Post Marketing Study to Evaluate Lip Augmentation & Satisfaction With Restylane Kysse
Phase: NA
Conditions: Lip Augmentation
Sponsor: Galderma R&D

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Post Marketing study to evaluate lip enhancement, 
naturalness and partner/subject satisfaction after 
treatment with Restylane Kysse
Study products:
Restylane® Kysse, Restylane® Defyne, and Restylane® 
Refyne
Clinical trial number (CTN):
05DF1807
Sponsor:
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. 
Title 
Doc id  
CTN 05DF1807 CIP Phase IV Study on Restylane Kysse, Canada
 
Effective date: 
 
Version: 
Effective
 2019-03-25 16:43
1.0
Print date:
 2019-12-05 14:03

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Investigators and Study Administrative Structure
Further details on all participating investigators and the complete administrative structure of 
the study are found in the study files.
Sponsor:
Q-Med AB
Medical expert:
         
 
Global Head of Clinical 
Development:
         
Clinical Project Manager:
Statistician:
 
  
 
 

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Synopsis
Title of study:
Post marketing study to evaluate lip enhancement, naturalness and 
partner/subject satisfaction after treatment with Restylane Kysse
Study population:
Adult men and women meeting inclusion/exclusion criteria.
Countries involved, 
number of sites/country:
4 sites in Canada
Number of subjects:
50 to 60
Study Design

Open-label, phase IV study. 

Lip treatment with Restylane Kysse in accordance with the approved 
instructions for use in Canada, except cannulas will not be used.

Treatment for severe facial wrinkles and folds with Restylane Defyne in 
accordance with the approved instructions for use in Canada.

Treatment for moderate facial wrinkles and folds Restylane Refyne in 
accordance with the approved instructions for use in Canada

20 subjects will receive treatment with Restylane Kysse only (Group A)

30 to 40 subjects will receive treatment with Restylane Kysse and 
Restylane Refyne and/or Defyne (Group B).

Touch-up (optional) at Week 4.

Follow-up at 4 weeks and 8 weeks after last treatment.

 
Primary Efficacy 
Objective and Endpoint:
Aesthetic improvement (overall appearance) with Restylane® Kysse 
compared to pre-treatment, 
 
Secondary Efficacy 
Objectives and 
Endpoints:

 
 
 
 
 
  
 
 

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Safety Objectives and 
Endpoints:

To evaluate the safety of Restylane Kysse, Defyne, and Refyne by 
assessment of adverse events (AEs) by the Treating Investigator 
throughout the study period.
o
Incidence, intensity, duration and onset of AEs collected during the 
study period post treatment.
Clinical Study Duration:
The total duration of the study is expected to be 6 months (includes two months 
of enrollment).
Duration of Subject 
Participation:
Clinical study participation for each subject is approximately 18 weeks if 
optional touch-up treatment is performed and 14 weeks if no touch-up 
treatment is performed.
Inclusion criteria
(applicable to subject 
only if not otherwise 
indicated): 
 
2.
Signed and dated informed consent to participate in the study and use 
of facial images for marketing purpose.
3.
Adult women and men who have a steady relationship with a partner 
since 6 months and intend to undergo lip augmentation.
 
Exclusion criteria:
1.
Subjects presenting with known allergy to hyaluronic acid (HA) filler 
or amide local anesthetics.
 
 
6.
Subjects with a previous implant other than HA in or near the 
intended treatment site. 
 
 
 
 
 
 
 
 
  
 
 

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11.
Participation in any other clinical study within three (3) months before 
treatment.
Study products:
Commercially available Restylane Kysse, Restylane Defyne, and Restylane 
Refyne
Reference therapy:
Not applicable.
Treatment regimen and 
location of treated area:

Restylane Kysse 
 
 
 
 

Restylane Defyne
 
 

Restylane Refyne 
 
 
 
Treatment procedures should follow the approved Instructions for Use (IFU) in 
Canada for all three products.
 
 
 
 
 
 
 
 
 
  
 
 

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Efficacy Assessments:
 
 
Safety Assessments:

AEs

Device deficiencies
Statistical Methods: 
 
e 
The other effectiveness objectives will mainly by analyzed by using descriptive 
statistics. Where appropriate, change from baseline will be calculated and if 
applicable, a suitable test will be performed (e.g. Student’s t-test or Wilcoxon 
signed-rank test).
AEs will be analyzed by using descriptive statistics.
 
  
 
 

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Abbreviations and Definitions of Terms
AE
Adverse event 
AOI
Area of interest 
CRF
Case report form
CRO
Contract research organization
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
ET
Early Termination 
FAS
Full analysis set
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
 
  
 
 

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MedDRA
Medical dictionary for regulatory activities
NSAID
Non-steroidal anti-inflammatory drugs
OTC
Over-the-counter
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
SDV
Source data verification
SOC
System organ class
Sponsor file
Essential documents relating to a clinical study as defined in 
applicable GCP guidance document and maintained by the 
Sponsor.
Study 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.
Touch-up
Repeated injection to be performed after treatment, if 
necessary, to achieve optimal correction.
U-HCG
Urinary human chorionic gonadotropin
WHO
World Health Organization
 
  
 
 

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Table of Contents
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
2
SYNOPSIS
3
ABBREVIATIONS AND DEFINITIONS OF TERMS
1
TABLE OF CONTENTS
3
LIST OF TABLES
6
LIST OF FIGURES
6
LIST OF APPENDICES
6
1.
ETHICAL CONSIDERATIONS
7
1.1
Statement of ethical compliance
7
1.2
Application to independent ethics committee and/or regulatory authorities
7
2.
BACKGROUND INFORMATION
7
2.1
Indication and population description
7
2.2
Study product profile
7
2.2.1
Study product description
7
2.3
Study rationale and justification for design
9
2.4
Risks and benefits
9
3.
OBJECTIVE(S) AND ENDPOINT(S)
10
3.1
Objectives and endpoints
10
3.1.1
Primary objective and endpoint
10
3.1.2
Secondary efficacy objectives and endpoints
10
3.1.3
Safety objective
10
3.1.4
Safety endpoints
11
4.
DESIGN OF THE STUDY
11
4.1
General outline
11
4.2
Number of subjects
12
4.3
Duration of subject participation
12
4.4
Randomization and blinding
12
4.4.1
Randomization
12
4.4.2
Blinding
12
4.4.3
Emergency unblinding
12
4.5
Medical history
13
4.6
Prior and concomitant therapies
13
4.6.1
Definition
13
4.6.2
Categories
13
4.6.3
Recording
13
4.6.4
Authorized concomitant therapies
13
4.6.5
Prohibited concomitant therapies
13
 
  
 
 

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4.7
Visits
14
5.
SUBJECTS
17
5.1
Subject information and informed consent
17
5.2
Inclusion criteria
18
5.3
Exclusion criteria
18
5.4
Screening and subject number
19
5.5
Withdrawal of subjects
19
6.
STUDY PRODUCT
20
6.1
Study products
20
6.2
Reference product
21
6.3
Additional products and materials
21
6.4
Packaging, labelling, and storage
21
6.4.1
Study products – Restylane Kysse, Restylane Defyne and Restylane Refyne
21
6.4.2
Reference product
21
6.5
Product accountability
21
6.6
Treatment
22
6.6.1
Treatment procedure
22
6.6.2
Treatment regimen (dose and interval)
22
6.6.3
Post-treatment care
23
6.6.4
Post-trial provisions
23
6.6.5
Electronic case report form recordings
23
6.6.6
Treatment compliance
23
7.
EFFICACY ASSESSMENTS
24
24
24
24
25
 
25
25
25
26
8.
SAFETY ASSESSMENTS
26
 
  
 
 

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8.1
Laboratory assessments
26
8.2
Adverse events
26
8.2.1
Definition of an adverse event
26
8.2.2
Definition of a serious adverse event
26
8.2.3
Recording instructions
27
8.2.4
Reporting of adverse events
28
8.2.5
Reporting of serious adverse events
28
8.2.6
Follow-up of unresolved events ongoing at termination of the study
29
8.2.7
Reporting and follow-up of events occurring after subject termination of the study
29
8.2.8
Pregnancy
30
8.2.9
Anticipated adverse events
30
8.3
Device deficiencies
30
8.3.1
Definition of a device deficiency
30
8.3.2
Recording instructions
30
8.3.3
Reporting of device deficiencies
31
9.
DATA HANDLING AND MANAGEMENT
31
9.1
Data management
31
9.2
Electronic case report forms
31
9.2.1
Data entry
32
9.2.2
The query process
32
9.2.3
User identification
32
9.2.4
Audit trail
33
9.3
Source documents
33
9.4
Record keeping and access to source data
33
9.5
Document and data retention
33
10.
STATISTICAL METHODS
34
10.1
General
34
34
10.3
Demographics, baseline assessments, and subject characteristics
34
10.4
Efficacy analysis
34
10.4.1
Primary analysis
34
10.4.2
Secondary analysis
34
10.5
Safety analysis
35
10.6
Handling of missing data
35
10.7
Interim analysis
35
10.8
Withdrawals and deviations
36
10.9
Sample size
36
11.
PROTECTION OF PERSONAL DATA
36
12.
QUALITY CONTROL AND QUALITY ASSURANCE
36
 
  
 
 

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12.1
Quality control
36
12.2
Quality assurance
37
12.3
Changes to the clinical study protocol
37
12.3.1
Amendments
37
12.3.2
Deviations
37
13.
FINANCING, INDEMNIFICATION, AND INSURANCE
37
14.
PUBLICATION POLICY
38
15.
SUSPENSION OR PREMATURE TERMINATION
38
16.
REFERENCES
39
List of Tables
List of Figures
List of Appendices
 
  
 
 

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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 study shall be conducted in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki (1).
The study shall follow the international standard for clinical study of medical devices for 
human subjects, International Organization for Standardization (ISO) 14155: 2011, and the 
International Conference on Harmonization (ICH) guideline for GCP (E6), as applicable for 
medical device.
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 favorable 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
 
 
 
 
 
 
 
 
2.2
Study product profile
 
  
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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2.3
Study rationale and justification for design
The intended use in this post-market study will be in accordance with the approved IFU.
The purpose of this study is to evaluate aesthetic improvement and partner/subject
satisfaction after treatment with Restylane Kysse for marketing purposes. Treatments with 
Restylane Defyne or Refyne are allowed in the facial wrinkles and folds surrounding the lips 
in order to provide optimal aesthetic outcome for the subjects. 
2.4
Risks and benefits
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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3. Objective(s) and Endpoint(s)
3.1
Objectives and endpoints
3.1.1
Primary objective and endpoint
Aesthetic improvement (overall appearance) with Restylane Kysse compared to pre-
treatment, assessed by the subject 8 weeks after last treatment, using the Global Aesthetic 
Improvement Scale (GAIS). The response rate is defined as a subject with a rating of at least 
“Improved”.
3.1.2
Secondary efficacy objectives and endpoints
 
 
 
 
 
 
 
 
3.1.3
Safety objective
The safety objective is:

To evaluate the safety of Restylane Kysse, Defyne, and Refyne by assessment of AEs 
by the Treating Investigator throughout the study period.
 
  
 
 

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3.1.4
Safety endpoints

Incidence, intensity, duration and onset of AEs collected during the study period post 
treatment.
4. Design of the Study
4.1
General outline
This is an open-label, phase IV, post-marketing study to evaluate aesthetic improvement and 
partner/subject satisfaction after treatment with Restylane Kysse, alone and in combination 
with Restylane Defyne and Restylane Refyne.
Approximately 50 to 60 subjects at 4 sites in Canada will be treated. Twenty subjects will be 
treated with Restylane Kysse in the lips only (Group A) and 30 to 40 subjects will be treated 
with Restyane Kysse in the lips and Restylane Defyne and/or Restylane Refyne in the facial 
wrinkles and folds (Group B). All injections will be per the IFUs. Optional touch-up 
treatment at Week 4 is allowed for all products injected at initial treatment. 
The treating investigator will determine if a subject is placed in Group A or B based on the 
optimal outcome for the subject. 
Adult women and men who have a steady relationship with a partner for 6 months and intend 
to undergo lip augmentation will be asked to participate in the study. Eligible subjects will be 
injected by the Treating Investigator at Day 1. If optimal correction of the lips or surrounding 
facial wrinkles and folds (if treated) is not achieved at the first treatment or if the aesthetic 
appearance could be further improved, a touch-up will be offered after 4 weeks; this decision 
should be agreed upon by the Treating Investigator and the subject. Touch-up treatment will 
not be performed if the subject has a disease or condition described in the exclusion criteria, 
or an ongoing treatment-related AE that in the opinion of the Treating Investigator would be 
worsened by a touch-up treatment.
The subjects will be treated to achieve optimal correction. Optimal correction is defined as 
the best possible aesthetic outcome as agreed to by the Treating Investigator and the subject.
The maximum volume recommended for both initial and touch-up treatments combined is 
2.5 mL for Restylane Kysse, 6.0 mL for Restylane Defyne and 4.0 mL for Restyane Refyne.
Subjects will be contacted by telephone 72 hours after initial treatment and optional touch-up 
treatment (as applicable) and will have in-clinic follow up visits at 4 weeks and 8 weeks after 
the last treatment.
 
 
 
  
 
 

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4.5
Medical history
History of relevant surgical events and medical conditions should be documented (including
any prior dermatological procedures or implants) in the electronic case report forms (eCRF)
using medical terminology.
4.6
Prior and concomitant therapies
4.6.1
Definition
Prior therapies include therapies that have been used within 30 days preceding the Screening 
visit or within the timelines specified in the Inclusion/Exclusion criteria, and then stopped 
prior to the Screening visit.
Concomitant therapies are defined as follows:

any existing therapies ongoing at the time of the Screening visit,

any changes to existing therapies (such as change in dose or formulation) during the 
course of the study, or

any new therapies received by the subject since the Screening visit
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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
 
 
 
 
 is 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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Table 2.
Schedule of events
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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
 
 
 
 
 
 
  
 
 

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5. Subjects
5.1
Subject information and informed consent
The PI or his/her authorized 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 authorized designee to give each subject and partner 
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 consequences to
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 
 
  
 
 

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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 authorized designee responsible for conducting the informed consent. The
consent includes information that data will be collected, recorded, processed, and may be 
transferred to other countries. 
Photographs collected during the study will be analyzed and stored in a database by the 
Sponsor and its representatives in order to evaluate the effect of the treatment in the study. 
The subjects will be recognizable 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:
 
 
2. Signed and dated informed consent to participate in the study and use of facial images 
for marketing purpose.
3. Adult women and men who have a steady relationship with a partner since 6 months 
and intend to undergo lip augmentation.
 
5.3
Exclusion criteria
The presence of any of the following exclusion criteria will exclude a subject from enrolment 
in the study:
1. Subjects presenting with known allergy to HA filler or amide local anesthetics. 
 
 
6. Subjects with a previous implant other than HA in or near the intended treatment site. 
 
 
 
 
  
 
 

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11. Participation in any other clinical study within three (3) months before treatment.
5.4
Screening and subject number
Each subject who has signed the informed consent form will be assigned a subject number.
The subject numbers will be allocated in ascending order within each center. The reason for 
excluding a consenting subject from entering the study should be specified in each case. A 
screen failure should not be re-entered in the study.
For the duration of the clinical study, each subject will be identified using the subject number 
for all documentation and discussion.
5.5
Withdrawal of subjects
An Investigator may decide to discontinue a subject from the clinical study for safety reasons.
Although the importance of completing the entire clinical study should be explained to the 
subject by the clinical study personnel, any subject is free to discontinue participation in this 
clinical study at any time and for whatever reason, specified or unspecified, and without any 
prejudice. No constraints are to be imposed on the subject, and when appropriate, a subject 
may be treated with other conventional therapy when clinically indicated. 
When a subject does not complete the clinical study, he/she will be fully assessed, if such 
assessment is possible. The procedures designated for the Early Termination (ET) visit 
should be completed for all subjects discontinuing the clinical study and the appropriate 
eCRF should be completed.
All discontinuations and the reason for discontinuation are to be documented by the 
Investigator.
For discontinuation due to an AE, the Adverse Event form is to be completed. The 
Investigator should also ensure that the subject receives suitable therapy for the AE.
 
  
 
 

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Pregnancies occurring during the screening period are considered as screening failures; they 
should be recorded as such in the eCRF and no pregnancy form is to be completed. 
In case of a pregnancy occurring after the baseline visit, the procedures described in 
Section 8.2.8 should be followed. The subject may remain in the study, but no invasive 
procedure should be conducted.
The Sponsor may also decide to prematurely terminate or suspend a subject’s participation in 
the clinical 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, is assessed by the Investigator to be “chronic” or 
“stable” or for at least 3 months.
6. Study Product
The term “study product” refers to Restylane Kysse, Restylane Defyne and Restylane Refyne. 
6.1
Study products
Restylane Kysse, Restylane Defyne and Restylane Refyne are manufactured by Q-Med AB 
(a Galderma affiliate located in Uppsala, Sweden). 
 
 
  
 
 

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6.2
Reference product
Not applicable. 
6.3
Additional products and materials
The sponsor Q-Med will provide pregnancy tests (urinary human chorionic gonadotropin [U-
HCG]).
6.4
Packaging, labelling, and storage
 
 
 
 
 
 
 
6.4.2
Reference product
Not applicable. 
6.5
Product accountability
The study products will be released to the PI or his/her authorized 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 products are kept in a secure location, with access limited 
to those authorized by the PI.
The study products must be traceable from the manufacturer 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, lot 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 study product, and number of syringes left in stock at the site.
When the study is completed, all unused or expired study product at each study site shall be 
returned to the Sponsor for destruction or destroyed locally at the site, if documented as 
agreed with the Sponsor. 
 
  
 
 

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Any malfunctioning study 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, needles 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.
All study product(s) sent to the PI will be accounted for and no unauthorized use is permitted.
6.6
Treatment
 
 
 
 
 
 
 
 
 
 
 
   
 
, 
 
 
 
  
 
 

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, 
 
 
 
 
 
6.6.6
Treatment compliance
The treatment will be administered by the Treating Investigator at the investigational site, and 
the details of administration are to be recorded in the eCRF. No other measurements of 
treatment compliance will be made. 
 
  
 
 

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7. Efficacy Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 

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8. Safety Assessments
 
8.1
Laboratory assessments
Pregnancy Test: For all women of childbearing potential, a urine pregnancy test (U-HCG) 
will be performed prior to treatment at Visit 2 (Baseline and treatment, Day 1) and at Visit 4 
(Optional touch-up treatment at 4 weeks), as applicable. The test result will be documented in 
the eCRF.
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 persons1, 
whether or not related to the study product. 
This definition includes:
a) events related to the study product or the reference product
b) events related to the procedures involved
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-threatening2 illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalization3, or
                                                
1 For users or other persons, this definition is restricted to events related to the study product.
2 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).
3 Planned hospitalization 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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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 fetal distress, fetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such (see Section 8.2.5).
8.2.3
Recording instructions
Each subject should be questioned about AEs at each study visit following signing of 
informed consent. 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. 
Exceptions from AE reporting are normal fluctuations in pre-existing diseases. However, pre-
existing illnesses that deteriorate shall be reported as AEs.
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 separately on the clinical study complaint form.
Investigators, or other study site personnel, shall record all AEs in the eCRF, including:
a) Event term (recorded in standard medical terminology and avoiding abbreviations)
b) 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 8.2.3.1)
f)
Seriousness (serious or not serious, according to definition in Section 8.2.3.2)
g) Causal relationship to study product or study product injection procedure (yes or no)
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.
8.2.3.1
Intensity
Intensity will be recorded for each reported AE. The following definitions of intensity are to 
be 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.
 
  
 
 

28(39)
8.2.3.2
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. 
8.2.4
Reporting of adverse events 
Adverse event reporting on each subject shall start at Visit 1 (Screening). 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, Visit 6 (Follow-up at 8 weeks after 
last treatment).
All AEs, non-serious as well as serious, are to be reported as an AE in the eCRF.
8.2.5
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 shall be 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:

Subject identification (age, gender, initials, subject number)

Adverse event description

Date when AE occurred

Name of 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 therapies form/list

AE form/list
 
  
 
 

29(39)

Medical history form/list

Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
___________________________________________________________________________
E-mail 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
Q-Med AB 
complementary information:
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, the PI shall report SAEs to the responsible IEC without undue delay. 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 Sponsor is responsible for reporting to the RA, if applicable and according to national 
regulations.
8.2.6
Follow-up of unresolved events ongoing at 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, or for three months. Final outcome after the end 
of the study shall be reported on AE follow-up form.
8.2.7
Reporting and follow-up of events occurring after subject termination of the study
All AEs with a causal relationship to the study products or treatment procedure that the 
Investigator becomes aware of, serious as well as non-serious, with onset after the study 
termination (subject’s last study visit) shall be reported to the Sponsor. The report should as a 
minimum include the information described in Section 8.2.3. The report can be sent via fax or 
e-mail according to contact details specified in Section 8.2.5. The events shall thereafter be 
followed up until resolved or considered chronic or stable, or for at least three months. Final 
outcomes shall be reported.
 
  
 
 

30(39)
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 8.2.5. The report can be prospective or 
retrospective. Follow-up shall be conducted to obtain outcome information on all prospective 
reports. 
Cases that led to fetal distress, fetal 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 hospitalization, shall be reported and handled as SAEs. Elective abortions without 
complications shall not be reported as AEs.
8.2.9
Anticipated adverse events
Injection related AEs such as bruising, erythema, itching, swelling, pain and tenderness are 
anticipated. Information regarding anticipated AEs for Restylane Kysse, Restylane Defyne, 
and Restylane Refyne are included in the IFUs (co-packed with product).
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, safety4, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
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 form shall be completed as applicable (refer to 
Section 8.2.5). 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
                                                
4 Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
 
  
 
 

31(39)
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.
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 8.2.5). 
If 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.
The deficient study product shall be kept by the study site until the Sponsor has confirmed 
whether the product shall be returned to Sponsor for further study or if it can be destroyed at 
the study site.
9. Data Handling and Management 
9.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter clinical data information into a database, efficiently and avoiding errors. The data 
management routine includes procedures for 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 and the CRF template. Data validation will be performed by computerized 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 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 electronic data capture application, compliant with regulatory requirements for software 
validation 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). 
 
  
 
 

32(39)
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.
Authorized study site personnel designated by the PI shall complete data collection. 
Appropriate training and security measures shall be completed with all authorized
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 authorized 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 and recorded.
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 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 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. 
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 authorized 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 by 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 authorized 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; 
 
  
 
 

33(39)
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 adequate and accurate source documents. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry and should be explained 
if necessary.
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 clinical trial number (CTN)
and 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, 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 eCRFs 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 or other relevant source. 
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 for 25 years after study completion or longer if required by 
national legislation. Sponsor will inform the site(s) as to when these documents no longer 
 
  
 
 

34(39)
needs to be retained. Measures shall be taken to prevent accidental or premature destruction 
of these documents (e.g. protection against damage and unauthorized access, preferably by 
storage in a fireproof cabinet).
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
10.1 General
 
 
 
 
 
10.3 Demographics, baseline assessments, and subject characteristics
Demographic endpoints, baseline assessments, and subject characteristics will be presented 
based on the FAS, using descriptive statistics.
10.4 Efficacy analysis
 
 
 
 
 
 
  
 
 

35(39)
 
 
 
 
 
 
 
 
 
 
 
 
 
10.5 Safety analysis
AEs will be coded according to MedDRA and summarized by system organ class (SOC), 
preferred term (PT). 
 
 
 
 
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 Interim analysis
Not applicable as this is an open study.
 
  
 
 

36(39)
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 in the statistical report. 
10.9 Sample size
 
 
 
11. Protection of personal data
All processing of personal data must be carried out in accordance with national legislation 
concerning the protection of personal data, including the Personal Information Protection and 
Electronic Documents Act (PIPEDA). 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.
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 other countries. If a subject decides 
to terminate the study prematurely, data collected before withdrawal of consent will be used 
in the evaluation of the study, however no new data may be collected. Authorized
representatives from the Sponsor, clinical research organization (CRO) or a RA may visit the 
study site to perform audits/inspections, including SDV, 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 documented appropriately, 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 
 
  
 
 

37(39)
subject or the scientific integrity of the study, including those that 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.
12.2 Quality assurance
The study site may be subject to quality assurance (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.
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
12.3.1
Amendments
The PI and other site personnel involved in the study must not implement any 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 dated and version-controlled written 
protocol amendment. 
12.3.2
Deviations
The PI is not allowed to deviate from the CSP. However, under emergency circumstances, 
deviations from the CSP to protect the rights, safety and well-being of the subjects may 
proceed without prior approval of the Sponsor and the IEC. Such deviations should be 
documented and reported to the IEC as soon as possible. Any CSP deviation shall be reported 
in the deviation log, which will be verified, discussed, and collected, by the monitor and 
appropriate actions will be taken. 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. 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 (within 24 hours following detection) as well as the IEC if required. 
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 
 
  
 
 

38(39)
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. 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 resolved5. 
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, or for business 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.
                                                
5 Defining the role of authors and contributors, compiled by the International Committee of Medical Journal 
Editors (ICMJE) (http://www.icmje.org).
 
  
 
 

39(39)
16. References
1.
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving 
Human Subjects.
2.
Segura S, Anthonioz L, Fuchez F, Herbage B. A complete range of hyaluronic acid 
filler with distinctive physical properties specifically designed for optimal tissue adaptations. 
J Drugs Dermatol. 2012;11(1 Suppl):s5-8.
3.
Klassen AF, Cano SJ, Schwitzer JA, Scott AM, Pusic AL. FACE-Q scales for health-
related quality of life, early life impact, satisfaction with outcomes, and decision to have 
treatment: development and validation. Plast Reconstr Surg. 2015;135(2):375-86.
4.
de Menezes M, Rosati R, Ferrario VF, Sforza C. Accuracy and reproducibility of a 3-
dimensional stereophotogrammetric imaging system. J Oral Maxillofac Surg. 
2010;68(9):2129-35.
 
  
 
 

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