A Randomised, Multi-center, Subject and Evaluator-blinded Study Comparing Pain and Safety Profile Associated With Correction of Moderate to Severe Nasolabial Folds Using Restylane With and Without Addition of 0.3% Lidocaine Hydrochloride
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 with and without  addition of 0.3% lidocaine hydrochloride
Study products:
Restylane Lidocaine
Restylane
Clinical Trial Number (CTN):
43CH1504
Co-ordinating Investigator 
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 43CH1504 from Version 
3.0 to Version 4.0
Added text is written in bold and deleted text is written as strikethrough.
Section in the 
clinical study 
protocol
Rational for changes
Description of changes
Cover Page
Co-ordinating Investigator
changed
Investigators and 
Study 
Administrative 
Structure
Co-ordinating Investigator
changed and site changed.
Co-ordinating Investigator
Principal Investigator
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Synopsis- co-
ordinating 
Investigator/ 
Principal 
Investigators
Co-ordinating Investigator
changed and site changed.
Section 8.4.5 
Reporting of 
Serious Adverse 
Events
SAE reporting process
changed according to new 
issued regulation by CFDA
and the email address 
updated
After aware of any SAE, tThe Investigator shall 
report any SAE to the Sponsor immediately but 
no later than 24 hours of awareness of the 
event. it to his/her administrative department 
of medical device clinical trials under the 
clinical trial institution, which in turn shall
notify the Sponsor in writing. This initial report 
can be made via fax or e-mail or submitted via 
the eCRF.
E-mail for SAE reporting:
complaints.q-med@galderma.com
safety.q-med@galderma.com
In addition, according to national regulations, the 
Investigator should report the event within 24 
hours of awareness to the Regulatory authority
(RA, including China Food and Drug 
Administration (CFDA) and relevant Provincial 
Food and Drug Administration). The Investigator
shall also report SAEs to the responsible IEC 
without undue delay, if applicable according to 
national regulations or local IEC requirements. 
The PI is responsible for checking what reporting 
procedures are applicable for his/her IEC 
regarding SAEs and final report of the outcome 
of the study and to comply with such reporting 
procedures during the study period. the 
administrative department of medical device 
clinical trials 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 with all 
required materials.
The local office in Beijing of the Sponsor is 
responsible for reporting SAE to the RA, within 
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five (5) business days upon being informed, 
reporting any SAE or device defect with the 
likelihood of SAE to the food and drug 
administrative department where it has been 
registered and the competent authorities of 
health and family planning at the same level; 
meanwhile, the Sponsor should notify other 
clinical trial institutions and investigators 
participating in the clinical trial, 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.
Appendix 3
Batch Number of Restylane 
Lidocaine 1ml updated
Label of Restylane Lidocaine 1ml updated.
Subject 
information and 
informed consent 
form
Updates required: 
Yes  
   No  
Electronic case 
report form 
(eCRF)
Updates required:
Yes  
   No 
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Investigators and Study Administrative Structure
Co-ordinating Investigator
Principal Investigator
Principal Investigator
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
Study Director
Clinical Project Manager
Study Statistician
Senior CRA
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
Study Director, 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:                                                      43CH1504
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
with and without addition of 0.3% lidocaine hydrochloride. 
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 Lidocaine and Restylane 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 with and without  addition of 0.3% lidocaine hydrochloride
Clinical Trial Number:  
43CH1504
Countries involved, 
number of sites/country, 
number of subjects:
The study will be conducted at approximately 3 sites located in China. The aim is to include 
approximately 70 subjects treated with Restylane Lidocaine in one nasolabial fold (NLF) 
and Restylane in the opposite NLF, as randomly assigned.
Co-ordinating 
Investigator / Principal 
Investigators:
Primary objective:
The primary objective is to evaluate the pain associated with injections of Restylane 
Lidocaine compared to Restylane using a visual analogue scale (VAS).
The proportion of subjects that have a within-subject difference in VAS score (Restylane-
Restylane Lidocaine) of at least 10 mm at injection will be calculated together with a two-
sided 95% confidence interval. The objective is to show that the confidence interval lies
above 50%.
Secondary objectives:
The secondary objectives are:

To evaluate the pain associated with injections of Restylane Lidocaine compared to 
Restylane by assessment of  
o
Proportion of subjects that have a within-subject difference in VAS score 
(Restylane-Restylane Lidocaine) of at least 10 mm (at 15, 30, 45 and 60 
minutes after injection). 
Safety objectives:
The safety objectives are:

To evaluate the safety of Restylane Lidocaine and Restylane during the whole 
study by collecting Adverse Events (AEs).
Study Design:
This is a randomised, multi-center, subject-blinded and evaluator-blinded study in China to 
evaluate the pain and the safety profile associated with correction of moderate to severe 
nasolabial folds using Restylane Lidocaine compared to Restylane for correction of 
moderate to severe nasolabial folds.
Written informed consent will be obtained before any study related procedure is performed. 
Subjects will be screened for eligibility within 14 days prior to study randomisation on 
Day 1. Subsequent to screening eligible subjects will be enrolled in the study. 
Each subject will receive treatment on Day 1 with Restylane Lidocaine in one NLF and 
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Restylane in the opposite NLF, as randomly assigned. The first injection will always start in 
the right NLF. No topical or local anesthetic or other pain-relieving medication, including 
ice, should be used before all VAS assessments are finished. The second injection, that is 
the injection in the left NLF, will be performed 20±5 minutes after the first injection in 
order to reduce possible influence of immediate acute pain from the first injection on the 
pain perception of the second injection.
In order to be able to evaluate the pain of injection separated from the pain of the needle 
insertion alone, a pause of 3 to 5 second is required after insertion of the needle before 
starting injection. Aspiration should be performed prior to injection in order to avoid 
accidental intravascular injection. The injection procedure for the two NLFs will be 
standardised as far as possible in terms of volume used, time needed for injection, and 
injection technique and will be recorded in the CRFs. 
Due to the similar method of administration, the treatment can be masked from the subject 
by simply preventing them from viewing the syringes during the injection procedure. This 
will be accomplished by placing an opaque drape or patch over the subject’s eyes during the 
time that the injections are administered.
The subject will assess pain experienced during treatment on a 100 mm VAS scale at the 
end of each injection (before massaging the treatment area).The time should be recorded in 
the CRF and the pain will thereafter be assessed by the subject at 15±3, 30±3, 45±3, and 
60±3 minutes on the VAS after the injection on the right and left NLF, respectively.
Scheduled visits:
Visit 1
Screening
Day -14 to Day 1
Visit 2
Baseline (treatment)
Day 1
Visit 3
Follow-up/Final visit 
Day 15 (after treatment)
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 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 
(e.g., laser or chemical resurfacing, needling, facelift, radiofrequency  etc).
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.
History of bleeding disorders or treatment with anticoagulants or inhibitors of 
platelet aggregation (e.g. aspirin or other non-steroid anti-inflammatory drugs 
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（NSAIDs）), Omega-3, or vitamin E within 2 weeks before treatment.
5.
Treatment with chemotherapy, immunosuppressive agents, immunomodulatory 
therapy (e.g. monoclonal antibodies), systemic or topical (facial) corticosteroids 
within 3 months before study treatment (inhaled corticoids are allowed).
6.
Previous use of any permanent (non-biodegradable) or semi-permanent facial 
tissue augmentation therapy or autologous fat 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.
8.
Previous use of neurotoxins below the level of the lower orbital rim (crow’s feet 
line is acceptable) within 12 months before treatment.
9.
Previous tissue revitalisation treatment with laser or light, mesotherapy,
radiofrequency, chemical peeling or dermabrasion in the midface within 6 months 
before treatment.
10. Previous surgery (including aesthetic facial surgical therapy or liposuction) or 
tattoo in the area to be treated.
11. 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.
12. History of or active autoimmune disease or connective tissue diseases such as 
systemic lupus erythematosus, rheumatoid  arthritis, polymyositis, dermatomyositis 
or localized or systemic scleroderma.
13. Tendency to form keloids, hypertrophic scars, or any other healing disorder.
14. History of radiation or cancerous or pre-cancerous lesions (e.g. actinic keratosis) in 
the area to be treated.
15. Any medical condition that in the opinion of the Investigator would make the 
subject unsuitable for inclusion (e.g. a chronic, relapsing or hereditary disease that 
may affect the general condition or may require frequent medical treatment, any 
abnormal screening laboratory value or ECG, or psychiatric disorders).
16. Subjects with abnormal 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.
17. Concomitant treatment with topical (facial) retinoids within 3 months or systemic 
retinoids within 6 months before treatment.
18. 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.
19. 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.
20. 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.
21. Participation in any other clinical study or study within 30 days before treatment.
Investigational product, 
dose and mode of 
Restylane 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 sterile 1 mL syringes.  A 29G thin walled (TW) × 
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administration:
½” needle will be used for injection.
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 
Restylane Lidocaine and the opposite NLF to treatment with Restylane.
Restylane Lidocaine should be injected into the middle layer of the dermis of the facial skin 
in the NLF. The injection procedure should strictly follow the rules of aseptic surgical 
technique (refer to the Restylane Lidocaine Instructions For Use for details).
For treatment, it is recommended not to use more than 1.5 mL for each NLF.
The linear threading technique can be used to carefully lift up the wrinkle. 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.
Reference therapy, dose 
and mode of 
administration
Restylane 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. A 29G thin walled (TW) × ½” needle will be used for injection. Restylane should 
be injected into the middle part of the dermis layer of the facial skin in the NLF. The 
injection procedure should strictly follow rules of aseptic surgical technique (refer to the 
Restylane Instructions For Use for details).
For treatment, it is recommended not to use more than 1.5 mL for each NLF. 
The linear threading technique can be used to carefully lift up the wrinkle. 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: 
Following screening and treatment, there is a follow-up/final visit at Day 15 (+3 days).
Efficacy Assessment: 
Pain Assessment:
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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Safety Assessment:
AE will begin to be collected after ICF signed. Each subject will be questioned about AEs at 
follow-up 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, observations by the study 
personnel, 
 or spontaneous reports from the subjects.
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Statistical Methods: 
In general, all efficacy, safety and baseline characteristics variables will be presented using 
descriptive statistics and graphs as appropriate. Efficacy and safety variables will be 
presented by treatment. Continuous data will be summarized by descriptive statistics n 
(number of observations), mean, standard deviation, median, minimum and maximum 
value, while categorical data will be presented by frequency and percentage.
Primary analysis
The proportion of subjects that have a within-subject difference in VAS (Restylane-
Restylane Lidocaine) of at least 10 mm at the time of injection will be calculated together 
with a two-sided 95% confidence interval. The objective is to show that the confidence 
interval lies above 50% based on the ITT analysis set.
Secondary analysis
The proportion of subjects that have a within-subject difference in VAS of at least 10 mm at 
post injection timepoints (15, 30, 45 and 60 minutes after injection) will be calculated 
together with a two-sided 95% confidence interval. 
Sample size
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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
G
Gauge
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
ITT
Intention to treat
MedDRA
NLF
Medical Dictionary for Regulatory Activities
Nasolabial fold
NSAIDs
non-steroid anti-inflammatory drugs
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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
Urinary human chorionic gonadotropin
VAS
Visual analogue scale
WHO
World Health Organization
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Table of Contents
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
5
SPONSOR SIGNATURES
6
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
7
SYNOPSIS
8
ABBREVIATIONS AND DEFINITIONS OF TERMS
14
TABLE OF CONTENTS
16
1
ETHICAL CONSIDERATIONS
19
2
BACKGROUND INFORMATION
19
2.2
Investigational product description
19
2.3
Reference product description
20
2.4
Previous experience
20
2.4.1
Non-Clinical Documentation
20
2.4.2
Clinical Documentation
20
2.5
Study rationale
21
2.6
Justification for the design of the study
21
2.7
Risk and benefits
21
3
OBJECTIVES AND ENDPOINTS
22
3.1
Primary objective and endpoint
22
3.2
Secondary objectives and endpoints
22
3.3
Safety objectives and endpoints
22
4
DESIGN OF THE STUDY
23
4.1
General Outline
23
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
24
4.4.3
Emergency unblinding
25
4.5
Medical history
25
4.6
Concomitant Medication, Treatment, and Procedure
25
4.7
Schedule of events
26
4.8
Visits
26
4.8.1
Visit 1: Screening (Day -14 to Day 1)
26
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
28
4.8.4
Demographics and baseline assessments
28
5
SUBJECTS
28
5.1
Subject information and informed consent
28
5.2
Inclusion Criteria
29
5.3
Exclusion Criteria
29
5.4
Screening and Subject Numbers
31
5.5
Withdrawal of Subjects
31
6
STUDY PRODUCTS
32
6.1
Investigational Product
32
6.2
Reference Product
32
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6.3
Additional Products and Material
32
6.4
Packaging, Labelling and Storage
32
6.5
Product accountability
33
6.6
Treatment
33
6.6.1
Treatment Procedure
33
6.6.2
Treatment regimen (dose)
34
6.6.3
Post-treatment Care
34
6.6.4
Post-trial provisions
34
6.6.5
Electronic case report form recordings
34
6.6.6
Treatment compliance
35
7
EFFICACY ASSESSMENTS
35
7.1
Visual analogue scale (VAS)
35
35
36
7.4
Photography
36
8
SAFETY ASSESSMENTS
37
37
8.2
Laboratory assessment - Screening
37
8.3
ECG-screening
38
8.4
Adverse Events
38
8.4.1
Definition of Adverse Events
38
8.4.2
Definition of Serious Adverse Event
38
8.4.3
Recording Instructions
38
8.4.4
Reporting of Adverse Events
40
8.4.5
Reporting of Serious Adverse Events
40
8.4.6
Follow-up of Unresolved Events after study termination
41
8.4.7
Pregnancy
41
8.4.8
Anticipated Adverse Events
42
8.5
Device Deficiencies
42
8.5.1
Definition of Device Deficiency
42
8.5.2
Recording Instructions
42
8.5.3
Reporting Device Deficiency
43
9
DATA HANDLING AND MANAGEMENT
43
9.1
Data management
43
9.2
Electronic case report forms
43
9.2.1
Data entry
44
9.2.2
The query process
44
9.2.3
User identification
44
9.2.4
Audit trail
44
9.3
Source documents
45
9.4
Record keeping and access to source data
45
9.5
Document and data retention
45
10
STATISTICAL METHODS
46
10.1
General
46
10.2
Analysis Populations
46
10.3
Demographics, baseline assessments, and subject characteristics
46
10.4
Efficacy Analysis
46
10.5
Safety Analysis
47
10.6
Handling of Missing Data
47
10.7
Interim Analysis
47
10.8
Data monitoring committee
47
10.9
Withdrawals and deviations
47
10.10
Sample Size
48
11
PROTECTION OF PERSONAL DATA
48
12
QUALITY CONTROL AND QUALITY ASSURANCE
48
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12.1
Quality control
48
12.2
Quality assurance
49
12.3
Changes to the clinical study protocol
49
13
FINANCING, INDEMNIFICATION, AND INSURANCE
49
14
PUBLICATION POLICY
49
15
SUSPENSION OR PREMATURE TERMINATION
50
16
REFERENCES
51
17
APPENDICES
53
List of Tables
Table 1. Schedule of Events.....................................................................................................26
...36
...36
........................................................................................................................................37
List of Figures
Figure 1. Flow chart.................................................................................................................24
List of Appendices
Appendix 1
Declaration of Helsinki 
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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: 2011shall 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
Restylane Lidocaine has been approved in the United States, Europe and several countries 
worldwide as a medical device for facial tissue augmentation. It is indicated for mid-to-deep 
dermal implantation for the correction of moderate to severe facial wrinkles and folds, such 
as nasolabial folds.
2.2
Investigational product description 
Among the different materials used as raw materials in injectable fillers for aesthetic use, 
sodium hyaluronate, also denoted hyaluronic acid (HA) 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 of HA 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 eliminate the risk for contamination, the HA used in the manufacture of Galderma’s HA 
gels is of non-animal source, biosynthesised from Streptococcus species of bacteria.
During manufacturing, cross-links are introduced between the HA chains using the 
NASHA(TM) technology in order to obtain a gel network. 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.
Restylane Lidocaine also consists of lidocaine hydrochloride 3 mg/ml.
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2.3
Reference product description
Except not containing lidocaine, Restylane has the same composition and property as 
Restylane Lidocaine.  
2.4
Previous experience
2.4.1
Non-Clinical Documentation
2.4.2
Clinical Documentation
Restylane Lidocaine has been proven safe and efficacious in a clinical trial3. The study was 
performed in US and the purpose was to study the safety and effectiveness of wrinkle 
treatment with Restylane-L for the correction of moderate to severe nasolabial folds.
Sixty patients were treated with Restylane-Lidocaine and Restylane treatment in a "within-
patient" model of bilateral NLF correction, with one treatment assigned to one side of the 
face and the other treatment to the remaining side. The primary efficacy analysis showed that 
71.7% of subjects had a within-subject difference in VAS (Restylane minus Restylane 
Lidocaine) of at least 10 mm at the time of injection.
Mean within-subject difference on 
VAS (Restylane –Restylane Lidocaine) was statistically significantly larger than zero at all 
timepoints (at injection and at 15, 30, 45 and 60 minutes post injection). The results showed 
the addition of lidocaine to Restylane has a substantial effect on reducing pain experienced by 
the subjects. 
The study also indicates that the safety profile of Restylane is maintained. There were no AEs 
of severe intensity recorded during the study. The majority of related events were mild in 
severity. Most related AEs were typical of local reactions associated with implantation, such 
as swelling, pain, and haematoma (bruising) and the AE profile was similar for the two 
products. There were also no SAEs and no AE resulted in subject discontinuation of the study.
The use of Restylane in the NLFs have been extensively evaluated in clinical studies3-17,
Restylane has also been proven safe and efficacious in a clinical trial in a Chinese study
population14. This study was performed in China and the aim was to study the safety and 
efficacy of Restylane for facial tissue augmentation (i.e. NLFs) (n=86). The study showed 
that efficacy was very well sustained with a significant improvement from baseline at all-time
points up to the last observation at 6 months post-treatment. Restylane was also well tolerated 
and no systemic reactions or other safety concerns were raised. Some transient anticipated 
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post-injection reactions were reported which were in general classified as being of mild 
severity. These reactions resolved spontaneously without need of specific treatment. The 
results from the study demonstrated that Restylane is at least as efficacious in a Chinese study
population as in a US study population 8,9,11 and that the frequency of AEs related to 
treatment was similar in a Chinese study population as in US study population 8,9,11.
Post market surveillance data for Restylane-L also support that the AE profile is acceptable 18.
2.5
Study rationale
Injectable lidocaine HCL as an analgesic is commonly used by physicians to help control or 
prevent pain and inflammation by numbing the area prior to performing minor surgical
procedures. Many physicians are known to inject subjects with lidocaine HCL or similar
analgesics in association with Restylane injections.
Since lidocaine HCL is a widely used, well characterized analgesic that is a component of a 
number of currently marketed dermal fillers, the sponsor proposed to add 0.3% lidocaine 
HCL to the Restylane formulation as a convenience for physicians and their patients and
undertook a two week study to assure that this modification of Restylane would not impact 
the safety of the product in US population. The results showed addition of lidocaine to 
Restylane has a substantial effect on reducing pain experienced by the subjects and the safety 
profile of Restylane is maintained. By June 2015, Restylane Lidocaine has been approved in 
52 countries/regions, including US, EU, Hong Kong, Korea, India, etc. 
According to the previous experience, a two-week study was anticipated to be adequate to
confirm the safety of adding lidocaine hydrochloride to Restylane in Chinese population.
2.6
Justification for the design of the study
The purpose of this study is to investigate the pain associated with injections of Restylane 
Lidocaine compared to Restylane using a visual analogue scale (VAS) by measuring the 
proportion of subjects that have a within-subject difference in VAS score (Restylane-
Restylane Lidocaine) of at least 10 mm at injection. Evaluation with standardised evaluation
tools will be used in the study.
2.7
Risk and benefits
Restylane and Restylane Lidocaine are by June 2015 registered in more than 50
countries/regions including the US and in several Asian countries and considered safe and 
effective for facial dermal tissue augmentation to correct moderate to severe NLFs. The study 
products will be administered in accordance with the instructions in section 6.6.1.
Restylane and Restylane Lidocaine, as all other injectable medical devices, have 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 substance 
itself.
After the injection of Restylane with or without lidocaine, 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 a few days after 
injection into the skin.
The frequency of post market Adverse Event reporting is based on the number of units sold. 
The reporting frequency of adverse events assessed as related to Restylane Lidocaine is in 
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line with those for Restylane without lidocaine, 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). 
Rare cases of hypersensitivity have been reported after treatment with Restylane Lidocaine. 
There may be an increased risk for these events in subjects with hypersensitivity to any
ingredient of study products. To minimise this risk, subjects with hypersensitivity to any 
ingredient of study products shall be excluded from the study.
There is a risk that the subject will not gain the full aesthetic correction of NLF. There is also 
a risk for development of palpable Restylane/Restylane Lidocaine lumps or displacement of 
the injected Restylane/Restylane Lidocaine. Inflammation or infection has been reported in a 
few cases after Restylane/Restylane Lidocaine treatment. There may be risk of bruising 
and/or damaging body structures such as nerves or blood vessels connected to the injection 
site, however these risks are minor. Detailed information on reported Adverse Events relevant 
for Restylane/ Resylane Lidocaine is provided in the IFUs.
Given the anticipated low level of transient and acceptable adverse events (AE) in
connection with the injection, the risk-benefit assessment of the use of Restylane/Restylane 
Lidocaine for correction of NLFs appears to offer a clinical benefit at reasonable risk.
3
Objectives and Endpoints
3.1
Primary objective and endpoint
The primary objective is to evaluate the pain associated with injections of Restylane 
Lidocaine compared to Restylane using a visual analogue scale (VAS).
The proportion of subjects that have a within-subject difference in VAS score (Restylane-
Restylane Lidocaine) of at least 10 mm at injection will be calculated together with a two-
sided 95% confidence interval. The objective is to show that the confidence interval lies
above 50%.
3.2
Secondary objectives and endpoints
The secondary objectives and endpoints are:

To evaluate the pain associated with injections of Restylane Lidocaine compared to
Restylane by assessment of 
o
Proportion of subjects that have a within-subject difference in VAS score (Restylane-
Restylane Lidocaine) of at least 10 mm (at 15, 30, 45 and 60 minutes after injection). 
3.3
Safety objectives and endpoints
The safety objectives and endpoints are:
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
To evaluate the safety of Restylane Lidocaine and Restylane during the whole study
by collecting AEs.
4
Design of the Study
4.1
General Outline
This is a randomised, multi-center, subject-blinded and evaluator-blinded study in China to 
evaluate the pain and the safety profile associated with correction of moderate to severe 
nasolabial folds using Restylane Lidocaine compared to Restylane for correction of moderate 
to severe nasolabial folds.
Written informed consent will be obtained before any study related procedure is performed. 
Subjects will be screened for eligibility within 14 days prior to study randomisation on day 1. 
Subsequent to screening eligible subjects will be enrolled in the study. 
Each subject will receive treatment on Day 1 with Restylane Lidocaine in one NLF and 
Restylane in the opposite NLF, as randomly assigned. The first injection will always start in 
the right NLF. No topical or local anesthetic or other pain-relieving medication, including ice, 
should be used before all VAS assessments are finished. The second injection, that is the 
injection in the left NLF, will be performed 20±5 minutes after the first injection in order to 
reduce possible influence of immediate acute pain from the first injection on the pain 
perception of the second injection.. 
In order to be able to evaluate the pain of injection separated from the pain of the needle 
insertion alone, a pause of 3 to 5 second is required after insertion of the needle before 
starting injection. Aspiration for blood should be done in order to avoid accidental 
intravascular injection. The injection procedure for the two NLFs will be standardised as far 
as possible in terms of volume used, time needed for injection, and injection technique and 
will be recorded in the CRFs.
The subject will assess pain experienced during treatment on a 100 mm VAS scale at the end 
of each injection (before massaging the treatment area). The time should be recorded in the 
CRF and the pain will thereafter be assessed by the subject at 15±3, 30±3, 45±3, and 60±3 
minutes on the VAS after the injection on the right and left NLF, respectively.
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Figure 1. Flow chart
4.2
Number of Subjects
The study will be performed at approximately 3 hospitals in China and approximately 70 
subjects will be randomised and treated. 
4.3
Duration of Subject Participation
The study subjects will be treated at the baseline visit and thereafter followed for 2 weeks. A 
subject will be involved in the study for up to 28 days.
4.4
Randomisation and blinding
4.4.1 Randomisation
Each subject will be randomised to one of two treatment sequences; either Restylane 
Lidocaine in the subject’s right NLF followed by Restylane in the subject’s left NLF, or 
Restylane in the subject’s right NLF followed by Restylane Lidocaine 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. 
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.
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. 
Informed Consent & Screening
Randomisation
Treatment with Restylane Lidocaine in 
one NLF and Restylane in the opposite
NLF, as randomly assigned. Treatment will 
always start in the right NLF.
Day 15 (+3 days), follow-up/final visit
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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 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.
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.
The following medications, treatments, and procedures are restricted or prohibited during the
study:

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 2 weeks before treatment to avoid increased bruising or bleeding at injection 
sites.

Any other anaesthetics or agents structurally related to amide-type anaesthetics, e.g.
certain antiarrhythmics, should not be used at day 1 visit.

Concomitant 
treatment 
with 
chemotherapy, 
immunosuppressive 
agents, 
immunomodulatory therapy (e.g. monoclonal antibodies), systemic or topical (facial)
retinoids and corticosteroids are prohibited (inhaled corticoids are allowed).

Procedures involving an active dermal response in the treated area(s) (e.g. tissue 
augmenting therapy, contouring or revitalisation treatment with permanent or non-
permanent fillers, mesotherapy, fat-injection, neurotoxin, laser or light treatment, 
chemical peeling or dermabrasion) are prohibited. 

Surgery (including aesthetic facial surgical therapy, liposuction, sinus surgery or 
dental root surgery), or tattoo in the area to be treated are 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 1. Schedule of Events
Activity
Screening1
Baseline/ treatment
Follow-up/ final visit
Day -14 to 1
Day 1
Day 15
(+3 days) 
Visit Number
Visit 1
Visit 2
Visit 3
Informed consent
X
Demography
X
Medical history & concurrent 
diseases
X
X
Vital signs
X2
Laboratory tests
X
ECG
X
Pregnancy test3
X2
X
Inclusion and Exclusion criteria
X
X
Randomisation
X
Photography
X4
X
Treatment
X
VAS evaluation5
X
Concomitant 
medication/procedures
X
X
X
Assessment of Adverse Events
X
X
X
1. Screening and baseline/treatment may be performed on the same day.
2. Should be done before randomization
3. Only for women with childbearing potential
4. Should be done before injection and after injection, also be done once AE occurs after injection
5. Subjects will evaluate injection site pain for each side of the face using the VAS at the end of treatment and 
15, 30, 45 and 60 minutes post-treatment.
4.8
Visits
4.8.1 Visit 1: Screening (Day -14 to Day 1)
Study subject will be informed about the study and the risks and benefits of participating. 
Information will be given both verbally and in writing and the Informed Consent Form (ICF) 
will be signed and dated by the subject and the Investigator before performing any study 
related procedures. Inclusion and exclusion criteria will be checked and demographic data 
such as date of birth, gender and ethnic origin, relevant medical history data as well as 
relevant ongoing medication and AEs will be collected by the Investigator. Screening 
laboratory tests and ECG will be performed in accordance to section 8.2 and 8.3 to verify 
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exclusion criteria 14.
If the subject meets all of the inclusion criteria and none of the exclusion criteria a baseline 
visit will be performed immediately or scheduled within the next 14 days.

Informed consent

Demography (Initials, Date of birth, Gender and Ethnic origin)

Screening laboratory assessments (haematology and serum chemistry)

ECG

Inclusion and exclusion criteria

Medical history/concurrent diseases

Concomitant medications and treatments

AE
4.8.2 Visit 2: Baseline (treatment) (Day 1)
The baseline visit can be performed in direct connection with the screening visit or at latest 
14 days after the screening visit. If the screening and baseline visits are separated the
inclusion/exclusion criteria will be re-checked and/or if any changes have occurred in the 
health status, concomitant medication or procedures performed before the subject can be 
included in the study. Standardized pre-treatment photographs will be taken as described in 
section 7.4 and a pregnancy test (U-HCG) will be performed in women of childbearing 
potential.
For each subject, one NLF will be randomly assigned to treatment with Restylane Lidocaine
and the opposite NLF to treatment with Restylane. Treatment will be administered according 
to the instructions in section 6.6. Any device deficiencies or AEs experienced during/after the 
treatment will be reported and post-treatment photographs will be taken. 

Vital signs (pulse rate, blood pressure, respiratory rate, axillary temperature)

Inclusion and exclusion criteria

Pregnancy test for childbearing potential women

Medical history/concurrent diseases

Concomitant medications and treatments

Photography (before and after injection)

Randomization 

Treatment 
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
VAS evaluation

AE
4.8.3 Visit 3: Follow-up/Final visit (day 15 (+3 days)) or early termination
Standardized photographs will be taken. 
any AEs experienced since the treatment or 
medications used will be reported. A final pregnancy test (U-HCG) will be performed in 
women of childbearing potential.

Pregnancy test for childbearing potential women

Photography 

Concomitant medications and treatments

AE
4.8.4 Demographics and baseline assessments
Demographics and baseline assessments include:

Informed consent date

Date of birth

Gender 

Initials

Ethnic origin

Screening laboratory assessments (haematology and serum chemistry) and ECG

Inclusion and exclusion criteria

Relevant medical history/concurrent diseases

Concomitant medications and treatments

Pregnancy test (for women of childbearing potential)
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.
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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 
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 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 (e.g., 
laser or chemical resurfacing, needling, facelift, radiofrequency, etc.).
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 lidocaine or other amide type 
anaesthetics.
3. History of severe or multiple allergies manifested by anaphylaxis.
4. History of bleeding disorders or treatment with 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 
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5. Treatment with chemotherapy, immunosuppressive agents, immunomodulatory
therapy (e.g. monoclonal antibodies), systemic or topical (facial) corticosteroids 
within 3 months before study treatment (inhaled corticoids are allowed)
6. Previous use of any permanent (non-biodegradable) or semi-permanent facial tissue 
augmentation therapy or autologous fat 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.
8. Previous use of neurotoxins below the level of the lower orbital rim (crow’s feet line 
is acceptable) within 12 months before treatment
9. Previous tissue revitalisation
treatment with laser or light, mesotherapy
radiofrequency, chemical peeling or dermabrasion in the midface within 6 months 
before treatment
10. Previous surgery (including aesthetic facial surgical therapy or liposuction) or tattoo 
in the area to be treated
11. 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.
12. History of or active autoimmune disease or connective tissue diseases such as 
systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis 
or localized or systemic scleroderma.
13. Tendency to form keloids, hypertrophic scars, or any other healing disorder.
14. History of radiation or cancerous or pre-cancerous lesions (e.g. actinic keratosis) in 
the area to be treated.
15. Any medical condition that in the opinion of the Investigator would make the subject 
unsuitable for inclusion (e.g. a chronic, relapsing or hereditary disease that may
affect the general condition or may require frequent medical treatment, any abnormal 
screening laboratory value or ECG, or psychiatric disorders).
16. Subjects with abnormal 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.
17. Concomitant treatment with topical (facial) retinoids within 3 months or systemic 
retinoids within 6 months before treatment.
18. 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.
19. 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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20. 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.
21. Participation in any other clinical study or 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 01 at each site, e.g. 101, 102.
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.

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 
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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 Restylane Lidocaine and Restylane.
6.1
Investigational Product 
Restylane Lidocaine 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 syringes with a luer-lock fitting. Each syringe contains 1 mL gel. The syringe is labeled 
and packaged in a blister.
6.2
Reference Product
Restylane 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 syringes with a luer-lock fitting. Each syringe contains 1 
mL gel. The syringe is labeled and packaged in a blister. The reference product is commercial 
product intended for the Chinese market. An Instruction for Use (IFU) is included in the 
carton.
6.3
Additional Products and Material
Restylane Lidocaine and Restylane will be supplied by the Sponsor. Two 29G thin walled 
(TW) × ½” needles are packed together with the Restylane Lidocaine and two same 29G thin 
walled (TW) × ½” needles are provided separately for Restylane injection. Any other 
materials will be supplied by the site.
6.4
Packaging, Labelling and Storage
Restylane Lidocaine and Restylane are manufactured by Q-Med AB, Uppsala, Sweden who 
will supply the study products. Restylane Lidocaine and commercial Restylane will be used 
for the study.
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The syringes are labelled with name of the product, name of the manufacturer (Q-Med AB). 
The syringes in its blister are packed in a carton. The carton will be 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 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 
6.6.1
Treatment Procedure
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 
Restylane Lidocaine and the opposite NLF to treatment with Restylane. Treatment will 
always start in the subject’s right NLF.
The Treating Investigator should keep the subject blind to the treatment by placing an opaque 
drape or patch over the patient's eyes during the time that the injections are administered. See 
section 4.4 for details of randomisation and blinding of subjects and Blinded Investigator. 
To avoid breakage of the needle, no attempt to bend or otherwise manipulate it before or 
during treatment is recommended. Before injecting, the air should be removed by pressing 
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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. In order to be 
able to evaluate the pain of injection separated from the pain of the needle insertion alone, a 
pause of 3 to 5 second is required after insertion of the needle before starting injection. Both 
products should be injected slowly while pulling the needle backwards. 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. Separate sterile needles should be used for each NLF.
For VAS assessment please refer to section 4.1,
Restylane Lidocaine and Restylane should be injected into the middle part of the dermis layer 
of the facial skin in the NLF. The injection sites may be gently massaged by the Treating 
Investigator to conform the contour of the surrounding tissue (but only after VAS assessment 
of the pain at injection).
The linear threading technique can be used to carefully lift up the wrinkle. Information 
regarding injection technique, time needed for injection, lot number and volume of study 
product used per NLF will be collected in connection to each treatment.
6.6.2
Treatment regimen (dose)
The maximum volume is 1.5 mL for each NLF.
Sufficient amount of study product should be injected to achieve optimal correction of NLF.
The same volume should preferably be used in both NLFs to be able to standardize the 
evaluation of pain.
6.6.3
Post-treatment Care 
Ice in appropriate packaging can be applied on the treatment site for a short period after all 
VAS assessments are finished 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 a few days. 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 treatment is an injectable gel administered by the Treating Investigator and the following 
details of the injection are to be recorded in the eCRF: 

Date for administration

Time point for administration per NLF

Administration completion time per NLF

Administered volume per NLF
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
Injection technique or procedure

Post-treatment care (massage, cooling，etc)

Time of VAS assessment per NLF
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
Efficacy Assessments
7.1
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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7.4
Photography
Digital photographs will be taken of each subject at baseline and at follow-up visit.
Photographs will be taken both pre- and post-treatment at baseline when treatment is 
performed. If necessary, the photo should be taken when AEs occurred.
Photo 1: 
Straight frontal view
Photo 2 and 3: 
Oblique pictures, 45o, right and left
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The same photographic equipment and standardised setting must be used at each visit
(e.g. distance, light, facial position and expression). No covering make-up should be used
on the photographs.
Photographs will be identified by subject initials, subject number, visit number and date/time
of visit. The photographs will be used to document condition at baseline, 
and to document AEs in the treated area.
8
Safety Assessments
8.2
Laboratory assessment - Screening
Laboratory samples will be taken at the screening visit (day -14 to day 1).
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, direct bilirubin and indirect bilirubin).

Urine: (U-HCG) Pregnancy test for women of childbearing potential (pregnancy test 
will be performed prior to treatment and at the study completion, in all women of 
childbearing potential).
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. The results will only be used for screening purposes 
by the investigator and will not be collected in the eCRF.
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8.3
ECG-screening
ECG will be taken at the screening visit (day -14 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.
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
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 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 
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from signs and symptoms detected during each examination or from a laboratory test, 
observations by the study personnel, 
or 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:

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 sequele, 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 
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
“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. 
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 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.
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 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 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.)
___________________________________________________________________________
E-mail for SAE reporting:
safety.q-med@galderma.com
Fax number for SAE reporting:
+46 18 474 91 01
___________________________________________________________________________
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.
___________________________________________________________________________
Surface mail for providing
Q-Med AB 
complementary information: 
Attn. Complaints QA
Seminariegatan 21 
SE-752 28 UPPSALA, Sweden
__________________________________________________________________________
The SAE form 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. A copy of the 
fully completed SAE form shall be kept at the site.
In addition, according to national regulations, the administrative department of medical 
device clinical trials 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 with all required materials.
The local office in Beijing of the Sponsor is responsible for, within five (5) business days 
upon being informed, reporting any SAE or device defect with the likelihood of SAE to the 
food and drug administrative department where it has been registered and the competent 
authorities of health and family planning at the same level; meanwhile, the Sponsor should 
notify other clinical trial institutions and investigators participating in the clinical trial, 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.
For a description of the procedure regarding emergency unblinding, see section 4.4.3.
8.4.6
Follow-up of Unresolved 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 
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 an AE Follow-up module in the eCRF.
8.4.7
Pregnancy
Pregnancy itself is not regarded as an AE.
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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 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 a few days after injection, as observed in the Chinese clinical study for Restylane and 
in consistent with international results for both products.
Refer to the Restylane Lidocaine EU IFU and Restylane China IFU.
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. 
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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
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.
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 
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, 
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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.
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.
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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.
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.
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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
All statistical analyses, including summary tables and data listings, will be performed using 
the SAS® system (version 9.0). Confidence intervals 
will be 2-sided and 
.
Continuous or semi-continuous variables will be summarised using descriptive statistics, e.g. 
mean, median and standard deviation. Categorical variables will be presented in frequency
tables with number and percent of observations for each level.
10.2 Analysis Populations
The following populations will be defined:

Safety
Includes all subjects who were injected in at least one 
NLF, based on the as treated principle.

Intention to treat (ITT) 
efficacy
Includes all subjects who were injected in both NLFs.
Subjects are analyzed according to the randomisation 
assignment.

Per Protocol (PP) 
efficacy
Includes all ITT subjects who completed the VAS 
assessment at injection without any deviations considered 
to have substantial impact on the primary efficacy
outcome. 
The ITT population is the primary population for all efficacy 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 study product using 
descriptive statistics.
10.4 Efficacy Analysis
Primary analysis
The proportion of subjects that have a within-subject difference in VAS (Restylane-Restylane 
Lidocaine) of at least 10 mm at the time of injection will be calculated together with a two-
sided 95% confidence interval. The objective is to show that the confidence interval lies 
above 50% based on the ITT analysis set. To assess the robustness of the results, the same 
analysis will be re-run using the PP analysis set.
Secondary analysis
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The proportion of subjects that have a within-subject difference in VAS of at least 10 mm at 
post injection timepoints (15, 30, 45 and 60 minutes after injection) will be calculated 
together with a two-sided 95% confidence interval. 
10.5 Safety Analysis
A similar summary will also be presented by severity. A graph will be generated to 
illustrate the incidence over time. 
All AEs will be coded according to MedDRA. All AEs will be summarised by system organ 
class (SOC) and preferred term (PT). The same summaries will be generated for related AEs, 
severe AEs, AEs leading to discontinuation, and serious AEs.  For related AEs, the number of 
days to onset and the duration of event will be summarised by SOC and PT using mean, SD, 
min, max and median statistics.
10.6 Handling of Missing Data
As the design is intra-individual, in which the outcome of both treatments to be compared is 
available on each subject, it is expected that when a data is missing, it will be missing for 
both NLFs in most of the cases. A majority of the deviations to the protocol can be expected 
to affect both NLFs and evaluations of the same subject the same way. 
ITT analysis of VAS at the time of injection will impute a difference (Restylane-Restylane 
Lidocaine) of 0 mm as the primary method of imputation. This corresponds to assuming no 
pain relief using Restylane Lidocaine compared to Restylane and is considered as a worst 
case approach.
All other endpoints will be analyzed on available data, i.e. no imputations will be done.
10.7 Interim Analysis
No interim analysis is planned.
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 database lock.
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Deviations from the statistical plan will be documented in protocol Deviation log.
10.10 Sample Size
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 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 Sponsoror 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.
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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.
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 
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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. 
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. Brandt F1, 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..
4.
Lindqvist C, Tveten S, Bondevik BE and Fagrell D. A randomized, evaluator-blind, 
multicenter comparison of the efficacy and tolerability of  Lidocaine versus Zyplast in the 
correction of nasolabial folds. Plast Reconstr Surg. 2005 Jan; 115(1):282-9.
5.
Carruthers A, Carey W, De Lorenzi C, Remington K, Schachter D and Sapra S. Randomized, 
double-blind comparison of the efficacy of 2 hyaluronic acid derivatives, restylane  Lidocaine 
and 
hylaform, 
in 
the 
treatment 
of 
nasolabial 
folds.
Dermatol Surg. 2005 Nov; 31(11 Pt 2):1591-8; discussion 1598.
6.
Cohen J, Dayan S, Brandt F, Nelson D, Axford-Gatley R, Theisen M and Narins R. Systemic 
review of clinical trials of small- and large-gel-particle hyaluronic acid injectable fillers for 
aesthetic soft tissue augmentation. Dermatol Surg 2013; 39:205-231.
7.
Narins RS, Brandt F, Leyden J, Lorenc PZ, Rubin M, Smith S. A randomized, double-blind, 
multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the 
correction of nasolabial folds. Dermatol Surg 2003; 29: 588-95.
8.
Taylor SC, Burgess CM, Callender VD. Efficacy of Variable-Particle Hyaluronic Acid 
Dermal Fillers in Patients with Skin of Color: A Randomized, Evaluator-Blinded 
Comparative Trial. Dermatol Surg. 2010 May; 36 Suppl 1:741-749.
9.
Taylor SC, Burgess CM, Callender VD.  Safety of nonanimal stabilized hyaluronic acid 
dermal fillers in patients with skin of color: a randomized, evaluator-blinded comparative 
trial. Dermatol Surg. 2009 Oct; 35 Suppl 2:1653-1660.
10. 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 
Jun;34 Suppl 1:S105-109. 
11. Dover JS, Rubin MG, Bhatia AC. Review of the efficacy, durability, and safety data of two 
nonanimal stabilized hyaluronic acid fillers from a prospective, randomized, comparative, 
multicenter study. Dermatol Surg. 2009 Feb; 35 Suppl 1:322-330; discussion 330-331.
12. Narins RS, Dayan SH, Brandt FS, Baldwin EK. Persistence and improvement of nasolabial 
fold correction with nonanimal-stabilized hyaluronic acid 100,000 gel particles/mL filler on 
two retreatment schedules: results up to 18 months on two retreatment schedules. Dermatol 
Surg. 2008 Jun;34 Suppl 1:S2-8; discussion S8.  
13. Narins RS, Brandt FS, Dayan SH, Hornfeldt CS. Persistence of Nasolabial Fold Correction 
with a Hyaluronic Acid Dermal Filler with Retreatment: Results of an 18-Month Extension 
Study. Dermatol Surg. 2011 May; 37(5):644-650.
14. Xiaoqing Y, Jun X, Changsheng L, Yongguang M, Wei L. A Multicenter Study of the 
Efficacy and Safety of Restylane in the Treatment of Nasolabial Folds in China. Plastic and 
Reconstructive Surgery. 2009 124(5); 256e-257e.
15. 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.
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16. Weiss R, Bank D, Brandt F. Randomized, 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.
17. Hamilton RG, Strobos J, Adkinson NF Jr. Immunogenicity studies of cosmetically 
administered nonanimal-stabilized hyaluronic acid particles. Dermatol Surg. 2007 Dec; 33 
Suppl 2:S176-85.
18. Q-Med AB internal report MA-27629. Periodic Safety Update Report 2014 - Restylane and 
Restylane Lidocaine.
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17 Appendices
Appendix 1
Declaration of Helsinki 
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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.
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 
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Appendix 1
Declaration of Helsinki
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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 
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.
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Declaration of Helsinki
3(5)
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.
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.
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Appendix 1
Declaration of Helsinki
4(5)
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
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 
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Declaration of Helsinki
5(5)
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 2
1(3)
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Appendix 2
2(3)
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Appendix 2
3(3)
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Appendix 3
1(2)
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Appendix 3
2(2)
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SIGNATURES PAGE
Date
Signed by
2016-06-15 07:23
Justification
Approved by Technical Expert
2016-06-15 07:25
Justification
Approved by Project Manager
2016-06-15 07:52
Justification
Approved by Owner
2016-06-15 08:07
Justification
Approved by Technical Expert
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