A Randomised, Evaluator-blind Comparative Study to Evaluate Performance and Safety of Restylane Lidocaine and No-treatment Control for Treatment of Depressed Facial Acne Scars
Phase: PHASE4
Conditions: Healthy Volunteers
Sponsor: Galderma R&D

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A randomised, evaluator-blind comparative study to evaluate 
performance and safety of Restylane Lidocaine and no-treatment control
for treatment of depressed facial acne scars
Study product:
Restylane® Lidocaine
Clinical trial number (CTN):
05DF1605
Coordinating Investigator:
Sponsor:
Q-Med AB
Confidentiality Statement
This study protocol contains confidential information belonging to Q-Med AB. Except as 
may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree 
to hold such information in confidence and neither disclose it to any third parties (except 
where required by applicable law) nor use it for any other purpose than in relation to the 
clinical study described herein.
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Investigators and Study Administrative Structure
Coordinating Investigator:
Principal Investigator(s):
Sponsor:
Q-Med AB
Medical expert:
 
Study director:
Study statistician:
Contract research 
organisation (CRO):
Monitor(s):
To be decided
Provider of eCRF:
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.
Head of Medical Affairs, Q-Med AB
 
Clinical Project Manager, Q-Med AB
Study Director, Q-Med AB
Statistician, Q-Med AB
Medical Expert, Q-Med AB
 
 
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Signed Agreement of the Clinical Study Protocol
CTN:
05DF1605
Title of the CSP:
A randomised, evaluator-blind comparative study to evaluate 
performance and safety of Restylane Lidocaine and no-treatment 
control for treatment of depressed facial acne scars
We, the undersigned, have read and understand the CSP specified above, and agree on the 
contents. The CSP, the clinical trial agreement (CTA) and the additional information given in 
the instructions for use (IFU) 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, evaluator-blind comparative study to 
evaluate performance and safety of Restylane Lidocaine
and no-treatment control for treatment of depressed facial 
acne scars
Clinical Trial Number:
05DF1605
Number of sites and 
subjects:
Approximately 60 subjects will be recruited at 3-5 sites. 
Approximately 12-25 subjects will be included per site.
Coordinating Investigator:
Principal Investigators:
Primary Objective:
To show greater improvement in depressed facial acne 
scars treated with Restylane Lidocaine compared with
untreated depressed facial acne scars in the same subject 
using a split-face design. The primary endpoint is 
proportion of subjects for whom the cheek treated by 
Restylane Lidocaine has a  lower scar severity compared to 
the opposite untreated cheek 
 
Secondary Objectives:
Assessment of:
Aesthetic improvement of depressed facial atrophic acne
scars using the Global Aesthetic Improvement Scale 
(GAIS)
 
 
 
 
 
 
 
 
 
 
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Study Design:
This is a 12-month prospective, randomised, evaluator-
blinded, multi-centre study to evaluate performance and 
safety of facial acne scars treatment with Restylane
Lidocaine by comparing with no-treatment control using a
split-face design. Subjects will be randomised to receive 
treatment with Restylane Lidocaine on either the right or 
left cheek and no treatment on the opposite cheek.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria:
1. Presence of 5-20 
 
 scars with a diameter of up to approximately 
4 mm within the treatment area
2. Similar type, size and number of scars on both cheeks 
 
 
3. Intent to undergo treatment of depressed acne scars
4. Men or non-pregnant, non-breast feeding women 
 
5. Fitzpatrick skin type I-IV
 
 
 
 
 
7. Signed and dated informed consent to participate in the 
study
 
 
 
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Exclusion criteria:
1. Presence of more than 3 scars per cheek (within the 
treatment area) of the following types: icepick scars 
or atrophic acne scars with a diameter of > 4 mm.
2. Active acne with inflammatory component
3. Use of per oral or topical (facial) substances containing 
retinoids, bensoyl peroxide, alpha-hydroxy acid at 
concentrations above 10%, beta-hydroxy acid at a 
concentration above 2%, or antibiotic treatment for 
active acne within 4 months before treatment
4. Use of isotretinoin within 6 months before treatment
5. Post-surgical scars in the treatment area
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.Previous tissue augmenting therapy or contouring with 
permanent filler or fat-injection in the treatment area
13.Previous tissue augmenting therapy, contouring or 
revitalisation treatment with Calcium Hydroxyapatite 
(CaHa), or Poly L-Lactic Acid (PLLA), in the treatment 
area within 24 months before treatment
14.Previous tissue augmenting therapy, contouring or 
revitalisation treatment with non-permanent filler such 
as HA or collagen in the treatment area within 12 
months before treatment
15.Previous tissue revitalisation treatment with neurotoxin, 
laser or light, mesotherapy, chemical peeling or 
dermabrasion in the treatment area within 6 months 
before treatment
16.Previous surgery including aesthetic facial surgical 
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therapy, liposuction, or tattoo in the treatment area
 
 
 
 
 
 
 
 
 
23.Any medical condition that, in the opinion of the
treating Investigator, would make the subject unsuitable 
for inclusion (e.g. a chronic, relapsing or hereditary 
disease that may interfere with the outcome of the 
study)
 
 
 
 
 
 
 
 
 
Investigational product, 
dose and mode of 
administration:
Commercially available Restylane Lidocaine (Q-Med AB, 
Sweden, Uppsala) 
 
 
Reference therapy, mode of 
administration:
Not applicable. The reference is a no-treatment control.
Duration of treatment and 
follow-up:
Subjects will be followed for 12 months after the first 
treatment with Restylane Lidocaine. 
 
 
 
Each subject 
will be involved in the study for approximately 12-14 
months.
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Efficacy Assessments:
GAIS assessment 
 
 
Assessment of acne scar severity
 
 
 
 
 
Safety Assessments:
Assessments of anticipated post-treatment events 
 
 
 
Safety should also be assessed by recording AEs and 
device deficiencies throughout the study
Statistical Methods:
 
 
 
 
 
 
 
 
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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.
CE
French: Conformité Européenne
Coordinating 
Investigator
Investigator who is appointed by the Sponsor to coordinate work in a 
multicenter study
CRF
Case report form
CRO
Contract research organisation
CSP
Clinical study protocol
CTA
Clinical trial agreement
CTN
Clinical trial number
CV
Curriculum vitae
Device deficiency
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance (includes malfunctions, use errors, and 
inadequate labelling)
DMP
Data management plan
eCRF
Electronic case report form
First treatment
Initial injection of study product
First subject in
First subject screened, i.e. who signs the informed consent form
First subject out
First subject who completed his/her last study visit
G
Gauge
GCP
Good clinical practice
HA
Hyaluronic acid
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 a 
clinical study is conducted.
Investigator
The Principal Investigator (PI) or other qualified person, i.e. sub-investigator, 
designated and supervised by the PI at a study site to perform critical study-
related procedures or to make important study-related decisions as specified on 
the signature and delegation log
Investigator file
Essential documents relating to a clinical study as defined in applicable GCP 
guidance document and maintained by the Investigator.
ISO
International Organization for Standardization
ITT
Intention-to-treat
MedDRA
Medical dictionary for regulatory activities
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NSAID
Non-steroidal anti-inflammatory drugs
PI
Principal Investigator; qualified person responsible for conducting the study at 
a study site
PP
Per protocol
PT
Preferred term
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
Sponsor file
Essential documents relating to a clinical study as defined in applicable GCP 
guidance document and maintained by the Sponsor.
Study files
The Investigator file and the Sponsor file
Study products
The investigational product and the reference product under study
Study site
Institution or site where the study is carried out
 
TW
Thin walled (needles)
U-HCG
Urinary human chorionic gonadotropin
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Table of Contents
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
2
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
4
SYNOPSIS
5
ABBREVIATIONS AND DEFINITIONS OF TERMS
10
LIST OF TABLES
15
LIST OF FIGURES
15
LIST OF APPENDICES
15
1.
ETHICAL CONSIDERATIONS
16
1.1
Statement of ethical compliance
16
1.2
Application to independent ethics committee
16
2.
BACKGROUND INFORMATION
16
2.1
Indication and population description
16
2.2
Investigational product description
16
2.3
Reference product description
17
2.4
Previous experience
17
2.4.1
Non-clinical documentation
17
2.4.2
Clinical documentation
17
2.5
Study rationale
17
2.6
Justification for the design of the study
18
2.7
Risks and benefits
18
3.
OBJECTIVES AND ENDPOINTS
19
3.1
Objectives and endpoints of the study
19
4.
DESIGN OF THE STUDY
19
4.1
General outline
19
4.2
Number of subjects
20
4.3
Duration of subject participation
20
4.4
Randomisation and blinding
20
4.4.1
Randomisation/treatment assignment
20
4.4.2
Blinding
21
4.4.3
Emergency unblinding
21
4.5
Medical history
21
4.6
Previous and concomitant medications and procedures
21
4.6.1
Definition
21
4.6.2
Categories
21
4.6.3
Recording
22
4.6.4
Authorised concomitant medications/procedures
22
4.6.5
Prohibited concomitant medications and procedures
22
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4.7
Schedule of events
23
4.8
Visits
24
4.9
Demographics and baseline assessments
27
5.
SUBJECTS
28
5.1
Subject information and informed consent
28
5.2
Inclusion criteria
28
5.3
Exclusion criteria
29
5.4
Screening and subject numbers
30
5.5
Withdrawal of subjects
31
6.
STUDY PRODUCTS
32
6.1
Investigational product
32
6.2
Reference product
32
6.3
Additional products and material
32
6.4
Packaging, labelling, and storage
32
6.4.1
Investigational product
32
6.4.2
Reference product
32
6.5
Product accountability
33
6.6
Treatment
33
6.6.1
Treatment procedure
33
6.6.2
Treatment regimen (volume and interval)
35
6.6.3
Post-treatment care
35
6.6.4
Post-trial provisions
36
6.6.5
Electronic case report form recordings
36
6.6.6
Treatment compliance
36
7.
PERFORMANCE ASSESSMENTS
36
7.1
General information
36
7.2
Photography
37
7.3
Global aesthetic improvement scale
38
39
7.5
Blinded Evaluator’s live assessment of scar severity comparing both cheeks
39
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8.
SAFETY ASSESSMENTS
41
8.1
Anticipated, post-treatment events and local tolerability
41
8.2
Adverse events
41
8.2.1
Definition of an adverse event
41
8.2.2
Definition of a serious adverse event
42
8.2.3
Definition of adverse events of special interest
42
8.2.4
Recording instructions
42
8.2.5
Reporting of adverse events
43
8.2.6
Reporting of serious adverse events
44
8.2.7
Follow-up of unresolved events after termination of the study
45
8.2.8
Pregnancy
45
8.3
Device deficiencies
45
8.3.1
Definition of a device deficiency
45
8.3.2
Recording instructions
46
8.3.3
Reporting of device deficiencies
46
8.4
Data safety monitoring board
46
9.
DATA HANDLING AND MANAGEMENT
47
9.1
Data management
47
9.2
Electronic case report forms
47
9.2.1
Data entry
47
9.2.2
The query process
48
9.2.3
User identification
48
9.2.4
Audit trail
48
9.3
Source documents
48
9.4
Record keeping and access to source data
49
9.5
Document and data retention
49
10.
STATISTICAL METHODS
49
10.1
General
49
10.2
Analysis populations
50
10.3
Demographics, baseline assessments, and subject characteristics
50
10.4
Performance analysis
50
10.4.1
Primary analysis
50
10.4.2
Secondary analysis
50
10.5
Safety analysis
51
10.6
Handling of missing data
51
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10.7
Analysis of data during the study
51
10.8
Withdrawals and deviations
51
10.9
Sample size
51
11.
PROTECTION OF PERSONAL DATA
52
12.
QUALITY CONTROL AND QUALITY ASSURANCE
53
12.1
Quality control
53
12.2
Quality assurance
53
12.3
Changes to the clinical study protocol
53
13.
FINANCING, INDEMNIFICATION, AND INSURANCE
54
14.
PUBLICATION POLICY
54
15.
SUSPENSION OR PREMATURE TERMINATION
54
16.
REFERENCES
55
List of Tables
List of Figures
List of Appendices
Appendix 1
Declaration of Helsinki....................................................................................57
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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), good clinical practice (GCP), and applicable regional or 
national regulations. The international standard for clinical study of medical devices for 
human subjects, ISO14155:2011 shall be followed. The International Conference on 
Harmonisation (ICH) guideline for GCP (E6) shall be followed as applicable for medical 
device. The study shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (Appendix 1).
1.2
Application to independent ethics committee
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 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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. Objectives and Endpoints
3.1
Objectives and endpoints of the study
The primary objective of the study is to show greater improvement in depressed facial acne 
scars treated with Restylane Lidocaine compared with untreated depressed facial acne scars 
in the same subject using a split face design. The primary endpoint is proportion of subjects
for whom the cheek treated by Restylane Lidocaine has a lower overall scar severity 
compared to the untreated opposite cheek
The secondary objectives of the study are to evaluate acne scar treatment by assessing:
Aesthetic improvement of depressed facial atrophic acne scars using the Global 
Aesthetic Improvement Scale (GAIS)
 
 
 
 
 
 
Short- and long-term safety throughout the entire study by collecting AEs and device 
deficiencies
4. Design of the Study
4.1
General outline
This is a 12-month prospective, randomised, evaluator-blinded, multi-centre study to evaluate
performance and safety of facial acne scars treatment with Restylane Lidocaine by comparing 
with no-treatment control. A split-face design will be used, i.e. subjects will be randomised to 
treatment with Restylane Lidocaine on the right or left cheek and no treatment on the other 
cheek.
Blinding will be accomplished by using a treating Investigator to administer the treatment 
and a blinded evaluator, to whom randomisation and treatment assignment are concealed, to 
conduct the assessments. The subjects and Sponsor will not be blinded to treatment 
assignment.
The first treatment will be administered by the treating Investigator according to a 
standardised procedure. 
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Subjects will be followed for 12 months
 Photographs will be taken before treatment and during each 
follow-up visit. 
 
 
AEs device deficiencies will be recorded after treatment by the treating Investigator.
Anticipated post-treatment events of expected severity do not have to be recorded as AEs in 
the eCRF (Section 8.1). 
t
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2
Number of subjects
Approximately 60 subjects will be recruited at 3-5 sites. The duration of the enrolment period 
is expected to approximately 3 months.
Approximately 12-25 subjects will be included per site.
4.3
Duration of subject participation
A subject will be involved in the study for approximately 12-14 months.
4.4
Randomisation and blinding
4.4.1
Randomisation/treatment assignment
Before starting the study, a randomisation list will be generated by a statistician. Treatment 
assignment for each cheek (Restylane Lidocaine to right or left cheek and no treatment on the 
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other cheek) will be randomised for each subject when all inclusion criteria and exclusion 
criteria have been verified at the treatment visit. Right or left side/cheek is defined as the 
subject’s right or left side in this study protocol.
All treatment information will be kept by the treating Investigator during the study not to be 
disclosed to the blinded evaluator.
4.4.2
Blinding
The blinded evaluator shall not be allowed to retrieve study supplies or to be present during 
opening of the study supplies or injections. The treating Investigator or the subjects are not 
allowed to discuss treatments with the blinded evaluator. All documents with information 
about study product and treatment shall be kept separately and not available to the blinded 
evaluator.
The treating Investigator, the subjects, Sponsor and the Sponsor representative shall not be 
blinded to treatment assignment during the study.
4.4.3
Emergency unblinding
Not applicable as the treating Investigator is not blinded to treatment assignment. 
4.5
Medical history
History of surgical events and medical conditions that are judged as relevant by the treating 
Investigator shall be documented in the eCRF using medical terminology in English.
4.6
Previous and concomitant medications and procedures
4.6.1
Definition
Previous medications or procedures are defined as therapies that have been stopped within 1 
day preceding the Screening visit.
 
 
4.6.2
Categories
The following two categories are to be considered for previous and concomitant medications 
or procedures:

Medications
 
 
 
 
 
 

Medical and surgical procedures 
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4.6.3
Recording
Previous and concomitant medications and procedures administered during the study are to 
be recorded on the dedicated forms in the eCRF. Concomitant medications and procedures
are to be recorded, reviewed, and updated at each visit. The generic name or the trade name 
of all concomitant medications or a description of the procedure and the reason for its use 
shall be documented in the eCRF. Any new concomitant medication/procedure or 
modification of an existing therapy may be linked to an AE or medical history. A 
corresponding AE form must be completed to account for the change in therapy, except in 
some cases such as therapy used for prophylaxis, dose modification for a chronic condition, 
etc.
4.6.4
Authorised concomitant medications/procedures
Unless listed under the exclusion criteria (Section 5.3) or in prohibited concomitant 
medications/procedures (Section 4.6.5), all medications/procedures are authorised.
4.6.5
Prohibited concomitant medications and procedures
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participation in any other clinical study is prohibited.
If a subject receives prohibited therapy during the study, a protocol deviation should be 
documented.
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5. Subjects
5.1
Subject information and informed consent
The PI or his/her authorised designee must always use the IEC-approved subject information
and informed consent form and it must not be changed without prior discussion with the 
Sponsor and approval from the applicable IEC.
It is the responsibility of the PI or his/her authorised designee to give each subject prior to 
inclusion in the study, full and adequate verbal and written information regarding all aspects 
of the clinical study that are relevant to the subject’s decision to participate throughout the 
study, e.g. explain the purpose and procedures of the study, the duration and number of 
expected participants, possible risks involved, and the opinion of the IEC. The subject shall
be informed that the participation is confidential and voluntary and that the subject has the 
right to withdraw from the study at any time, without any affect 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 delegated 
Investigator. The consent includes information that data will be collected, recorded, 
processed, and may be transferred to other EU or non-EU countries. The data will not contain 
any information that can be used to identify any subject.
Photographs collected during the study will be analysed and stored by the Sponsor and its 
representatives in order to evaluate the effect of the treatment in the study. The subjects will 
be recognisable on the photographs, but their names will not be disclosed.
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 subjects must meet the following criteria to be eligible for the study:
1. Presence of 5-20 
 scars with a diameter of up to 
approximately 4 mm within the treatment area
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2. Similar type, size and number of scars on both cheeks 
 
 
3. Intent to undergo treatment of depressed acne scars
4. Men or non-pregnant, non-breast feeding women
5. Fitzpatrick skin type I-IV
 
 
7. Signed and dated informed consent to participate in the study
 
5.3
Exclusion criteria
The presence of any of the following exclusion criteria will exclude a subject from enrolment 
in the study:
1.
Presence of more than 3 scars per cheek (within the treatment area) of the following 
types: icepick scars or atrophic acne scars with a diameter of > 4 mm.
2.
Active acne with inflammatory component
3.
Use of per oral or topical (facial) substances containing retinoids, bensoyl peroxide, 
alpha-hydroxy acid at concentrations above 10%, beta-hydroxy acid at a concentration 
above 2%, or antibiotic treatment for active acne within 4 months before treatment
4.
Use of isotretinoin within 6 months before treatment
5.
Post-surgical scars in the treatment area
 
 
 
 
 
 
 
12. Previous tissue augmenting therapy or contouring with permanent filler or fat-injection
in the treatment area
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13. Previous tissue augmenting therapy, contouring or revitalisation treatment with Calcium 
Hydroxyapatite (CaHa), or Poly L-Lactic Acid (PLLA), in the treatment area within 24 
months before treatment
14. Previous tissue augmenting therapy, contouring or revitalisation treatment with non-
permanent filler such as HA or collagen in the treatment area within 12 months before 
treatment
15. Previous tissue revitalisation treatment with neurotoxin, laser or light, mesotherapy, 
chemical peeling or dermabrasion in the treatment area within 6 months before treatment
16. Previous surgery including aesthetic facial surgical therapy, liposuction, or tattoo in the 
treatment area
 
 
 
 
 
23. Any medical condition that, in the opinion of the treating Investigator, would make the 
subject unsuitable for inclusion (e.g. a chronic, relapsing or hereditary disease that may 
interfere with the outcome of the study)
 
 
5.4
Screening and subject numbers
Each subject who has signed the informed consent form will be assigned a screening number
and 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 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 treating Investigator has confirmed that all inclusion criteria and no exclusion 
criteria are met, each subject will be assigned a subject number.
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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 he/she has the right to 
withdraw from the study at any time, for any reason, without prejudice. Subjects may also be 
discontinued from this study if the Investigator determines that it is in the subject’s best 
interest to do so, and may be withdrawn at the Investigator's discretion at any time.
 
 
 
 
 
 
 
 
 
 
The reason and date for withdrawal shall be documented in the eCRF. When possible, an 
explanatory comment shall be added in the study termination module to further explain the 
reason for withdrawal.
If withdrawal of a subject occurs during a regular study visit, the eCRF for that specific visit 
shall be completed as far as possible together with the study termination eCRF module.
If withdrawal of a subject occurs between regular study visits the subject should when
possible (irrespective of the reason for withdrawal) be scheduled for a termination visit to 
document subject outcome for the primary and secondary endpoints. In these cases the eCRF 
for the next upcoming visit should be completed.
If a subject is withdrawn from the study, all data collected including photographs 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 (3) months shall be provided to the Sponsor. 
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6. Study Product
The term “study product” refers to Restylane Lidocaine.
6.1
Investigational product
Commercially available Restylane (Q-Med AB, Sweden, Uppsala) with lidocaine will be 
provided by the Sponsor.
 
 
6.2
Reference product
Not applicable. The reference in this study is a no-treatment control 
 
6.3
Additional products and material
The study site will provide urine pregnancy tests (U-HCG).
Topical or local anaesthesia may be used at the discretion of the treating Investigator before 
the treatment. If used, the anaesthesia shall be supplied by the study site. Type of anaesthesia, 
product name, and quantity used must be recorded in the eCRF.
The study site shall provide adequate equipment in case of emergency.
 
 
 
 
 
 
 
 
 
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6.5
Product accountability
The investigational product will be released to the PI or his/her authorised designee after 
study approvals have been received from the IEC and RA, if applicable, and the CTA has
been signed by all parties.
The PI must ensure that the study products are kept in a secure location, stored according to 
the IFU (Appendix 2), with access limited to those authorised by the PI.
The investigational product must be traceable from the manufacturer(s) to their 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
products, deliveries, and return of study products between the Sponsor 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, batch number, expiry date, dispense date, the number 
of syringes used, the subject receiving investigational product, and number of syringes left in 
stock at the site.
When the study is completed, all unused or expired investigational products at each study site 
shall be returned to the Sponsor for destruction. Any malfunctioning investigational products
shall be reported as described in section 8.3.3.
Products 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 investigational 
product must not be used outside the study. 
 
 
 
 
 
 
 
 
 
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6.6.6
Treatment compliance
The study product shall be injected by the treating Investigator. No other measurements of 
treatment compliance shall be made.
7. Performance Assessments
7.1
General information
The methods for collecting performance data include photography (section7.2), global 
aesthetic improvement scale31 (GAIS) (section7.3), 
assessment of scar severity
 
 
Right or left side/cheek is defined as the subject’s right or left side in this study protocol.
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To avoid inter-observer variability, every effort should be made by each study site to ensure 
that the same individual who made the initial baseline assessments completes all 
corresponding follow-up assessments.
7.2
Photography
Standardised photographs shall be taken 
 prior to the first injection of the 
study product and at every follow-up visit in order to document treatment effect. Note that no 
covering make-up should be used on the photographs. Each Investigator and other study site 
personnel designated to take photographs shall be thoroughly trained in the photographic 
equipment and techniques before study start, if applicable.
Photographs shall be taken at the baseline visit before treatment. If the photographs are 
considered as of good quality, the Investigator may proceed with treatment of the subject at 
the Day 1 visit, which can be scheduled separately from the screening visit or at the same 
day. If the photographs are considered not good enough, the photography shall be repeated.
The quality of the photographs 
should be assessed by the Investigator or other designated person and repeat photography if 
needed.
All photographs shall be taken against a neutral background and artificial light only. Several 
lightning modalities, as specified in the separate instruction, including the parallel-polarized 
modality shall be used. The subject should keep the eyes closed during photography. The 
subject shall have a neutral facial expression. The photographs shall be taken in a 
standardised way according to the following scheme:
 
For further details, please see the instruction of images procedures in 
user guide
and study specific instructions regarding photography.
Each photograph shall be traceable and labelled with the subject number, the visit number 
and with which lighting modality the photograph was taken. In order to maintain 
confidentiality, the photographs must not include any information that may reveal the 
subject’s identity. The photographs should be used in the assessment of GAIS.
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8. Safety Assessments
 
 
 
 
 
 
 
 
 
 
8.2
Adverse events
8.2.1
Definition of an adverse event
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other personsa, 
whether or not related to the study product.
This definition includes:
a) events related to the investigational product or the reference product
b) events related to the procedures involved
                                                
a For users or other persons, this definition is restricted to events related to the investigational product.
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8.2.2
Definition of a 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-threateninga illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalisationb, or
4. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,
c) led to foetal distress, foetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such.
8.2.3
Definition of adverse events of special interest
Not applicable.
8.2.4
Recording instructions
Each subject should be questioned about AEs at each study visit following the first treatment.
The question asked should be: ”Since your last clinical visit have you had any health 
problems?”. Information on AEs can also be obtained from signs and symptoms detected 
during each examination or from a laboratory test, observations made by the study site
personnel, subject diaries, or spontaneous reports from the subjects or their relatives.
 
 
 
 
 
 
 
 
When an AE is related to a device deficiency (refer to section 8.3), including technical device 
malfunction, the AE shall be recorded on the AE form/module in the eCRF and the technical 
complaint shall be reported on the clinical study complaint form provided separately.
All AEs in the eCRF shall be recorded, including:
                                                
a 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).
b 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).
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a) Event term (recorded in standard medical terminology and avoiding abbreviations)
b) Description of event and affected area
c) Start date (first day with symptoms)
d) Stop date (last day with symptoms)
e) Intensity (mild, moderate, or severe according to definition in section 8.2.4.1)
f)
Seriousness (serious or not serious, according to definition in section 8.2.2)
g) Causal relationship to study product or study product injection procedure (yes or no)
should be assessed by treating Investigator
h) Action taken (none, medication treatment, non-pharmacological treatment, or other 
procedures/tests, subject withdrawn)
i)
Outcome of the AE (ongoing, recovered, recovered with sequelae, death, chronic/ 
stable, not recovered at the end of the study)
The AE form/module in the eCRF must be signed and dated by the Investigator.
8.2.4.1
Intensity
Intensity will be recorded for each reported AE. The following definitions of intensity are to e 
used:
Mild:
Awareness of symptoms or signs, but easily tolerated (acceptable)
Moderate:
Enough discomfort to interfere with usual activity (disturbing)
Severe:
Incapacity to work or to do usual activity (unacceptable)
If the intensity changes within one day, the maximum intensity of the AE during that day 
shall be recorded.
8.2.4.2
Causal relationship and seriousness
Each AE, serious as well as non-serious, shall 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 response) shall be used for the causality assessments. The
Investigators shall be asked to indicate a response to each of the following questions in the 
eCRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?”, and

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product injection procedure?”
If any of these questions is answered Yes, the AE is considered related.
Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in order 
to fulfil regulatory requirements.
8.2.5
Reporting of adverse events
Adverse event reporting on each subject shall start after treatment. The reporting shall 
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.
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8.2.6
Reporting of serious adverse events
The Investigator shall report any SAE to the Sponsor immediately but not later than 24 
hours of awareness of the event. This initial report can be submitted via the eCRF or sent
via fax or e-mail
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:

Subject identification (age, gender, subject number)

AE description

Date when AE occurred

Name of PI and original reporter (if other than the PI)

Name of study product 
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

Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
___________________________________________________________________________
E-mail for SAE reporting:
Fax number for SAE reporting:
___________________________________________________________________________
For non urgent complementary information not possible to send by e-mail or fax, please use 
surface mail.
Surface mail for providing
Galderma Uppsala
complementary information:
 
__________________________________________________________________________
The SAE form must be signed and dated by the treating 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, the PI shall report SAEs to the responsible IEC without undue delay, if applicable 
according to national regulations. The PI is responsible for checking what reporting 
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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 Sponsor is responsible for reporting to the RA, if applicable and according to national 
regulations.
For a description of the procedure regarding emergency unblinding, see section 4.4.3.
8.2.7
Follow-up of unresolved events after termination of the study
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. Follow-up information for at least three (3) 
months shall be provided to Sponsor. Final outcome after the end of the study shall be 
reported on the AE follow-up form.
8.2.8
Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy during the study period the subject must be withdrawn from any 
following study treatment, but should continue to be followed within the study and the 
outcome of pregnancy must be reported even if the 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 8.2.6. 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 shall not be reported as AEs.
8.3
Device deficiencies
8.3.1
Definition of a device deficiency
A device deficiency is defined as an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safetya, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
                                                
a Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
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8.3.2
Recording instructions
When a device deficiency is discovered, Part A of the clinical study complaint form shall 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 or an SAE shall be recorded as applicable. 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
In Part B of the clinical study complaint form the Sponsor will make the same assessment.
8.3.3
Reporting of device deficiencies
The Investigator shall send the completed clinical study complaint form to the Sponsor using
the contact details:
___________________________________________________________________________
E-mail for device deficiency reporting:
Fax number for device deficiency reporting:
___________________________________________________________________________
For non urgent complementary information not possible to send by e-mail or fax, please use 
surface mail:
Galderma Uppsala 
A device deficiency that led to a SAE and any device deficiency that could have led to a SAE 
shall be reported to the Sponsor within 24 hours after the Investigator’s awareness (for 
contact information, see section 8.2.6).
In order to fulfil regulatory reporting requirements, all deficiencies with the study product 
must be assessed by both the Investigator and the Sponsor to determine if it could have led to 
a SAE.
If a SAE has resulted from a device deficiency or if either the Investigator or the Sponsor 
assesses that the device deficiency could have led to a SAE the Sponsor is responsible for 
reporting the device deficiency to RA and the PI is responsible for reporting it to the IEC, if 
applicable.
The deficient study product shall be kept by the study site until the Quality Assurance (QA)
complaints group has confirmed whether the product shall be returned to Sponsor for further 
study or if it can be destroyed at the study site.
8.4
Data safety monitoring board
Not applicable.
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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 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 and if applicable AE of special interest) 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 eCRF 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
A 21 Code of Federal Regulations (CFR) Part 11-compliant electronic data capture 
application will be used to collect, modify, maintain, archive, retrieve, and transmit study 
data. 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 shall
be entered 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
investigation 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, except for authorised representatives of appropriate RA, without written 
permission from the Sponsor. At the end of the study, electronic data are kept at the Sponsor 
and a copy (provided by the vendor) at the study site as part of the Investigator file.
Any delegation of collection of data shall be specified in a signature and delegation log.
9.2.1
Data entry
All data shall be entered in English. The eCRF should always reflect the latest observations 
on the subjects participating in the study. Therefore, the eCRF shall be completed as soon as 
possible during or 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 eCRF or 
in the database. The Investigator must verify that all data entries in the eCRF are accurate and 
correct. If some assessments are not done, or if certain information is not available, not 
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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 eCRF and evaluate them for completeness and consistency. 
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 eCRF. 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 UserID. 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 UserID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry 
in an eCRF requires change, the correction shall be made in accordance with the relevant 
software procedures.
9.2.4
Audit trail
All changes will be fully recorded in a protected audit trail and a reason for the change shall 
be stated. Once all data have been entered, verified, and validated, the database will be 
locked.
9.3
Source documents
The eCRF is essentially considered a data entry form and does not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used 
by the Investigator or hospital that relate to the subject’s medical history, that verifies the 
existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study. They include laboratory notes, 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 laboratory or hospital records, shall be 
clearly identified with the CTN and subject number. Any personal information, including 
name, shall be removed or rendered illegible to preserve individual confidentiality.
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9.4
Record keeping and access to source data
The PI/Institution shall permit study-related monitoring, audits, IEC review, and RA
inspections 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 shall 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 shall 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 eCRF will 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 shall be available in the medical record. 
The source data location log shall 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 eCRF, informed consent 
forms, study product accountability records, source documents, and other study 
documentation must be retained for 15 years after study completion or longer if required by 
national legislation. Sponsor will inform the site(s) as to when these documents no longer 
needs to be retained. Measures shall be taken to prevent accidental or premature destruction 
of these documents (e.g. protection against damage and unauthorised access, preferably by 
storage in a fire-proof cabinet). Refer to the CTA.
After study completion and database lock, a security sealed CD with electronic study data 
shall be provided by the eCRF vendor for archiving.
It is the PI’s responsibility to inform the Sponsor in writing if the Investigator file is moved 
or if the responsibility for the documents is transferred to someone else.
10. Statistical Methods
 
 
 
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10.2 Analysis populations
The following populations will be defined:

Safety/Intention-to-treat (ITT)

Per protocol (PP)
 
 
 
 
 
 
 
 
Intention-to-treat is the primary population for all performance analyses. The primary 
performance outcome will also be analysed with the PP population. Safety analysis is 
performed based on the safety population set.
The disposition of subjects will be presented in tables and/or figures as appropriate. The 
number of screened, treated, completed, and withdrawn subjects will be presented, as well as 
number of subjects in each analysis population set.
10.3 Demographics, baseline assessments, and subject characteristics
Demographic endpoints and subject characteristics will be presented using descriptive 
statistics.
 
 
 
 
 
 
 
 
 
 
 
 
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10.6 Handling of missing data
Study data will be presented based on observed cases, i.e. no imputation of missing values
will be performed.
10.7 Analysis of data during the study
Data will be analysed when all subjects have performed their 3-month visit (visit 4). Any 
withdrawn subjects prior to the 3-month visit will be included in the analyses.
10.8 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.
Deviations from the statistical plan will be documented.
 
 
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11. Protection of personal data
The study shall include collection and processing of personal data as specified in 
Directive 95/46 EC on the protection of individuals with regard to the processing of personal 
data and on the free movement of such 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 not having same high 
level of security for processing of personal data than Sweden and EU, and the length of time 
during which personal data will be stored. The subject shall have the right of access to stored 
personal data, and the right to correction of incorrect information. If a subject decides to 
terminate the study prematurely, data collected before withdraw of consent will be used in the 
evaluation of the study, however no new data may be collected. Authorised representatives 
from the Sponsor, CRO or a RA may visit the study site to perform audits/inspections, 
including source data verification, i.e. comparing data in the subjects’ medical records and 
the eCRF. Data and information shall be handled strictly confidential.
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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 verified, discussed, and collected by the monitor and 
appropriate actions will 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 will be reviewed to
determine the need to amend the CSP or to terminate the study. Handling of CSP deviations 
will be performed as described in the monitoring manual.
12.2 Quality assurance
The study site may be subject to QA 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 will confirm 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.
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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, Institution’s, 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 multicenter study shall have 
made a substantial, direct, intellectual contribution to the work. Authorship will be based on 
(1) substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; and (2) drafting the work or revising it 
critically for important intellectual content; and (3) final approval of the version to be
published; and (4) agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.34 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 will 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.
15. Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IEC or RA, 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.
Kraning K, Odland. Prevalence, morbidity, and cost of dermatological diseases. J Invest 
Dermatol 1979 Nov;73(5 Pt 2):395–401.
2.
Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late adolescence and in adults. 
Br Med J 1979;1(6171):1109–10.
3.
Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 
1999;41(4):577–80.
4.
Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its 
incidence. Clin Exp Dermatol 1994;19(4):303–8.
5.
Hayashi N, Miyachi Y, Kawashima M. Prevalence of scars and “mini-scars”, and their impact 
on quality of life in Japanese patients with acne. J Dermatol 2015 Jul;42(7):690–6.
6.
Cotterill JA, Cunliffe WJ. Suicide in dermatological patients. Br J Dermatol. 
1997;137(2):246–50. –50.
7.
Jacob CI, Dover JS, Kaminer MS. Acne scarring: a classification system and review of 
treatment options. J Am Acad Dermatol. 2001 Jul;45(1):109–17.
8.
Goodman GJ. Postacne scarring: a review of its pathophysiology and treatment. Dermatol 
Surg. 2000 Sep;26(9):857–71.
9.
Hession MT, Graber EM. Atrophic acne scarring: a review of treatment options. J Clin 
Aesthet Dermatol. 2015;8(1):50–8.
10. Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol. 2006 May-Jun;19(3):141-50.
11. Gold M. The science and art of hyaluronic acid dermal filler use in esthetic applications. J 
Cosmet Dermatol. 2009 Dec;8(4):301–7.
12. Matarasso SL, Carruthers JD, Jewell ML, Restylane Consensus Group. Consensus 
recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid 
(Restylane). Plast Reconstr Surg. 2006 Mar;117(3 Suppl):3S – 34S; discussion 35S – 43S.
13. 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. 
Dermatologic Surg. 2008;34(SUPPL 1):2–8.
14. 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):322–30; discussion 330–1.
15. Ascher B, Bayerl C, Brun P, Kestemont P, Rzany B, Poncet M, et al. Efficacy and safety of a 
new hyaluronic acid dermal filler in the treatment of severe nasolabial lines - 6-month interim 
results of a randomized, evaluator-blinded, intra-individual comparison study. J Cosmet 
Dermatol. 2011 Jun;10(2):94–8.
16. Rzany B, Bayerl C, Bodokh I, Boineau D, Dirschka T, Queille-Roussel C, et al. Efficacy and 
safety of a new hyaluronic acid dermal filler in the treatment of moderate nasolabial folds: 6-
month interim results of a randomized, evaluator-blinded, intra-individual comparison study. 
J Cosmet Laser Ther. 2011 Jun;13(3):107–12.
17. 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. 
Dermatologic Surg. 2010;36(SUPPL. 1):741–9. 
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18. Glogau RG, Kane MAC. Effect of injection techniques on the rate of local adverse events in 
patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatologic Surg. 
2008;34(SUPPL 1):105–9. 
19. Solish N, Swift A. An open-label, pilot study to assess the effectiveness and safety of 
hyaluronic acid gel in the restoration of soft tissue fullness of the lips. JDD. 2011;10(2):145–
9.
20. DeLorenzi C, Weinberg M, Solish N, Swift A. The long-term efficacy and safety of a 
subcutaneously injected large-particle stabilized hyaluronic acid-based gel of nonanimal 
origin in esthetic facial contouring. Dermatol Surg. 2009 Feb;35 Suppl 1(SUPPL. 1):313–21.
21. Abdel Hay R, Shalaby K, Zaher H, Hafez V, Chi C-C, Dimitri S, et al. Interventions for acne 
scars. Cochrane database Syst Rev. 2016;4(4):CD011946.
22. Goodman GJ. Treatment of acne scarring. Int J Dermatol. 2011 Oct;50(10):1179-94. Review.
23. Cooper JS, Lee BT. Treatment of facial scarring: Lasers, filler, and nonoperative techniques. 
Facial Plastic Surgery. 2009. p. 311–5.
24. Q-Med AB/Galderma internal data. 05DF1206.
25. Karnik J, Baumann L, Bruce S, Callender V, Cohen S, Grimes P, et al. A double-blind, 
randomized, multicenter, controlled trial of suspended polymethylmethacrylate microspheres 
for the correction of atrophic facial acne scars. J Am Acad Dermatol. 2014;71(1):77–83.
26. The Fitzpatrick Skin Type Classification Scale. Skin Inc. (November 2007). Retrieved from 
http://www.skininc.com/skinscience/physiology/10764816.html 20 August 2014. (The 
Fitzpatrick skin type classification scale that is used in this template)
27. Fitzpatrick TB. "Soleil et peau" [Sun and skin]. Journal de Médecine Esthétique (in French) 
1975;2:33-34. (Reference to the original Fitzpatrick scale).
28. Pathak MA, Jimbow K, Szabo G, Fitzpatrick TB. Sunlight and melanin pigmentation. In 
Smith, KC (ed.): Photochemical and photobiological reviews, Plenum Press, New York, 
1976:211-239. (Original Fitzpatrick scale extended to include non-white skin types).
29. Fitzpatrick TB. Ultraviolet-induced pigmentary changes: Benefits and hazards, Therapeutic 
Photomedicine, Karger, vol. 15 of Current Problems in Dermatology, 1986:25-38. (Original 
Fitzpatrick scale extended to include non-white skin types).
30. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, 
multicenter comparison of the efficacy and tolerability of restylane versus zyplast for the 
correction of nasolabial folds. Dermatologic Surg. 2003;29(6):588–95.
31. Jaspers S. Fringe projection for in vivo topometry. In: Wilhelm KP, Elsner P, Berardesca E, 
editors. Bioengineering of the skin: skin imaging and analysis (2nd ed). Boca Raton: Informa 
Healthcare; 2006. pp 137–47.
32. Friedman PM, Skover GR, Payonk G, Kauvar ANB, Geronemus RG. 3D in-vivo optical skin 
imaging for topographical quantitative assessment of non-ablative laser technology. 
Dermatologic Surg. 2002;28(3):199–204.
33. Luebberding S, Krueger N, Kerscher M. Quantification of age-related facial wrinkles in men 
and women using a three-dimensional fringe projection method and validated assessment 
scales. Dermatologic Surg. 2014;40(1):22–32.
34. Defining the role of authors and contributors, compiled by the International Committee of 
Medical Journal Editors (ICMJE) (http://www.icmje.org).
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Appendix 1
Declaration of Helsinki
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 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.
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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.
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 
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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.
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.
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Clinical Study Protocol CTN 05DF1605 - Acne scars Restylane vs no-
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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 
performance or safety of an intervention and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions 
for post-trial access for all participants who still need an intervention identified as beneficial in the trial. 
This information must also be disclosed to participants during the informed consent process.
Research Registration and Publication and Dissemination of Results
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject.
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent from 
the patient or a legally authorised representative, may use an unproven intervention if in the physician's 
judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention 
should subsequently be made the object of research, designed to evaluate its safety and performance. In all 
cases, new information must be recorded and, where appropriate, made publicly available.
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Sign page:1 of 1
SIGNATURES PAGE
Date
Signed by
2016-10-27 09:08
Justification
Approved by Technical Expert
2016-10-27 11:17
Justification
Approved by Technical Expert
2016-10-27 11:57
Justification
Approved by Medical Affairs
2016-10-27 12:36
Justification
Approved by Owner
Title 
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Clinical Study Protocol CTN 05DF1605 - Acne scars Restylane vs no-
treatment control
MA-31665
 
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Version: 
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2016-10-27 12:36
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