 

GCRS (by Blinded Evaluator and Treating Investigator)

Concomitant medications /procedures

AE since last visit
4.8.2.3
4W (±3d) Follow-up after randomization 

Photography

GCRS (by Treating Investigator)

Concomitant medications /procedures

AE since last visit
4.8.2.4
3M (±1w) Follow-up after randomization 

Photography

GCRS (by Blinded Evaluator and Treating Investigator)

Concomitant medications /procedures

AE since last visit
4.8.2.5
6M (±1w) Follow-up after randomization / treatment

Vital signs (pulse rate, blood pressure, respiratory rate, body temperature)

laboratory tests (haematology and serum chemistry)

U-HCG for childbearing potential women (before injection)

GCRS (by Blinded Evaluator and Treating Investigator)

Photography (before injection)

Treatment

Concomitant medications /procedures

Device deficiencies

AE since last visit
4.8.2.6
Optional Touch-up 4W (±3d) after 6M treatment (only for subjects who received 
touch-up)

Photography (before injection)

GCRS (by Treating Investigator)

U-HCG for childbearing potential women (before injection)

Treatment
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
Concomitant medications /procedures

Device deficiencies

AE since last visit
4.8.2.7
4W (±3d) Follow-up after last treatment

Photography

GCRS (by Treating Investigator)

Concomitant medications /procedures

AE since last visit
4.8.2.8
3M (±1w), 6M (±1w) and 9M (±2w) Follow-up after last treatment

Photography

GCRS (by Blinded Evaluator and Treating Investigator)

Concomitant medications /procedures

Laboratory tests (Only performed at 6M)

AE since last visit
4.8.2.9
12M (±2w) after last treatment Final visit / early termination 

Photography 

GCRS (by Blinded Evaluator and Treating Investigator)

U-HCG for childbearing potential women

laboratory tests (haematology and serum chemistry) (Only performed at early 
termination if termination occurs before 6 months visit after last treatment)

Concomitant medications /procedures

AE since last visit

Study termination
5
Subjects
5.1
Subject information and informed consent
The PI or his/her authorised designee must always use the IEC-approved subject information 
and Informed Consent Form and it must not be changed without prior discussion with the 
Sponsor and approval from the applicable IEC.
It is the responsibility of the PI or his/her authorised designee to give each subject prior to 
inclusion in the study, full and adequate verbal and written information regarding all aspects 
of the clinical study that are relevant to the subject’s decision to participate throughout the 
study, e.g. explain the purpose and procedures of the study, the duration and number of 
expected participants, possible risks involved, and the opinion of the IEC. The subject shall 
be informed that the participation is confidential and voluntary and that the subject has the 
right to withdraw from the study at any time, without any effect on his/her future medical 
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care, treatment or benefits to which the subject is otherwise entitled. The information
shall be provided in a language clearly and fully understandable to the subject. The subject
shall be given sufficient time to read and understand the Informed Consent Form and to 
consider participation in the study. Before any study-related activities are performed, the 
Informed Consent Form shall be personally signed and dated by the subject and the PI or 
his/her authorised designee responsible for conducting the informed consent process. The 
consent includes information that data will be collected, recorded, processed, and 
transferred to countries outside China. The data will not contain any information that can be 
used to identify any subject.
All signed Informed Consent Forms shall be filed in the Investigator file. The subject shall be 
provided with a copy of the signed and dated Informed Consent Form and any other written 
information.
The Investigator shall ensure that important new information is provided to new and 
existing subjects throughout the study
5.2
Inclusion Criteria
The subject must meet the following criteria to be eligible for the study:
1. Signed and dated informed consent to participate in the study.
2. Men or women aged 18 years of age or older of Chinese origin.
3. Subjects seeking augmentation therapy for chin retrusion. 
4. GCRS score of 1 or 2 as assessed by the Blinded Evaluator.
5.3
Exclusion Criteria
The presence of any of the following exclusion criteria will exclude a subject from enrolment 
in the study:
1. Known/previous allergy or hypersensitivity to any injectable HA gel.
2. Known/previous allergy or hypersensitivity to local anaesthetics, e.g. lidocaine or 
other amide-type anaesthetics. 
3. History of severe or multiple allergies, manifested by anaphylaxis. 
4. Previous facial surgery, or tissue revitalization treatment with laser or light, needling, 
mesotherapy, radiofrequency, ultrasound, cryotherapy, chemical peeling or 
dermabrasion below the level of the horizontal line from subnasale within 6 months 
before treatment.
5. Previous surgery (including aesthetic facial surgical therapy or liposuction), piercing 
or tattoo in the area to be treated. 
6. Previous tissue augmentation therapy or contouring with any permanent (non-
biodegradable) or semi-permanent filler, autologous fat, lifting threads or 
permanent implant below the level of the horizontal line from subnasale. 
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7. Previous use of any hyaluronic acid based or collagen based biodegradable facial 
tissue augmentation therapy in the chin and lips within 12 months before 
treatment.
8. Previous use of any neurotoxin below the level of the horizontal line from subnasale
within 12 months before treatment.
9. Presence of any disease or lesions near or at the area to be treated, e.g.
- Inflammation, active or chronic infection (e.g., in mouth, dentals, head and neck 
region);
- Facial psoriasis, eczema, acne, rosacea, perioral dermatitis, herpes zoster;
- Scars or deformities;
- Cancer or precancer (e.g. actinic keratosis).
10. History of radiation or cancer/precancer near or in the area to be treated.
11. Subjects with temporomandibular joint dysfunction.
12. Subjects with a dental or oral status on visual inspection that in the opinion of the 
Investigator would make the subject unsuitable for inclusion, or Subjects with 
dental, oral or sinus surgery within past 12 months prior to the treatment visit or 
planned surgery, including dental implants, during the study period.
13. History of or active collagen diseases such as systemic lupus erythematosus, 
rheumatoid  arthritis, polymyositis, dermatomyositis, skin or systemic scleroderma.
14. Subjects presenting with porphyria. 
15. Tendency to form keloids, hypertrophic scars, or any other healing disorder.
16. History of bleeding disorders or treatment with thrombolytics, anticoagulants or 
inhibitors of platelet aggregation (e.g. aspirin or other non-steroid anti-
inflammatory drugs (NSAIDs), Omega-3, or vitamin E within 2 weeks before 
treatment. 
17. Treatment with chemotherapy, immunosuppressive agents, immunomodulatory 
therapy (e.g. monoclonal antibodies), systemic corticosteroids within 3 months 
before treatment (inhaled corticoids are allowed).
18. Treatment with topical (facial below the level of the horizontal line from subnasale) 
retinoids or corticosteroids within 1 month, or systemic retinoids within 6 months 
before treatment.
19. Any medical condition that in the opinion of the Investigator would make the 
subject unsuitable for inclusion.
20. Other condition preventing the subject from entering the study in the Investigator’s 
opinion, e.g. subjects not likely to avoid other facial cosmetic treatments, subjects 
anticipated to be unreliable, unavailable or incapable of understanding the study 
assessments or having unrealistic expectations of the treatment result.
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21. Women who are pregnant or breast feeding, or Woman of childbearing potential 
who are not practicing adequate contraception or planning to become pregnant 
during the study period. 
22. Subjects planning to accept any other facial plastic surgical or cosmetic procedures 
below the level of the horizontal line from subnasale during the study (e.g., laser or 
chemical resurfacing, needling, facelift, radiofrequency etc.).
23. Study site personnel, close relatives of the study site personnel (e.g. parents, 
children, siblings, or spouse), employees, or close relatives of employees at the 
Sponsor Company. 
24. Participation in any other clinical study within 30 days before treatment.
5.4
Screening and Subject Numbers
Each screened subject will be assigned a screening number consisting of “S” and the site 
number followed by a consecutive number starting with 01 at each site, e.g. S101, S102.The
screening number shall be listed on a subject screening and inclusion log. 
A “screening failure” is defined as a subject who does not fulfil the eligibility criteria. For 
screening failures, the eCRF screening visit shall be completed to an extent that makes it 
clear which assessments have been made and the reason why the subject did not fulfil the 
eligibility criteria. The reason for excluding a subject from entering the study shall also be 
specified in the subject screening and inclusion log. 
When the Investigator has confirmed that all inclusion criteria and no exclusion criteria are 
met, each enrolled subject will be assigned a subject number by the eCRF, consisting of the 
site number followed by a consecutive number starting with 001 at each site, e.g. 1001, 
1002.
The subject number, subject name, and other information sufficient to link the eCRF to the 
medical records (e.g. national identification number, chart number, etc.) shall be recorded 
on a subject identification list. The subject identification list shall only be available at the site, 
both throughout and after the study.
5.5
Withdrawal of Subjects
Each subject shall be advised in the Informed Consent Form that the subject has the right to 
withdraw from the study at any time, for any reason, without prejudice. Subjects may also 
be discontinued from this study if the Investigator determines that it is in the subject’s best 
interest to do so, and may be withdrawn at the Investigator's discretion at any time.
The withdrawal criteria are:

Medical reasons: If the subject suffers from a medical condition that in the judgement 
of the Investigator makes it medically necessary to withdraw the subject. The specific 
rationale for Investigator-initiated withdrawal of a subject for medical reasons shall 
document the specific condition for withdrawing the subject.

Withdrawal of informed consent: A subject can withdraw their consent to participate 
in the study at their own request or be withdrawn from participation in the study at 
the request of their legally authorised representative at any time for any reason.
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
Lost to follow-up: If a subject does not return for a scheduled visit, reasonable effort 
shall be made to contact that subject, e.g. call three times at different hours and leave 
messages if applicable before declaring the subject lost to follow-up.

Other: Examples of other reasons for withdrawal may be failure to comply with 
protocol requirements or to complete the protocol-specified evaluations.
The reason and date for withdrawal shall be documented in the eCRF. When possible, an 
explanatory comment shall be added in the study termination module/pages to further 
explain the reason for withdrawal. If withdrawal of a subject occurs during a regular study 
visit, the eCRF for that specific visit shall be completed as far as possible together with the 
study termination eCRF module. 
If withdrawal of a subject occurs between regular study visits the subject should when 
possible (irrespective of the reason for withdrawal) be scheduled for a termination visit. In 
these cases the eCRF for the early termination visit should be completed. The subject will 
need to follow the same requirements for the final visit.
If a subject is withdrawn from the study, all data collected until the time of withdrawal will 
be used in the analyses.
A withdrawn or discontinued subject must not be replaced or re-entered into the study.
If an AE which, according to the Investigator’s assessment, is related to the use of any of the 
study products and is still ongoing at the time of the withdrawal, such events shall be 
followed-up after the last study visit until resolved, assessed as chronic or stable, or for at 
least three months.
6
Study Products 
6.1
Investigational Product 
Restylane Defyne (with lidocaine) consists of stabilized hyaluronic acid of non-animal origin 
at a concentration of 20 mg/mL in phosphate buffered saline with lidocaine hydrochloride 
3 mg/mL. The study product is supplied in 1 mL syringes. The contents of the syringe are 
sterile. Two 27G × ½” ultra-thin wall needles are co-packed with the syringe for injection.
6.2
Reference Product
Not applicable.
6.3
Additional Products and Material
The study product is supplied in 1 mL syringes with sterile contents, together with two 27G 
× ½” Ultra thin wall needles for injection. Any other materials will be supplied by the site.
6.4
Packaging, Labelling and Storage
Restylane Defyne is manufactured by Q-Med AB, Uppsala, Sweden who will supply the study 
products. Restylane Defyne, commercially available in EU, will be used for the study.
The syringes are labelled with name of the product, name of the manufacturer (Q-Med AB).  
The syringe and needles are packed in a blister and put in a carton. The carton will be 
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labelled in local language, specifying the protocol number, lot number, expiry date and that 
the product is to be used for clinical studies exclusively.
The study products should be stored at a temperature up to 25oC and protected from 
sunlight and freezing. Opened syringes should not be re-used. Accountability will be 
performed as specified in section 6.5.
6.5
Product accountability
The study product will be released to the PI or his/her authorised designee after study 
approvals have been received from the IEC and the CTA has been signed by all parties.
The PI must ensure that the study product is kept in a secure location, with access limited to 
those authorised by the PI.
The study product must be traceable from the manufacturer to its use in subjects until 
return or disposal. It is therefore important that the PI maintains accurate product 
accountability records, i.e. documentation of the physical location of all study product, 
deliveries, and return of study product between the Sponsor or a third-party vendor and the 
PI, and documentation of administration of product to the subject. A shipping record shall 
be kept of all study products received from the Sponsor; including the product name, date 
received, batch number, expiration date, and amount received. In addition, dispensing logs 
shall be maintained including the product name, dispense date, the number of syringes 
used, the number of syringes left in stock, and the subject receiving study product. A log for 
accountability procedure is provided by the Sponsor. 
When the study is completed, all unused or expired study product at each study site shall be 
returned to the Sponsor or a third-party vendor for destruction. Any malfunctioning study 
products shall be reported as described in Section 8.5.3.
Product deliberately or accidentally destroyed during shipment or at a study site shall be 
accounted for and documented. Used syringes, disposable needle, and any opened unused 
material must be discarded and must not be reused according to standard procedures at the 
site. Disposal of hazardous material, i.e. syringes and needles must conform to applicable 
laws and regulations. The study product must not be used outside the study.
6.6
Treatment 
6.6.1
Treatment Procedure
The subjects will be informed about the indications, expected result, precautions, and
potential AEs.
Injection procedures are associated with a risk of infection. Aseptic technique and standard
practice to prevent cross-infections should be observed at all times including the use of
disposable gloves during the injection procedure. The subject should not wear make-up that 
might affect the treatment or evaluation on the day of treatment, if such make-up was 
already applied this must be completely removed prior to any injection. The treatment site 
should be thoroughly cleaned at least twice with a suitable antiseptic solution.
Restylane Defyne should be injected in the mid to deep dermis, subcutis or suprapriostic 
zone depending on the area to be treated and the tissue support. .
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Restylane Defyne will be administered inferior to the lower lip, including the area between 
the two lines from oral commissure to pre-jowl sulcus (Figure 2).
Figure 2. Treatment area
The injection technique is at the discretion of the Investigator. One potential injection 
technique includes administration of Restylane Defyne at one injection point at the most 
anterior portion of the chin with or without 2 points (one per side) on the sides of the chin 
for certain subjects based on the discretion of investigators. Other areas in the chin may 
also be treated to obtain optimal correction. Optimal correction is defined as the best 
possible aesthetic result that can be obtained for an individual study subject, as agreed 
upon by the Treating Investigator and subject.
To avoid breakage of the needle, no attempt to bend or otherwise manipulate the needle
before or during treatment is recommended. Before injecting, the air should be removed by
pressing the rod carefully until a small droplet is visible at the tip of the needle. Aspiration
prior to injection in order to avoid accidental intravascular injection is recommended. 
Injection should stop just before the needle is pulled out from the skin to prevent material
from leaking out from the injection site. Excessive pressure must not be applied at any time
during injection. If resistance is encountered the needle should be partially withdrawn and
repositioned or fully withdrawn and checked for function. The injection sites may be gently 
massaged by the Treating Investigator to conform the contour of the surrounding tissue.
6.6.2
Treatment regimen (dose)
A maximum dosage of 2 mL for Chin Retrusion, and if other areas in the chin are treated for 
optimal correction, another maximum dosage of 2mL are recommended, at each treatment 
session, i.e., initial treatment or touch-up treatment respectively.
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6.6.3
Post-treatment Care 
Ice in appropriate packaging can be applied on the treatment site for a short period to
reduce swelling and discomfort.
After the injection, some common injection-related reactions might occur. These reactions 
include erythema, swelling, pain, itching, bruising or tenderness at the implant site. Typically, 
resolution is spontaneous within one week after injection into the skin. The patient must 
avoid exposing the treated area to heat (sun bathing, sauna, steam baths, etc.) or extreme 
cold least until any initial swelling and erythema has resolved. In order to prevent infections, 
the patient should avoid touching the treated area and no creams or cosmetics should be 
applied before the skin has healed completely.
6.6.4
Post-trial provisions 
After the study is finalised Q-Med AB will not supply any more treatments to the subjects, 
even if the result does not persist.
6.6.5
Electronic case report form recordings
The following details of each injection are to be recorded in the eCRF: 

Date for administration

Lot number 

Local anaesthetic used (product name, volume injected/amount applied, and 
concentration)

Administered volume (for chin retrusion and other areas in the chin for optimal 
correction) 

Injection technique (retrograde/anterograde line injection, etc)

Depth of injection

Post-treatment care (massage, ice pack, etc)
In addition, any technical problems (device deficiencies) or clinical complications (AEs) 
associated with the injection will be recorded in the eCRF.
6.6.6
Treatment compliance
The treatment is an implant administered by the Treating Investigator and the details of the 
administration are recorded in the eCRF. No other measurements of treatment compliance 
will be made.
7
Effectiveness Assessments
7.1
General information
The methods for collecting effectiveness data include assessment of GCRS 9(Section 7.2), 
. A description of the
laboratory assessments is given in Section 8.2 and the ECG assessment in Section 8.3.
Assessments will be performed by 
, the Treating Investigator, and the Blinded
Evaluator, as described in the respective section. To avoid inter-observer variability, every 
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effort should be made to ensure that preferably the same individual who made the initial 
baseline determinations completes all corresponding follow-up evaluations. If it is not 
possible to use the same evaluator/investigator to follow the subject, evaluations should be 
overlapped (examine the subject together, discuss findings, and both sign in souce data) for 
at least 1 visit.
7.2
Galderma Chin Retrusion Scale (GCRS)
GCRS is a validated Four-Point scale assesses the Chin Retrusion from no retrusion (0) to 
severe retrusion (3) as described below.  A validation study concluded that the accuracy of 
this assessment tool was acceptable for use in assessing correction of Chin Retrusion in live 
assessment of subjects9. The Blinded Evaluator will rate the subject’s Chin Retrusion using 
the GCRS at screening, baseline, 3, 6, 9 and 12 months after last treatment in Treatment 
Group; and at screening, baseline, 3 and 6 months after randomization, as well as 3, 6, 9 and 
12 months after last treatment in Control Group. The Treating Investigator will do the GCRS
evaluation at all visits in each group. The Blinded Evaluator and Treating Investigator will 
conduct their GCRS assessments using a photoguide (Appendix 2). During the GCRS 
assessment, the subject shall have a neutral facial expression; with the head in an upright 
position and look straight at eye level with closed and relaxed lips. 
Table 3. Galderma Chin Retrusion Scale
GCRS
0
No Retrusion: The most anterior portion of the chin is at or near a 
vertical line drawn from the vermillion border of the lower lip.
1
Mild Retrusion: The most anterior portion of the chin is clearly 
recessed, but less than midway, between vertical lines drawn from 
the vermillion border of the lower lip and the oral commissure.
2
Moderate Retrusion: The most anterior portion of the chin is 
recessed approximately midway between vertical lines drawn from 
the vermillion border of the lower lip and the oral commissure
3
Severe Retrusion: The most anterior portion of the chin is clearly 
posterior to the midway point between vertical lines drawn from the 
vermillion border of the lower lip and the oral commissure.
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7.5
Photography 
Digital photographs will be taken of each subject pre-treatment at visits when treatment is 
performed and at each follow-up visit. The photographs will be used to document condition 
during the study; 
. If necessary, the 
photo should be taken when AEs occur to document AEs in the treated area. Note that no 
make-up that might affect the treatment or evaluation should be used on the photographs.
Each Investigator and other study site personnel designated to take photographs, if 
applicable, shall be thoroughly trained in the equipment and techniques, and how to upload 
photographs to the secured web portal, if applicable, before study start. The same 
photographic equipment and standardized setting must be used at each visit (e.g., distance, 
light, facial position and expression). For further details, please see the instruction of image 
procedures in the photo user guide.
All photos should be taken from a straight frontal view and both lateral views with full face 
frame. The subject shall have a neutral facial expression; with the head in an upright 
position and look straight at eye level with closed and relaxed lips. 
Each photograph shall be labelled with the subject initials, subject number, as well as the 
visit ID and visit date at which the photograph was taken. In order to maintain 
Confidentiality, the photographs must not include any information that may reveal the 
subject’s identity.
8
Safety Assessments
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8.2
Laboratory assessment
Laboratory samples will be taken at the screening visit (day -21 to day 1), at 6 months visit
after last treatment or at early termination if termination occurs before 6 months visit after 
last treatment for all subjects. In Control Group, it will also be taken at 6 months visit before 
treatment.
The following laboratory assessments will be performed:

Haematology: haemoglobin, red blood cells, white blood cells, differential count and 
platelet count.

Serum chemistry: renal function tests (creatinine and BUN); and liver function tests 
(aspartate amino transferase (ASAT), alanine amino transferase (ALAT) total bilirubin
and direct bilirubin).
A serum pregnancy test (S-HCG) in women of childbearing potential will be performed at 
screening. A urine pregnancy test (U-HCG) in women of childbearing potential will be 
performed prior to randomization at baseline, if the screening S-HCG was done 2 weeks 
before the baseline visit, prior to 6M treatment (only for Control Group), prior to touch-up 
treatment, and at the study completion or early termination.   The results of the hematology 
and serum chemistry will only be used for safety assessment by investigator and will not be 
collected in the eCRF. The pregnancy test results for women of childbearing potential will be 
recorded in the eCRF.
Other laboratory test might be performed at the discretion of the investigator. All 
laboratory assays will be performed at a local laboratory. Reference ranges will be supplied 
by the laboratory and used by the Investigator to assess the laboratory data for clinical 
significance and out of range pathological changes. 
Any clinical significant abnormal laboratory values at the 6 months visit after last treatment 
or early termination visit will be reported as AEs in the eCRF. In the control group, clinical 
significant abnormal laboratory values at the 6 months visit after randomization will also be 
reported as AEs.
8.3
ECG-screening
ECG will be taken at the screening visit (day -21 to day 1) and assessed by investigator for 
clinical significance. The results of ECG will only be used for screening purposes by the 
investigator and will not be collected in the eCRF.
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8.4
Adverse Events
8.4.1
Definition of Adverse Events
An AE is 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 study product. 
This definition includes:

events related to the investigational product or the reference product

events related to the procedures involved
. *For users or other persons, this definition is restricted to events related to the investigational product
8.4.2
Definition of Serious Adverse Event 
A serious adverse event (SAE) is an AE that:
a) led to death,
b) led to 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 body function, or
3. in-patient or prolonged hospitalisation***, 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) led to foetal distress, foetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such (see section 8.4.4).
**The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe. (Source: ICH-E2A clinical safety data management: definitions and standards for 
expedited reporting).
*** Planned hospitalisation for a pre-existing condition, or a procedure required by the CSP, without serious 
deterioration in health, is not considered a SAE. (Source: ISO14155:2011).
8.4.3
Recording Instructions
AE will begin to be collected after ICF signed. Each subject will be questioned about AEs at 
each clinical visit following the screening visit. The question asked will be "Since your last 
clinical visit have you had any health problems?" Information on AEs can also be obtained 
from signs and symptoms detected during each examination or from a laboratory test, 
observations by the study personnel, 
spontaneous reports from the 
subjects. 
When an AE is related to a device deficiency (refer to section 8.5), including technical device 
malfunction, the AE shall be recorded on the AE module in the eCRF and the technical 
complaint shall be reported separately on the clinical study complaint form.
Investigators, or other study personnel, will record all AEs in the eCRF, including:
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
Event term (recorded in standard medical terminology and avoiding abbreviations),

Description of event and affected area (if applicable),

Start date (First day with symptoms)

Stop date (Last day with symptoms)

Intensity (mild, moderate or severe according to definition in section 8.4.3.1)

Seriousness (serious or not serious, according to definition in section 8.4.2)

Causal relationship to study product and study product injection procedure (yes or 
no)

Action taken (none, medication treatment, non-pharmacological treatment or other 
procedures/ tests, subject withdrawn)

Outcome of the AE (ongoing, recovered, recovered with sequelae, death, chronic/ 
stable, not recovered at study end)
The AE module in the eCRF must be signed and dated by the Investigator.
8.4.3.1
Intensity
For each reported AE, the intensity will be recorded. The following definitions of intensity 
are to be used:
Mild:
A mild AE means awareness of symptoms or signs, but easily tolerated 
(acceptable).
Moderate:
A moderate AE means enough discomfort to interfere with usual activity 
(disturbing).
Severe:
A severe AE means incapacity to work or to do usual activity 
(unacceptable).
If the intensity changes over time the maximum intensity of the AE should be recorded.
8.4.3.2
Causal Relationship and Seriousness
Each AE, serious as well as non-serious, will be assessed by the Investigator for causal 
relationship with the study product and its use (the injection procedure) and for seriousness
(yes or no) of the event. 
A two-point scale (Yes or No) will be used for causality assessments. The Investigators shall 
be asked to indicate a response to each of the following questions in the eCRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?” and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product injection procedure?”
If any of these questions is answered Yes, the AE is considered related. There may be events 
that are only related to product or procedure.
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Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in 
order to fulfil regulatory requirements. 
8.4.4
Reporting of Adverse Events
AE reporting on each subject will start after the ICF has been signed. The reporting will 
continue during each follow-up visit (including telephone contacts and extra visits between 
planned visits) until the last scheduled visit in the study.
All AEs, non-serious as well as serious, are to be reported as an AE in the eCRF.
8.4.5
Reporting of Serious Adverse Events
After aware of any SAE, the Investigator shall report it to his/her administrative department 
of medical device clinical trials under the clinical trial institution, which in turn shall notify 
the Sponsor Representative in writing. This initial report can be made via fax or e-mail or 
submitted via the eCRF.
In case of difficulty to obtain all the required information within 24 hours, an initial report 
can be submitted, with the following information as a minimum, irrespective of whether 
some of it is regarded as preliminary:

CTN
Subject identification (age, gender, subject number)
AE description
date when AE occurred
date when AE became serious
Name of PI and original reporter (if other than Investigator)
Name of study product
Treatment specification
The Investigator will assure completeness of the SAE information and the supporting 
documentation.
Follow-up information and data missing in the initial SAE reporting shall be gathered as soon 
as possible and reported to the Sponsor via Sponsor’s representative immediately but not 
later than 24 hours of awareness of the new data. Complete and adequate information on 
each SAE is required. All attempts to obtain this information, including dates for follow-up 
activities, must be documented by the Investigator.
Supporting documentation to be provided with the SAE report:

Concomitant Medication Form/list

Concomitant Procedure/Treatment Form/list

AE Form/list

Medical History Form/list
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
Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
_______________________________________________________________________
Fax number for SAE reporting:               +46 18 474 91 01
E-mail for SAE reporting:
safety.q-med@galderma.com
Surface mail for providing
              
complementary information:                     Q-Med AB
                                                                     Attn. Corporate Medical Affairs & Vigilance
                                                                       Seminariegatan 21
                                                                       SE-752 28 UPPSALA, Sweden
E-mail for Device deficiency, 
Clinical Study Complaint Form:               Complaints.q-med@galderma.com  
_______________________________________________________________________
E-mail address will be pre-programmed in the eCRF system.
For non-urgent complementary information not possible to send by e-mail or fax, please use 
surface mail.
The SAE form (CFDA template in Chinese) must be signed and dated by the Investigator. If 
the initial 24-hour SAE report does not contain full information or if it is made without using 
the SAE form, the fully completed and signed SAE form shall be e-mailed or faxed to the 
Sponsor (contact details refer to 24-hour contact person list in ISF). A copy of the fully 
completed SAE form shall be kept at the site.
In addition, according to national regulations, the investigator will report a SAE Form (CFDA 
SAE template) to the administrative department of medical device clinical trials in his/her 
hospital, and they should, within 24 hours, deliver a written report to the corresponding 
Ethics Committee and the local food and drug administrative department of province, 
autonomous region and municipality at the place where the clinical trial institution locates. 
In case of a death incident, the clinical trial institutions and investigators should furnish the 
Ethics Committee and the Sponsor Representative with all required materials.
The Sponsor Representative in China is responsible for, within five (5) business days upon 
being informed, reporting any SAE or device defect with the likelihood of SAE to Shanghai 
Municipal FDA and Shanghai Municipal Commission of Health and Family Planning by fax or 
mail. The relevant correspondence will be documented in TMF; meanwhile, the Sponsor 
Representative should notify other clinical trial institutions and investigators participating in 
the study, and promptly report it to the Ethics Committee of the involved clinical trial 
institutions via the administrative department of medical device clinical trials according to 
national regulations.
8.4.6
Follow-up of Unresolved Events after study termination and new Events after study 
termination. 
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure and ongoing at study end, shall be followed up after the subject's 
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participation in the study is over. Such events shall be followed-up after the last study visit
until resolved, assessed as chronic or stable, or for at least three months. Final outcome 
after study end should be reported on a paper AE form.
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure with onset after subject participation in the study has ended that the 
investigator become aware of, shall be collected and reported to Sponsor on a paper AE 
form or in the post marketing AE form or SAE paper form if applicable. The events shall 
thereafter be followed up until resolved or considered chronic or stable, or for at least three 
months. Final outcomes shall be reported on the AE follow up form or in the post marketing 
AE form. The Investigator shall report any such AE or SAE including all previous Adverse 
events reported during the study and medical history of the patient to the Sponsor 
immediately but not later than 24 hours of awareness of the event. This report can be made 
via fax or e-mail according to contact details specified in section 8.4.5.
8.4.7
Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy during the study period the subject must continue to be followed 
within the study and the outcome of pregnancy must be reported even if the expected date 
of delivery occurs after study completion.
A pregnancy confirmed during the study period must be reported by the Investigator on a 
pregnancy report form immediately upon acknowledge be submitted to the Sponsor 
according to contact details specified in section 8.4.5. The report can be prospective or 
retrospective. Follow-up shall be conducted to obtain outcome information on all 
prospective reports. 
Cases that led to foetal distress, foetal death or a congenital abnormality or birth defect are 
to be regarded as SAEs and shall be reported on the exposure in utero report form to the 
Sponsor immediately but no later than 24 hours after the Investigators awareness. These 
events shall be handled as SAEs during data processing. Other complications during the 
pregnancy that are related to the pregnant woman and fulfils any serious criteria, such as 
pre-eclampsia requiring hospitalisation, shall be reported and handled as SAEs. Elective 
abortions without complications will not be reported as AEs.
8.4.8
Anticipated Adverse Events
After the injection some common injection-related reactions might occur with both 
products. These reactions include bruising, erythema, swelling, pain, tenderness and itching
at the injections site. Typically these reactions start on the day of treatment and resolve
spontaneous within one week after injection, as observed in the Chinese clinical study for 
Restylane and in consistent with international results for both products.
Refer to the Restylane Defyne IB for all anticipated AEs.
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8.5
Device Deficiencies
8.5.1
Definition of Device Deficiency
A device deficiency is defined as an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety* or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
*Inadequacy of device safety refers to properties of the device which could have or have led to an AE. 
8.5.2
Recording Instructions
When a device deficiency is discovered the Clinical Study Complaint Form in the eCRF will be 
completed by the Investigator. The type of complaint shall be described and injury to the 
subject or user or unintended exposure to study product shall be reported as applicable. If 
an injury has occurred, an AE module or a SAE Form should be completed following 
instructions in section 8.4. If no SAE was experienced as a result of the device deficiency the 
Investigator shall assess whether or not the device deficiency could have led to an SAE if:

Suitable action had not been taken,

Intervention had not been made or,

Circumstances had been less fortunate
The Sponsor will also make the same assessment in the Clinical Study Complaint Form. 
8.5.3
Reporting Device Deficiency
The Investigator will complete the Clinical Study Complaint Form to the Sponsor using the 
contact details specified in section 8.4.5. A device deficiency that led to a SAE and any 
device deficiency that could have led to a SAE shall be reported within 24 hours after the 
Investigator’s awareness in accordance to section 8.4.5.
In order to fulfil regulatory reporting requirements, all deficiencies with the study product 
must be assessed by both the Investigator and the Sponsor to determine if it could have led 
to a SAE. This assessment will be documented in the Clinical Study Complaint Form.
If an SAE has resulted from a device deficiency or if either the Investigator or the Sponsor 
assesses that the device deficiency could have led to an SAE the event will be reported in 
accordance with Regulatory requirements, as applicable.
The deficient study product shall be kept, if applicable, by the study site until the QA 
complaints group has confirmed whether the product shall be returned to Sponsor for 
further study or if it can be destroyed at the study site.
9
Data Handling and Management 
9.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter clinical data information into a database, efficiently and avoiding errors. The data 
management routine includes procedures for handling eCRFs, database set-up and 
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management, data entry and verification, data validation, and documentation of the 
performed activities including information of discrepancies in the process. The data 
management process will be described in detail in the data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the 
CSP. Data validation will be performed by computerised logical checks and manual review. 
Drugs and events will be coded in accordance with World Health Organization (WHO) Drug 
and medical dictionary for regulatory activities (MedDRA) dictionaries as specified in the 
DMP. Safety data (SAE) in the clinical database will be reconciled against the data in the 
safety database.
When all efforts have been made to ensure that the data recorded in the eCRFs and entered 
in the database is as correct and complete as possible, the clinical database will be locked. 
Study data will be transferred to SAS datasets which thereafter will be write-protected. 
Statistical analyses will be generated in SAS using data from the locked datasets.
9.2
Electronic case report forms 
An eCRF is required and shall be completed electronically for each screened subject 
(screening visit) and included subjects (subsequent visits). 
The eCRF includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Study data will 
be transcribed directly from the source documents, which are to be defined at each site 
before inclusion of the first subject.
Authorised study site personnel designated by the PI shall complete data collection. 
Appropriate training and security measures shall be completed with all authorised study site 
personnel prior to the study being initiated and any data being entered into the system for 
any subject.
The study data is the sole property of the Sponsor and shall not be made available in any 
form to third parties without written permission from the Sponsor. At the end of the study, 
electronic data are kept at the Sponsor and a copy (provided by the vendor) at the study site 
as part of the Investigator file.
Any delegation of collection of data shall be specified in a signature and delegation log.
9.2.1
Data entry
All data shall be entered in English. The eCRFs should always reflect the latest observations 
on the subjects participating in the study. Therefore, the eCRFs shall be completed within 5 
working days after the subject’s visit. The subject’s identity must always remain confidential, 
i.e. the name and address of the subjects must not be registered in the eCRFs or in the 
database. The Investigator must verify that all data entries in the eCRFs are accurate and 
correct. If some assessments are not done, or if certain information is not available, not 
applicable or unknown, the Investigator shall indicate this in the eCRF. The Investigator shall 
electronically sign off the study data. By signing, the Investigator takes responsibility for the 
accuracy, completeness, and legibility of the data reported to the Sponsor in the eCRF.
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9.2.2
The query process
The monitor shall review the eCRFs and evaluate them for completeness and consistency by 
100%. Each eCRF shall be compared with the respective source documents to ensure that 
there are no discrepancies between critical data. All entries, corrections, and alterations 
shall be made by the PI or his/her authorised designee. The monitor cannot enter data in 
the eCRFs. Once study data have been submitted to the central server via the eCRF, 
corrections to the data fields will be audit trailed, meaning that the reason for change, the 
name of the person who made the change, together with time and date will be logged. 
Roles and rights of the site personnel responsible for entering study data into the eCRF shall 
be determined in advance. If discrepant data is detected during review of the data, either by 
the Sponsor or its representatives, the responsible data manager or monitor shall raise a 
query in the electronic data capture application. The query shall state the question or data 
to be changed and shall be resolved in the system by the PI or his/her authorised designee. 
The appropriate study site personnel shall answer the queries in the eCRF. This will be audit 
trailed by the electronic data capture application meaning that the name of study site 
personnel, time, and date is logged.
9.2.3
User identification
Electronic CRF records will be automatically appended with the identification of the creator, 
by means of their unique User ID. Specified records shall be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data 
are accurate. This will be facilitated by means of the Investigator’s unique User ID and 
password; date and time stamps will be added automatically at time of electronic signature. 
If an entry in an eCRF requires change, the correction shall be made in accordance with the 
relevant software procedures. 
9.2.4
Audit trail
All changes will be fully recorded in a protected audit trail and a reason for the change shall 
be stated. Once all data have been entered, verified, and validated, the database will be 
locked.
9.3
Source documents
The eCRF is essentially considered a data entry form and does not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents 
used by the Investigator or hospital that relate to the subject’s medical history, that verifies 
the existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study. They include photographs, memoranda, material 
dispensing records, subject files, etc.
The PI is responsible for maintaining source documents. These shall be made available for 
inspection by the monitor at each monitoring visit. The Investigator must submit a 
completed eCRF for each subject for whom signed informed consent has been collected. All 
supportive documentation submitted with the eCRF, such as photographs, should be clearly 
identified with the subject number. Any personal information, including name, shall be 
removed or rendered illegible to preserve individual confidentiality.
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9.4
Record keeping and access to source data
The PI/institution shall permit study-related monitoring, audits and IEC review and shall 
provide direct access to the source data/medical record including the identity of all 
participating subjects (sufficient information to link records, i.e. eCRF, medical records, 
original signed Informed Consent Forms and detailed records of study product 
accountability). The records should be retained by the PI as required by local legislation and 
international guidelines. Any transfer of responsibility for storage of the records shall be 
documented and the Sponsor should be informed in writing.
The Sponsor shall verify that each subject has consented in writing to direct access to the 
original medical record/source data (by the use of written subject information and signed 
informed consent). The data recorded in the eCRFs shall be checked for consistency with the 
source documents/medical record by the monitor during monitoring (source data 
verification; SDV). In order to be able to perform SDV, information about each subject’s 
participation in the study has to be detailed in the medical record. 
The source data location log specifies what data that should be available in the medical 
record. The source data location log should also specify the data for which the eCRF serves 
as the source. Such data only need to be recorded in the eCRF and are typically associated 
with study-specific procedures and not with normal clinical care practice. For this type of 
study data the Investigator would not be expected to duplicate the information into the 
medical record.
9.5
Document and data retention
All records pertaining to the conduct of the study, including signed eCRFs, Informed Consent 
Forms, study product accountability records, source documents, and other study 
documentation must be retained after study completion according to national legislation 
and the CTA. Sponsor will inform the sites as to when these documents no longer needs to 
be retained. Measures should be taken to prevent accidental or premature destruction of 
these documents (e.g. protection against damage and unauthorised access, preferably by 
storage in a fire-proof cabinet). Refer to the CTA.
After study completion and database lock, a security sealed CD with electronic study data 
shall be provided by the eCRF vendor for archiving.
It is the PI’s responsibility to inform Q-Med AB in writing if the Investigator file is moved or if 
the responsibility for the documents is transferred to someone else
10 Statistical Methods
10.1 General
A comprehensive Statistical Analysis Plan (SAP) with detailed description of all statistical 
analyses will be written and finalized prior to database lock (DBL). All statistical analyses, 
including summary tables and data listings, will be performed using the SAS® system (version 
9.4 or later). 
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Continuous variables will be summarised using standard statistical measures, such as mean, 
median, standard deviation, minimum and maximum values. Categorical variables will be 
presented in frequency tables with number and percent of observations for each level.
All confidence intervals will be two-sided and use the 95% confidence level. All statistical 
testing will be two-sided and performed at a significance level of 5%.
10.2 Analysis Populations
The following populations will be defined:

Safety
Includes all subjects who were treated with Restylane 
Defyne or randomized to no-treatment group. Subjects 
are analyzed based on the as treated principle.

Full Analysis Set (FAS)
Includes all subjects who were treated with Restylane 
Defyne or randomized to no-treatment group. Subjects 
are analysed according to the randomisation assignment.

Per Protocol (PP) 
Includes all subjects in FAS that comply to the protocol 
procedures with no deviations that can affect the 
evaluation of the primary variable.
The FAS population is the primary population for all effectiveness analyses. All safety 
analyses will be based on the Safety population.
10.3 Demographics, baseline assessments, and subject characteristics
Demographic endpoints and subject characteristics will be presented by treatment group
using descriptive statistics.
10.4 Effectiveness Analysis
Primary analysis
The percentage of responders (a responder will be defined as a subject with at least 1 point 
improvement from baseline GCRS ) will be calculated for Restylane Defyne group at 6 
months after last treatment, and for no treatment Control Group at 6 months after 
randomization based on the Blinded Evaluator's assessment. 
In addition, for each group the two-sided 95% confidence intervals around the 
estimates of the percentage of responders will also be calculated. 
Secondary analysis
The percentage of responders based on the GCRS will also be derived at all applicable 
follow-up visits for both the Blinded Evaluator’s assessment and the Treating Investigator’s 
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assessment respectively. The response rates and their 95% confidence interval will be 
presented by visit and group. 
10.5 Safety Analysis
A graph will be generated to illustrate the incidence over time. Number of days 
with the event will be summarized using mean, SD, min, max and median.
All AEs will be coded by preferred terms in the MedDRA dictionary. 
Related AEs will be summarised by SOC, PT and intensity. In addition, for related AEs the 
number of days to onset and the duration of event will be summarised by SOC and PT and 
treatment using mean, SD, min, max and median. 
Serious AEs will be listed. 
Non-related AEs will be summarised by SOC, PT, and intensity and by treatment. 
10.6 Handling of Missing Data
Number of missing values will be summarized and reported as appropriate. 
Different assumptions regarding the missing data will be used. For the primary effectiveness 
analysis, missing values in the FAS will be assumed to be missing due to lack of effect. 
Therefore missing data up to the Month 6 visit will be imputed using the baseline 
observation carried forward (BOCF) method. As an alternative approach, missing data will 
be assumed to be unrelated to treatment effect. 
More details will be 
given in the SAP. Both of these alternatives will estimate the effectiveness of the treatment 
policy (irrespective of use of unallowable treatments, procedures, or medications) rather 
than the true, clinical treatment effect.
To obtain an estimate of the true clinical treatment effect, the primary effectiveness 
analysis will be performed using the PP.
All other endpoints will be analysed on available data, i.e. no imputations will be done.
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10.7 Interim Analysis
An interim analysis is planned once all subjects in Treatment Group complete the 12 months 
visit after last treatment (or discontinued before) and all subjects in Control Group complete 
the 6 months visit after last treatment (or discontinued before).
10.8 Data monitoring committee
Not applicable for this study.
10.9 Withdrawals and deviations
All withdrawn subjects will be listed individually, including at least subject number, date and 
reason for withdrawal, and last visit performed.
Subjects with CSP deviations will be listed individually, including subject number and 
observed deviation. Depending on the seriousness of the deviation, subject might be 
excluded from the PP population, which shall be documented prior to DBL.
Deviations from the statistical plan will be documented in protocol Deviation log.
10.10 Sample Size
To 
account for 15% drop-outs, approximately 111 will be randomized to the Restylane Defyne 
Treatment Group and approximately 37 to the Control Group.
11 Protection of personal data
For the purposes of the study, Sponsor will be considered the data controller, and 
Institution and PI will both be considered data processors.
All processing of personal data must be carried out in accordance with national legislation 
concerning the protection of personal data. The Institution and the PI are responsible for 
complying with all requirements pursuant to national legislation in the country in which the 
Institution and the PI are located. The Sponsor will ensure that all requirements are 
complied with for data processing, which is carried out in Sweden by the Sponsor.
The Informed Consent Form shall contain information about what personal data to be 
collected in the study and that this will be kept confidential. The provided information shall 
be sufficient to enable all subjects to give their consent not only to the participation in the 
study, but also to the processing of personal data. Such information includes information 
regarding the purposes of the collecting, processing, data transfer to countries outside 
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China, and the length of time during which personal data will be stored. The subject shall 
have the right of access to stored personal data, and the right to correction of incorrect 
information. If a subject decides to terminate the study prematurely, data collected before 
withdraw of consent will be used in the evaluation of the study, however no new data may 
be collected. Authorised representatives from the Sponsor or a RA may visit the study site to 
perform audits/inspections, including source data verification, i.e. comparing data in the 
subjects’ medical records and the eCRF. Data and information shall be handled strictly 
confidential.
12 Quality Control and Quality Assurance
12.1 Quality control
On-site monitoring of the study will be arranged by the Sponsor according to GCP guidelines 
to verify that the rights and well-being of the subjects are protected, the reported data are 
accurate, complete, verifiable from source documents, and that the conduct of the study 
complies with the approved CSP, subsequent amendment(s), GCP and the applicable 
regulatory requirements. 
Any CSP deviation shall be reported in the eCRF, which shall be verified, discussed, and 
collected, by the monitor and appropriate corrective and preventive actions shall be taken. 
The PI is responsible for promptly reporting any deviations from the CSP that affects the 
rights, safety or well-being of the subject or the scientific integrity of the study, including 
those which occur under emergency circumstances, to the Sponsor as well as the IEC if 
required by national regulations. Deviations shall be reviewed to determine the need to 
amend the CSP or to terminate the study. Handling of CSP deviations shall be performed as 
described in the monitoring manual.
Prior to subject enrolment, all individuals involved in the conduct and/or surveillance of a 
clinical trial are made aware of the deviation categories and reporting requirements via 
information/training session ensured by the Clinical Trial Team.
12.2 Quality assurance
The study site may be subject to quality assurance audit by the Sponsor as well as inspection 
by appropriate RA. It is important that the PI and other relevant study site personnel are 
available during the monitoring visits, possible audits, and inspections, and that sufficient 
time is devoted to the monitoring process.
Each participating member of the study site team shall provide a curriculum vitae (CV) or 
equivalent that demonstrates their qualifications to conduct the study. The CV shall give 
name, date and place of birth, address and place of work, and shall show the training, 
appointments and, for the PI, any other information that confirms the suitability of the PI to 
be responsible for the study. 
It is the responsibility of the PI to ensure that all personnel involved in the study are fully 
informed of all relevant aspects of the study, including detailed knowledge of and training in 
all procedures to be followed. All Investigators and other responsible persons shall be listed 
together with their function in the study on the signature and delegation log.
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12.3 Changes to the clinical study protocol
The PI and other site personnel involved in the study must not implement any deviation 
from or changes to the CSP without agreement with the Sponsor and prior review and 
documented approval from the IEC, except where necessary to eliminate an immediate 
hazard to the subjects. All changes to the final CSP must be documented in a written 
protocol amendment. However, administrative changes are to be documented in the 
Sponsor file without requiring a protocol amendment.
13 Financing, Indemnification, and Insurance
The CTA outlines the compensation and payment terms of the study. The CTA must be 
signed before the first subject is screened in the study. If there are differences between the 
CTA and the CSP regarding certain rights and obligations, the CTA is the prevailing 
document. Q-Med AB’s obligations in this clinical study are covered by Galderma’s global 
general liability program. An insurance certificate will be provided upon request. The 
institution/PI is obligated to maintain insurance coverage for their obligations in the clinical 
study according to the CTA.
14 Publication Policy
The PI’s, institutions, and Q-Med AB’s obligations regarding intellectual property rights, 
confidentiality, and publications are described in detail in the CTA.
The aim is to submit the results of this study for publication in the public database 
ClinicalTrials.gov and to a medical journal for a first joint publication of the results. Everyone 
who is to be listed as an author of the results of this multicentre study shall have made a 
substantial, direct, intellectual contribution to the work. Authorship will be based on (1) 
substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; and (2) drafting the work or revising it 
critically for important intellectual content; and (3) final approval of the version to be 
published; and (4) agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved*. Conditions 1, 2, 3, and 4 must all be met in order to be 
designated as author. Those who do not meet all four criteria should be acknowledged. 
Among the authors that fulfil the above mentioned criteria, one author will be appointed by 
Q-Med AB to take primary responsibility for the overall work as primary author.
*Defining the role of authors and contributors, compiled by the International Committee of 
Medical Journal Editors (ICMJE) (http://www.icmje.org). 
15 Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IEC or if it is 
judged that the subjects are subjected to unreasonable risks, or for valid scientific or 
administrative reasons. 
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The Sponsor may also decide to close a single study site due to unsatisfactory subject 
enrolment or non-compliance with the CSP, GCP, or applicable regulatory requirements.
In the event of premature termination, Q-Med AB will provide information on the handling 
of currently enrolled subjects who have not completed the study
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16 References
1.
Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol 2006 May-Jun; 19(3):141-50.
2.
Gold M. The science and art of hyaluronic acid dermal filler use in esthetic applications. J Cosmet 
Dermatol 2009 Dec; 8(4):301-7.
3.
Pons-Guiraud A. Classification des produits de comblement disponsible en France. Ann Dermatol 
Venerol 2008;135:I S27-34.
4.
Ascher B et al. Chapter 34: Hyaluronic acids. In: Ascher B ed. Injection Treatment in Cosmetic Surgery. 
Informa UK Ltd. 2009.
5.
Talarico S et al. High Patient Satisfaction of a Hyaluronic Acid Filler Producing Enduring Full-Facial 
Volume Restoration: An 18-Month Open Multicenter Study. Dermatologic Surgery 2015, 41(12):1361-
1369.
6.
Rzany,B., et al. Full-face rejuvenation using a range of hyaluronic acid fillers: efficacy, safety, and 
patient satisfaction over 6 months. Dermatol. Surg 2012a. 38, 1153-1161.
7.
Kestemont,P et al. Sustained efficacy and high patient satisfaction after cheek enhancement with a 
new hyaluronic acid dermal filler. J Drugs Dermatol 2012. 11, s9-16.
8.
Farhi,D., et al. The Emervel French survey: a prospective real-practice descriptive study of 1,822 
patients treated for facial rejuvenation with a new hyaluronic acid filler. J Drugs Dermatol 2013; 12, 
e88-e93.
9.
Galderma Chin Retrusion Scale Validation Report (internal document MA-33370).
10. Weiss RA et al. Effectiveness and Safety of Large Gel Particle Hyaluronic Acid with Lidocaine for 
Correction of Midface Volume Deficit or Contour Deficiency. Dermatol Surg. 2016 Jun; 42(6):699-709.
11. Glogau RG et al. A randomized, evaluator-blinded, controlled study of the effectiveness and safety of 
small gel particle hyaluronic acid for lip augmentation. Dermatol Surg. 2012 Jul;38(7 Pt 2):1180-92.
12. Galderma. A pivotal USA randomized evaluator-blinded, active-controlled, multi-center, splitface 
comparison study of Emervel® Deep Lidocaine versus Juvederm® Ultra Plus in the treatment of 
moderate to severe facial wrinkles and folds. Clinical Investigationa Report: RD.06.CIR.18156. 2013.
13. Galderma. A phase IV European randomized, evaluator-blinded, controlled, multi-center, 
intraindividual right-left comparison study of Evenor Deep versus Perlane in the treatment of soft 
tissue contour deformities. Clinical Investigational Report: RD.03.SRE.40072. 2011.
14. Ascher B, et al. Efficacy and safety of a new hyaluronic acid dermal filler in the treatment of severe 
nasolabial lines - 6-month interim results of a randomized, evaluator-blinded, intra-individual 
comparison study . J Cosmet Dermatol. 2011 Jun;10(2):94-8.
15. Rzany B, Cartier H, Kestermont P, Trevidic P, Sattler G, Kerrouche N, Dhuin JC. Correction of tear 
troughs and periorbital lines with a range of customized hyaluronic acid fillers. J Drugs Dermatol. 2012 
Jan;11(1 Suppl):s27-34.
16. Cartier H, Trevidic P, Rzany B, Sattler G, Kestemont P, Kerrouche N, Dhuin JC. Perioral rejuvenation 
with a range of customized hyaluronic acid fillers: efficacy and safety over six months with a specific 
focus on the lips. J Drugs Dermatol. 2012 Jan;11(1 Suppl):s17-26.
17. Talarico S, et al. High Patient Satisfaction of a Hyaluronic Acid Filler Producing Enduring Full-Facial 
Volume Restoration: An 18-Month Open Multicenter Study. Dermatol Surg. 2015 Dec;41(12):1361-9.
18. Zhou J, et al. Chin augmentation with hyaluronic acid injection. Chin J Aesth Plast Surg. 2014 Jan; 11 
(1): 26-28.
19. Zhang HJ, et al. Clinical application and observation of injectable modified sodium hyaluronate gel 
filler for facial cosmetic surgery. Zhonghua Kou Qiang Yi Xue Za Zhi. 2017 Mar 9;52(3):194-197.
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17 Appendices
Appendix 1
Declaration of Helsinki 
Appendix 2
Photo guide for Galderma Chin Retrusion Scale
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Appendix 1
Declaration of Helsinki
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WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving
Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be
applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient
will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients,
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving human subjects.
6.
The primary purpose of medical research involving human subjects is to understand the causes,
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the life, health, dignity,
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
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or other health care professionals and never with the research subjects, even though they have given 
consent.
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of 
the protections for research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that minimises possible harm to the environment.
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional.
13. Groups that are underrepresented in medical research should be provided appropriate access to
participation in research.
14. Physicians who combine medical research with medical care should involve their patients in research
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in
research must be ensured.
Risks, Burdens and Benefits
16. In medical practice and in medical research, most interventions involve risks and burdens. Medical 
research involving human subjects may only be conducted if the importance of the objective
outweighs the risks and burdens to the research subjects.
17. All medical research involving human subjects must be preceded by careful assessment of predictable
risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation.
Measures to minimise the risks must be implemented. The risks must be continuously monitored,
assessed and documented by the researcher.
18. Physicians may not be involved in a research study involving human subjects unless they are confident
that the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof of
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.
Vulnerable Groups and Individuals
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
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addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research.
Scientific Requirements and Research Protocols
21. Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used 
for research must be respected.
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.
Research Ethics Committees
23. The research protocol must be submitted for consideration, comment, guidance and approval to the
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence 
and must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information.
Informed Consent
25. Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees.
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of 
the study and the discomfort it may entail, post-study provisions and any other relevant aspects of 
the study. The potential subject must be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without reprisal. Special attention should be given to 
the specific information needs of individual potential subjects as well as to the methods used to 
deliver the information.
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After ensuring that the potential subject has understood the information, the physician or another
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed.
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study.
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship.
28. For a potential research subject who is incapable of giving informed consent, the physician must seek
informed consent from the legally authorised representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden.
29. When a potential research subject who is deemed incapable of giving informed consent is able to give
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be 
respected.
30. Research involving subjects who are physically or mentally incapable of giving consent, for example,
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative.
31. The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship.
32. For medical research using identifiable human material or data, such as research on material or data
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or
Where for compelling and scientifically sound methodological reasons the use of any intervention less
effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention
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and the patients who receive any intervention less effective than the best proven one, placebo, or no
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. In advance of a clinical trial, sponsors, researchers and host country governments should make
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process.
Research Registration and Publication and Dissemination of Results
35. Every research study involving human subjects must be registered in a publicly accessible database
before recruitment of the first subject.
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven interventions do not exist or other known
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.
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43CH1627 Clinical Study Protocol
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Appendix 2
Photo guide for GCRS 
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Appendix 3
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Title
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43CH1627 Clinical Study Protocol
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Appendix 3
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43CH1627 Clinical Study Protocol
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SIGNATURES PAGE
Date
Signed by
2018-01-15 07:26
Justification
Approved by Technical Expert
2018-01-15 07:30
Justification
Approved by Project Manager
2018-01-15 08:33
Justification
Approved by Technical Expert
2018-01-15 10:39
Justification
Approved by Owner
Title
Doc id 
43CH1627 Clinical Study Protocol
MA-34970
Effective date: 
Version: 
Effective
2018-01-15 10:39
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Print date:
2023-04-18 09:24
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