A Randomised, Multi-center, Subject and Evaluator-blinded Study Comparing the Pain and the Safety Profile Associate With Correction of Moderate to Severe Nasolabial Folds Using Restylane Perlane Lidocaine Compared to Restylane Perlane
Phase: NA
Conditions: Nasolabial Fold
Sponsor: Galderma R&D

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A randomised, multi-center, subject-blinded and evaluator-blinded study comparing the pain 
and the safety profile associated with correction of moderate to severe nasolabial folds using 
Restylane® Perlane Lidocaine compared to Restylane® Perlane 
Study products:
Restylane® Perlane Lidocaine
Restylane®  Perlane
Clinical Trial Number (CTN):
43TW1628
Sponsor:
Q-Med AB
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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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.
Head of Global A&C Clinical Development, 
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:                                                        43TW1628
Title of the CSP:
A randomised, multi-center, subject-blinded and 
evaluator-blinded study comparing the pain and the 
safety profile associated with correction of moderate 
to severe nasolabial folds using Restylane® Perlane
lidocaine compared to Restylane® Perlane. 
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 Instruction For Use for Restylane® Perlane Lidocaine and
Restylane® Perlane 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 randomised, multi-center, subject-blinded and evaluator-blinded study  
comparing the pain and the safety profile associated with correction of moderate 
to severe nasolabial folds using  Restylane® Perlane lidocaine compared to
Restylane® Perlane
Clinical Trial 
Number:  
43TW1628
Countries involved, 
number of 
sites/country, 
number of 
subjects:
The study will be conducted at approximately 3 sites located in Taiwan. The aim 
is to include 70 subjects treated with Restylane® Perlane Lidocaine (Perlane-Lido)
in one nasolabial fold (NLF) and Restylane® Perlane (Perlane) in the opposite NLF, 
as randomly assigned.
Objectives:
Primary objective:
To evaluate the pain associated with injections of Perlane-Lido compared to 
Perlane for correction of moderate to severe NLFs.
Secondary objective:
To evaluate the dermal filler effectiveness of Perlane-Lido compared to 
Perlane for correction of moderate to severe NLFs.
Safety objective:
To evaluate the safety of Perlane-Lido and Perlane throughout the study.
Endpoints:
Primary endpoint:
Proportion of subjects that have a within-subject difference in VAS score 
(Perlane - Perlane-Lido) of at least 10 mm at injection.
Secondary endpoints:

Proportion of subjects that have a within-subject difference in VAS score 
(Perlane - Perlane-Lido) of at least 10 mm at 15, 30, 45 and 60 minutes 
after injection. 

 
 
 
 
 
 
 
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2.
Men or women aged 20 years of age or older of Chinese origin.
3.
Subjects willing to abstain from any other facial plastic surgical or 
cosmetic procedures below the level of the lower orbital rim for the 
duration of the study of a maximum of 31 days (e.g., laser or chemical 
resurfacing, needling, facelift, radiofrequency  etc.).
4.
Intent to undergo correction of both NLFs
 
 
Exclusion criteria:
The presence of any of the following exclusion criteria will exclude a subject from 
enrolment in the study:
 
4.
Previous tissue revitalization treatment with laser or light, mesotherapy, 
radiofrequency, 
ultrasound, 
cryotherapy, 
chemical 
peeling 
or 
dermabrasion in the midface within 6 months before treatment.
 
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 lower orbital rim. 
7.
Previous use of any hyaluronic acid based or collagen based 
biodegradable facial tissue augmentation therapy below the level of the 
lower orbital rim within 12 months before treatment.
 
 
10. Scars or deformities, active skin disease, inflammation or related 
conditions, such as infection, perioral dermatitis, seborrheic eczema, 
rosacea, acne psoriasis and herpes zoster near or in the area to be 
treated.
 
 
 
 
 
 
 
 
 
  
 
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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.
 
 
 
 
 
 
Investigational 
product:
Restylane® Perlane lidocaine (Perlane-Lido)
Perlane-Lido 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 sterile 1 mL syringes 
with sterile contents, using a 29G thin walled (TW) × ½” needle.
The Treating Investigator will check the randomisation via the eCRF system, for 
study product i.e. the NLF on one side of the face will be randomly assigned to 
treatment with Perlane Lido and the opposite NLF to treatment with Perlane.
Perlane-Lido should be injected into the deep layer of the dermis and/or the 
surface layer of the subcutis of the facial skin in the NLF. The injection procedure 
should strictly follow the rules of aseptic surgical technique.
For treatment, it is recommended not to use more than 2 mL for each NLF.
The injection technique and the depth of injection should be the same for both 
sides of the face in any one subject to limit variability due to technique. Sufficient 
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amounts of product should be injected to fully correct the defect. Defects should 
be fully corrected, but not overcorrected.
No topical or local anaesthetic or other pain-relieving medication, including ice, 
should be used before all VAS assessment finished.
Reference therapy: Restylane® Perlane (Perlane)
Perlane consists of stabilized hyaluronic acid of non-animal origin at a 
concentration of 20 mg/mL, in phosphate buffered saline. The study product is 
supplied in sterile 1 mL syringes with sterile contents, using a 29G thin walled 
(TW) × ½” needle.
The Treating Investigator will check the randomisation via the eCRF system, for 
study product i.e. the NLF on one side of the face will be randomly assigned to 
treatment with Perlane Lido and the opposite NLF to treatment with Perlane.
Perlane should be injected into the deep layer of the dermis and/or the surface 
layer of the subcutis of the facial skin in the NLF. The injection procedure should 
strictly follow the rules of aseptic surgical technique.
For treatment, it is recommended not to use more than 2 mL for each NLF.
The injection technique and the depth of injection should be the same for both 
sides of the face in any one subject to limit variability due to technique. Sufficient 
amounts of product should be injected to fully correct the defect. Defects should 
be fully corrected, but not overcorrected.
No topical or local anaesthetic or other pain-relieving medication, including ice, 
should be used before all VAS assessment finished.
Duration of 
treatment and 
follow-up: 
A subject will be involved in the study for up to 31 days including an up to 14 
days screening period, treatment on Day 1, and 14 (+3) days follow up.
Assessments: 
Pain assessment by Visual Analogue Scale (VAS):
The VAS is a subjective scale to measure pain intensity. The subject shall be 
instructed to put a vertical mark, approximating the pain experienced during the 
procedure, on a 100 mm horizontal line labelled “no pain” at the left end and 
“the worst pain you can imagine” at the right end. The distance in mm from the 
left end (no pain) to the subject’s VAS mark shall be measured with a standard 
ruler. Each NLF will be evaluated independently.
Subjects will evaluate injection site pain for each side of the face at the time of 
injection (before massaging) and at 15, 30, 45, and 60 minutes post-treatment by 
completing a VAS.
Visual Analogue Scale (VAS)
Put a vertical mark ( ) on the line below to show your pain experience.
No pain __________________________________The worst pain you can imagine
                                                                                                                                
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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.
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
eCRF
FAS
Electronic Case Report Form
Full Analysis Set
G
Gauge
Generation 1
Generation 2
Includes parents, children and spouse. 
Includes siblings, grandparents and grandchildren.
GCP
Good Clinical Practice
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.
IRB
Institutional Review Board
MedDRA
NLF
Medical Dictionary for Regulatory Activities
Nasolabial fold
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NSAIDs
Perlane lido
Perlane
non-steroid anti-inflammatory drugs
Restylane® Perlane lidocaine
Restylane® Perlane
PI 
Principal Investigator
PP
Per protocol
QA
Quality assurance
RA
Regulatory authority
Reference 
product
Medical device, therapy (e.g. active control), placebo or no treatment, 
used in the reference group in a study
SAE
Serious adverse event
SDV
Source data verification
Sponsor file
Essential documents relating to a clinical study as defined in applicable 
GCP guidance document and maintained by the Sponsor.
U-HCG
Unanticipated AE
Urinary human chorionic gonadotropin
Related Adverse Event not described in the Instructions For Use
VAS
Visual analogue scale
WHO
World Health Organization
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Table of Contents
STUDY ADMINISTRATIVE STRUCTURE
2
SPONSOR SIGNATURES
3
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
4
SYNOPSIS
5
ABBREVIATIONS AND DEFINITIONS OF TERMS
13
TABLE OF CONTENTS
15
1
ETHICAL CONSIDERATIONS
18
2
BACKGROUND INFORMATION
18
2.2
Investigational product description
18
2.3
Reference product description
19
2.4
Previous experience
19
2.4.1
Non-Clinical Documentation
19
2.4.2
Clinical Documentation
19
2.5
Study rationale and Justification for design
20
2.6
Risk and benefits
20
3
OBJECTIVES AND ENDPOINTS
21
3.1
Objectives
21
3.1.1
The primary objective
21
3.1.2
The secondary objective
22
3.1.3
The safety objective
22
3.2
Endpoints
22
3.2.1
Primary endpoint
22
3.2.2
Secondary endpoints
22
3.2.3
Safety endpoints
22
4
DESIGN OF THE STUDY
22
4.1
General Outline
22
4.2
Number of Subjects
24
4.3
Duration of Subject Participation
24
4.4
Randomisation and blinding
24
4.4.1
Randomisation
24
4.4.2
Blinding
25
4.4.3
Emergency un-blinding
25
4.5
Medical history
25
4.6
Concomitant Medication, Treatment, and Procedure
25
4.7
Schedule of events
26
4.8
Visits
27
4.8.1
Visit 1: Screening (Day -14 to Day 1)
27
4.8.2
Visit 2: Baseline (treatment) (Day 1)
27
4.8.3
Visit 3: Follow-up/Final visit (Day 15 (+3 days)) or early termination
27
5
SUBJECTS
28
5.1
Subject information and informed consent
28
5.2
Inclusion Criteria
28
5.3
Exclusion Criteria
29
5.4
Screening and Subject Numbers
30
5.5
Withdrawal of Subjects
31
6
STUDY PRODUCTS
31
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11.9
Sample Size
49
12
PROTECTION OF PERSONAL DATA
49
13
QUALITY CONTROL AND QUALITY ASSURANCE
50
13.1
Quality control
50
13.2
Quality assurance
50
13.3
Changes to the clinical study protocol
51
14
FINANCING, INDEMNIFICATION, AND INSURANCE
51
15
PUBLICATION POLICY
51
16
SUSPENSION OR PREMATURE TERMINATION
52
17
REFERENCES
53
18
APPENDICES
54
List of Tables
Table 1. Schedule of Events .............................................................................................................................26
Table 5. Contact details for Sponsor and Sponsor’s representative................................................................42
List of Figures
Figure 1. Flow chart of the study.....................................................................................................................23
Figure 1. Flow chart of VAS Assessment..........................................................................................................24
List of Appendices
Appendix 1
Declaration of Helsinki 
Appendix 3        Restylane® Perlane lidocaine and Restylane® Perlane Taiwan IFU.
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2.5
Study rationale and Justification for design
 
 
 
 
 
 
 
 
2.6
Risk and benefits
 
 
 
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3
Objectives and Endpoints
3.1
Objectives
3.1.1 The primary objective
To evaluate the pain associated with injections of Perlane-Lido compared to Perlane for 
correction of moderate to severe NLFs.
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4.2
Number of Subjects
The study will be performed at approximately 3 hospitals in Taiwan and 70 subjects will be 
randomised and treated. 
4.3
Duration of Subject Participation
A subject will be involved in the study for up to 31 days including an up to 14 days screening 
period, treatment on Day 1, and 14 (+3) days follow up.
4.4
Randomisation and blinding
4.4.1 Randomisation
Each subject will be randomised to one of two treatment sequences; either Perlane-Lido in 
the subject’s right NLF followed by Perlane in the subject’s left NLF, or Perlane in the 
subject’s right NLF followed by Perlane-Lido in the subject’s left NLF. Treatment will always 
start in the subject’s right NLF. The randomisation list will be prepared under the 
supervision of a designated statistician. The randomisation list will be stratified by center.
Each subject will be assigned a subject number as they arrive for the treatment visit. 
Randomisation will be assigned via the eCRF system.  At the time for randomisation, the 
subject’s initials, date of randomisation, subject number, randomised treatment sequence, 
and the signature of the Investigator must be documented in a randomisation log.  The 
treatment information will be kept by the Treating Investigator during the study not to be 
disclosed to the Blinded Evaluator.
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4.4.2 Blinding
Because the method of administration is similar, the treatment can be partially masked 
from the subjects by simply preventing them from viewing the syringes during 
administration of the study products. This will be done by placing an opaque drape or patch 
over the subject’s eyes during the injection procedure. The Treating Investigator should also 
make sure that the subjects are kept blinded during the intervals between the two 
treatments. 
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 is not allowed to 
discuss treatments with the Blinded Evaluator or the subjects. All documents with 
information on study products shall be kept in a separate binder not available to the Blinded 
Evaluator.
4.4.3 Emergency un-blinding
Not applicable as the Treating Investigator is un-blinded.
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 
utilised when the PI or his/her authorised designee considers it medically necessary. 
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.
 
 
 
 
 
 
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4.8
Visits
 
 
 
 
 
 
 
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
5
Subjects
5.1
Subject information and informed consent
The PI or his/her authorised designee must always use the IEC/IRB-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/IRB.
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/IRB. 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 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 Subject Information 
and 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 Taiwan. 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 20 years or older of Chinese origin.
3. Subjects willing to abstain from any other facial plastic surgical or cosmetic 
procedures below the level of the lower orbital rim for the duration of the study of a 
maximum of 31 days(e.g., laser or chemical resurfacing, needling, facelift,
radiofrequency, etc.).
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4. Intent to undergo correction of both NLFs 
 
5.3
Exclusion Criteria
The presence of any of the following exclusion criteria will exclude a subject from enrolment 
in the study:
 
4. Previous tissue revitalization treatment with laser or light, mesotherapy, 
radiofrequency, ultrasound, cryotherapy, chemical peeling or dermabrasion in the 
midface within 6 months before treatment.
 
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 lower orbital rim. 
7. Previous use of any hyaluronic acid based or collagen based biodegradable facial 
tissue augmentation therapy below the level of the lower orbital rim within 12 
months before treatment.
 
10. Scars or deformities, active skin disease, inflammation or related conditions, such as 
infection, perioral dermatitis, seborrheic eczema, rosacea, acne psoriasis and herpes 
zoster near or in the area to be treated.
 
 
 
 
 
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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.
 
 
 
 
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 01 at each site, e.g. 101, 102.
The screening number, 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.
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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 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 to 
document subject outcome for the primary and secondary endpoints. In these cases the 
eCRF for the early termination visit should be completed. The subject will need to follow the 
same requirements for the visit at day 15.
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, the Investigator shall 
follow-up the subject until the AE resolves or is assessed by the Investigator to be “chronic” 
or “stable”. Follow-up information for at least three months shall be provided to the 
Sponsor.
6
Study Products 
The term “study products” refers to Perlane-Lido and Perlane.
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6.1
Investigational Product 
Perlane-Lido is a sterilized injectable gel consisting of stabilized HA of non-animal origin with 
concentration 20 mg/mL in phosphate buffered saline with lidocaine hydrochloride 
3 mg/mL. The gel is transparent and colorless. The product is supplied in single use sterile
syringes with a luer-lock fitting. Each syringe contains 1 mL gel. The syringe is labeled and 
packaged in a blister, with two 29G thin walled (TW) × ½” needles. The Investigational 
Product is a commercial product intended for the Taiwan market. An Instruction for Use 
(IFU) is included in the carton.
6.2
Reference Product
Perlane is a sterilized injectable gel consisting of stabilized HA of non-animal origin with 
concentration 20 mg/mL in phosphate buffered saline. The gel is transparent and colorless. 
The product is supplied in single use sterile syringes with a luer-lock fitting. Each syringe 
contains 1 mL gel. The syringe is labeled and packaged in a blister with two 29G thin walled 
(TW) × ½” needles. The Reference Product is a commercial product intended for the Taiwan
market. An Instruction for Use (IFU) is included in the carton.
6.3
Additional Products and Material
Perlane-Lido and Perlane will be supplied by the Sponsor. Any other materials will be 
supplied by the site.
6.4
Packaging, Labelling and Storage
 
 
 
 
 
 
 
 
 
 
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/IRB and the CTA has been signed by all parties.
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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 immediately after the treatment session and must not be 
reused due to risk for contamination of the unused material and the associated risks 
including infections 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 
 
 
 
 
 
 
 
 
 
 
 
 
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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
Pain Assessments
7.1
Pain assessment by Visual Analogue Scale (VAS)
The VAS is a subjective scale to measure pain intensity. The subject shall be instructed to put 
a vertical mark, approximating the pain experienced during the procedure, on a 100 mm 
horizontal line labelled “no pain” at the left end and “the worst pain you can imagine” at the 
right end. The distance in mm from the left end (no pain) to the subject’s VAS mark shall be 
measured with a standard ruler. Each NLF will be evaluated independently. 
Subjects will evaluate injection site pain for each side of the face at the time of injection 
(before massaging) and at 15, 30, 45, and 60 minutes post-treatment by completing a VAS.
Visual Analogue Scale (VAS)
Put a vertical mark ( ) on the line below to show your pain experience.
No pain                                                                                                                                                            The worst pain you can imagine
                                                                                                                             
 
 
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9
Safety Assessments
 
 
 
 
 
 
 
 
 
9.2
Adverse Events
9.2.1
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
9.2.2
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
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An AE does not need to be recorded as a SAE if it only represents a relapse or an expected 
change or progression of the condition that was the cause of the treatment, without the 
development of new symptoms and signs. 
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 9.2.5).
**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).
9.2.3
Recording Instructions
AEs will begin to be collected after ICF has been 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, subject diaries or spontaneous reports 
from the subjects. 
When an AE is related to a device deficiency (refer to Section 9.3), 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:

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 9.2.3.1)

Seriousness (serious or not serious, according to definition in Section 9.2.2)

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 sequele, death, chronic/ 
stable, not recovered at study end)
The AE module in the eCRF must be signed and dated by the Investigator.
9.2.3.1
Intensity
For each reported AE, the intensity will be recorded. The following definitions of intensity 
are to be used:
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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.
9.2.3.2
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 with a ‘Yes’, the AE is considered related. 
Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in 
order to fulfil regulatory requirements. 
9.2.4
Reporting of Adverse Events
AE reporting on each subject will start at the screening visit. 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.
9.2.5
Reporting of Serious Adverse Events
The Investigator shall report any SAE (both related and unrelated) to Sponsor and Sponsor´s 
representative immediately but not later than 24 hours of awareness of the event. This 
initial report shall be made via the eCRF system by completing the SAE module. Via the 
eCRF-system, the SAE-report will be automatically sent to Sponsor and Sponsor´s 
representative via the pre-programmed e-mail address in the eCRF system. If there are 
difficulties accessing the eCRF, an SAE paper form should be completed and sent via fax or 
e-mail to Sponsor and Sponsor´s representative (see contact details in Table 5).
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:

Clinical Trial Number (CTN)
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Subject identification (age, gender, subject number)
AE description
Classification of seriousness (according to definition in Section 9.2.2)
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 via the eCRF system to the Sponsor 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 

AE Form/list

Medical History Form/list

Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
If fax or e-mail is used for SAE-reporting, separate lists including the above information shall 
be submitted together with the SAE form.
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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 
immediately upon acknowledge. The report can be prospective or retrospective. The report 
shall be made via the eCRF system by completing the Pregnancy report module. The 
pregnancy report will be automatically sent to the Sponsor and Sponsor´s representative via 
pre-programmed e-mail address in the eCRF system. If there are difficulties accessing the 
eCRF, a paper pregnancy report form should be completed and sent via fax or e-mail to 
Sponsor and Sponsor´s representative according to contact details specified in Table 5.
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 and Sponsor´s representative immediately but no later than 24 hours after the 
Investigators awareness and sent via fax or e-mail according to contact details specified in 
Table 5. 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, in 
accordance to Section 9.2.5. 
Elective abortions without complications will not be reported as AEs.
9.2.8
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
spontaneously within a few days after injection.
Refer to the Perlane-Lido and Perlane Taiwan IFU.
9.3
Device Deficiencies
9.3.1
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. 
9.3.2
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 9.2. 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:
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
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. 
9.3.3
Reporting Device Deficiency
The Investigator will complete the Clinical Study Complaint Form in the eCRF system and 
send to the Sponsor and Sponsor´s representative via the pre-programmed e-mail address 
in the eCRF system. If there are difficulties accessing the eCRF, a paper Clinical Study 
Complaint Form should be completed and sent via e-mail or fax to Sponsor 
 
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 9.2.5.
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 an SAE.
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.
10 Data Handling and Management 
10.1 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 
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.
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10.2 Electronic case report forms (eCRFs)
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.
10.2.1 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.
10.2.2 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.
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10.2.3 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. 
10.2.4 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.
10.3 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.
10.4 Record keeping and access to source data
The PI/institution shall permit study-related monitoring, audits and IEC/IRB 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 
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11.3 Demographics, baseline assessments, and subject characteristics
Demographic endpoints and subject characteristics will be presented by study product using 
descriptive statistics.
11.4 Analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
Taiwan, 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.
13 Quality Control and Quality Assurance
13.1 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 PD log, 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/IRB 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.
13.2 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. 
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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.
13.3 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/IRB, 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.
14 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.
15 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). 
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16 Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IEC/IRB or if it is 
judged that the subjects are subjected to unreasonable risks, or for valid scientific or 
administrative reasons. 
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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17 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.
Fernandez-Cossio S and Castano-Oreja MT. Biocompatibility of two novel dermal fillers: 
histological evaluation of implants of a hyaluronic acid filler and a polyacrylamide filler. Plast 
Reconstr Surg. 2006 May; 117(6):1789-96.
4.
Heden P, Fagrell D, Jernbeck J, Rylander R, Samuelson U, Sellman G, Stark B. Injection of 
stabilized hyaluronic acid-based gel of non-animal origin for the correction of nasolabial 
folds: comparison with and without lidocaine. Dermatol Surg. 2010;36:775-781.
5.
Brandt F, Bank D, Cross SL, Weiss R. A lidocaine-containing formulation of large-gel particle 
hyaluronic acid alleviates pain. Dermatol Surg. 2010 Nov;36 Suppl 3:1876-85.
6.
Hamilton RG, Strobos J, Adkinson NF, Jr. Immunogenicity studies of cosmetically 
administered nonanimal-stabilized hyaluronic acid particles. Dermatol Surg. 2007;33 Suppl 
2:S176-85.
7.
Taylor SC, Burgess CM, Callender VD. Safety of nonanimal stabilized hyaluronic acid dermal 
fillers in patients with skin of color: a randomised, evaluator-blinded comparative trial. 
DermatolSurg. 2009;35 Suppl 2:1653-60.
8.
Taylor SC, Burgess CM, Callender VD. Efficacy of Variable-Particle Hyaluronic Acid Dermal 
Fillers in Patients with Skin of Color: A Randomised, Evaluator-Blinded Comparative Trial. 
Dermatol Surg. 2010;36:741-9.
9.
Glogau RG, Kane MA. Effect of injection techniques on the rate of local adverse events in 
patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg. 2008;34 
Suppl 1:S105-9.
10. Dover JS, Rubin MG, Bhatia AC. Review of the efficacy, durability, and safety data of two 
nonanimal stabilized hyaluronic acid fillers from a prospective, randomised, comparative, 
multicenter study. DermatolSurg. 2009;35 Suppl 1:322-30.
11. Lindqvist C, Tveten S, Bondevik BE, Fagrell D. A randomised, evaluator-blind, multicenter 
comparison of the efficacy and tolerability of Perlane versus Zyplast in the correction of 
nasolabial folds. Plast Reconstr Surg. 2005;115(1):282-9.
12. Carruthers A, Carey W, De LC, Remington K, Schachter D, Sapra S. Randomised, double-blind 
comparison of the efficacy of two hyaluronic acid derivatives, Perlane Perlane and Hylaform, 
in the treatment of nasolabial folds. DermatolSurg. 2005;31(11 Pt 2):1591-8.
13. Ascher B, Bayerl C, Brun P, Kestemont P, Rzany B, Poncet M, 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 randomised, evaluator-blinded, intra-individual comparison study. J 
Cosmet Dermatol. 2011;10(2):94-8.
14. Brandt F, Bassichis B, Bassichis M, O'Connell C, Lin X. Safety and effectiveness of small and 
large gel-particle hyaluronic acid in the correction of perioral wrinkles. J Drugs Dermatol. 
2011;10(9):982-7.
15. Weiss R, Bank D, Brandt F. Randomised, double-blind, split-face study of small-gel-particle 
hyaluronic acid with and without lidocaine during correction of nasolabial folds. Dermatol 
Surg 2010; 36:750–7.
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18 Appendices
Appendix 1
Declaration of Helsinki 
Appendix 3
Restylane® Perlane Lidocaine and Restylane® Perlane Taiwan IFU
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Appendix 1
Declaration of Helsinki
1(5)
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.
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Appendix 1
Declaration of Helsinki
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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 
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.
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Declaration of Helsinki
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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 
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.
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Declaration of Helsinki
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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.
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.
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Declaration of Helsinki
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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
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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Appendix 3
Restylane® Perlane Lidocaine and Restylane® Perlane Taiwan IFU
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Appendix 3
Restylane® Perlane Lidocaine and Restylane® Perlane Taiwan IFU
2(4)
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Appendix 3
Restylane® Perlane Lidocaine and Restylane® Perlane Taiwan IFU
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Appendix 3
Restylane® Perlane Lidocaine and Restylane® Perlane Taiwan IFU
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Sign page:1 of 1
SIGNATURES PAGE
Date
Signed by
2017-04-11 12:27
Justification
Approved by Technical Expert
2017-04-11 12:35
Justification
Approved by Owner
2017-04-11 13:12
Justification
Approved by Technical Expert
2017-04-13 06:29
Justification
Approved by Technical Expert
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