A Multi-center, Evaluator-blinded Study to Evaluate Effectiveness and Safety of HA Fillers for Lifting, Contouring and Correcting Volume Deficiency of the Midface Using an Individualized Treatment Algorithm
Phase: NA
Conditions: Volume Deficiency of the Midface
Sponsor: Galderma R&D

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A multi-centre, evaluator-blinded study to evaluate effectiveness and safety of HA 
fillers for lifting, contouring and correcting volume deficiency of the midface using an 
individualized treatment algorithm
Study products:
Restylane® Volyme™ 
Restylane® Defyne™ 
Restylane® Lyft Lidocaine
Clinical trial number (CTN):
05DF1707
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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Study Administrative Structure
Sponsor:
Q-Med AB
Medical expert:
Clinical Project Manager and 
Study Director:
Scientific Writer:
Study statistician:
Further details on all participating Investigators and the complete administrative structure of 
the study are found in the study files. Note that administrative changes are to be documented in 
the study files without requiring a clinical study protocol (CSP) amendment.
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Sponsor Signatures
The CSP is electronically signed in the document management system within the Q-Med AB 
quality management system by the representatives listed below.
Head of Clinical Development, Q-Med AB
Global Head of Medical Affairs, Q-Med AB
Medical Expert, Q-Med AB
Statistician, Q-Med AB
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Signed Agreement of the Clinical Study Protocol
CTN:
05DF1707
Title of the CSP:
A multi-centre, evaluator-blinded study to evaluate effectiveness 
and safety of HA fillers for lifting, contouring and correcting 
volume deficiency of the midface using an individualized treatment 
algorithm
I, 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 multi-centre, evaluator-blinded study to evaluate effectiveness and 
safety of HA fillers for lifting, contouring and correcting volume 
deficiency of the midface using an individualized treatment algorithm
Clinical Trial 
Number (CTN)
05DF1707
Number of sites
Approximately 2-5 sites will participate.
Number of subjects 
Approximately 90 subjects will be enrolled.
Target Indication
Lifting, contouring or volumizing therapy for midface.
Effectiveness 
Objectives and 
Endpoints
1.
To evaluate improvement of midface 
 
2.
To evaluate midface fullness 
 
 
 
 
4.
To evaluate naturalness of  treatment result 
 
 
Safety Objectives 
and Endpoints
1.
To evaluate local tolerability by direct questioning to subject at 4 weeks 
after first treatment and touch-up.
2.
To evaluate Adverse Events (AEs) collected throughout the study
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Exploratory 
Objectives and 
Endpoints
 
 
 
 
 
Study Design
This is a 24-week evaluator-blinded, multi-centre study to evaluate the safety 
and effectiveness of midface treatments with Restylane Volyme, Restylane 
Defyne, or Restylane Lyft Lidocaine, using an individualized treatment 
approach and treatment algorithm
Approximately 90 subjects requiring volumization, lifting and/or contouring 
of midface and fulfilling all eligibility criteria will be enrolled in the study. 
Approximately 30 subjects should be allocated to each treatment group. The 
aim is to include 20% male subjects.
Product selection for treatment of midface will be based on Investigator 
assessment of subject tissue coverage and main treatment goal; volumizing, 
lifting or contouring. Based on those parameters, one of the products 
Restylane Volyme, Restylane Defyne or Restylane Lyft Lidocaine will be 
used according to a defined treatment algorithm. After screening and first 
treatment there is a 24-week follow-up period 
 
Information about the subjects’s tissue thickness and rationale for product 
choice will be collected. Details regarding the treatment procedure will also 
be collected, e.g. product used, injection technique, depth, injection volume, 
cannula/needle selection and anaesthesia used.
Photographs will be taken before treatment and at follow-up visits to be used 
for effectiveness assessments.
 
Safety data, including AE reporting and device deficiencies, will be collected 
and reviewed throughout the study. A question regarding local tolerability 
will be asked 4 weeks after first treatment and touch-up, for collection of 
injection-related events. 
Inclusion criteria
1. Male/Female 25 to 55 years old.
2. Subjects needing lifting, contouring or volumization of the midface.
 
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5. Signed and dated informed consent to participate in the study.
Exclusion Criteria
1.
Known/previous allergy or hypersensitivity to any injectable HA gel.
2.
Known/previous allergy or hypersensitivity to lidocaine 
 
 
4.
Previous use of any permanent (non-biodegradable) or semi-permanent 
(i.e., calcium hydroxylapatite or Poly-L-Lactic acid) facial tissue 
augmentation therapy or contouring with, lifting threads, permanent 
implants, or autologous fat in the treatment area.
5.
Previous use of any hyaluronic acid or collagen based facial tissue 
augmentation therapy in the facial area within 12 months before 
treatment.
6.
Previous use of any neurotoxin in the facial area within 6 months before 
treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.
Previous facial surgery (including aesthetic facial surgical therapy or 
liposuction) in the facial area. 
 
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19. Any medical condition that in the opinion of the Investigator would make 
the subject unsuitable for inclusion (e.g. a chronic, relapsing or hereditary 
disease that may affect the general condition or may require frequent 
medical treatment, any abnormal screening laboratory value or ECG, or 
psychiatric disorders).
 
 
 
 
                                                
 
 
 
 
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Investigational 
product, dose and 
mode of 
administration
Restylane Volyme, Restylane Defyne, or Restylane Lyft Lidocaine will be 
used for midface treatment according to the Instructions For Use (IFU) in the 
applicable country.
Midface is defined as the area inferior to the maxillary prominence, superior 
to the plane of nasal alae, including the area from the attachment of the ear to 
the face to the medial canthus and lateral to the nose on the subject’s right and 
left sides. Product selection will be based on treatment algorithm.
 
 
 
 
 
 
 
 
Reference product, 
dose and mode of 
administration
Not applicable
                                                                                                                                                       
3 months prior to screening; Strict abstinence (at least one month prior to baseline and agrees to continue for the duration of the study or use 
acceptable form or birth control).
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Number of 
treatments 
A first treatment including an optional touch-up can be given during the 
study.
Effectiveness 
Assessments
The 5-graded 
 Scale 
 will be used to 
assess the aesthetic improvement of midface. The Investigator, the blinded 
evaluator and the subject will, independently of each other, respond to the 
question: “How would you describe the subject’s/your aesthetic 
appearance of the midface, i.e. the treated area, compared to the 
photographs taken before treatment?”
Rating
(for the subject)
Definition 
(for the Investigator and blinded evaluator)
Very much 
improved
Optimal cosmetic result for the subject.
Much improved
Marked improvement in appearance from the original 
condition, but not completely optimal for this subject.
Improved
Obvious improvement in appearance from the original 
condition.
No change
The appearance is essentially the same as original 
condition.
Worse
The appearance is worse than the original condition.
Midface Volume Scale 
 
 is a 4-grade scale to assess the fullness of the midface from Fairly 
Full (1) to Substantial Loss of Fullness (4) as described below. The 
Investigator and blinded evaluator will rate the subject’s right and left midface 
for severity of volume deficiency 
 at baseline and at follow-
up visits. The Investigator and blinded evaluator will conduct their MMVS 
assessments live independently of each other using a photographic scale. 
 
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Naturalness
Naturalness of treatment result will be assessed 
 
 
 
 
 
 
 
Safety Assessments
1.
A question to evaluate local tolerability profile asked 4 weeks after each 
treatment.
2.
Adverse Event reporting through-out the study period to evaluate short-
and long term safety.
Statistical Methods 
Effectiveness
 
 the proportion of 
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improved subjects (improved, much improved and very much improved) will 
be calculated together with a 95% confidence interval.
 
 
the proportion of improved subjects (decrease  
 of 
at least one grade compared to baseline) will be calculated together with a 
95% confidence interval.
 
Evaluation of naturalness after treatment 
 
will be presented descriptively by treatment group and visit.
 
 
 
 
 
Safety
Local tolerability and Adverse Events will be analyzed descriptively by 
treatment group.
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Abbreviations and Definitions of Terms
AE
Adverse event 
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
GAIS
Global aesthetic improvement scale
GCP
Good clinical practice
HA
Hyaluronic acid
HIV
Human immunodeficiency virus
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”.
Blinded evaluator
An evaluator responsible for blinded evaluation of treatment result(s). The 
evaluator must not be involved in the treatment of the subject.
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
Last subject in
Last subject who entered the study
Last subject out
Last subject who completed his/her last study visit
MedDRA
Medical dictionary for regulatory activities
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NLF
Nasolabial fold
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
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 4 weeks ± 3 days after first treatment if 
necessary to achieve optimal correction as assessed by the treating Investigator
and subject. 
U-HCG
Urinary human chorionic gonadotropin
WHO
World Health Organization
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Table of Contents
STUDY ADMINISTRATIVE STRUCTURE
2
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
4
SYNOPSIS
5
ABBREVIATIONS AND DEFINITIONS OF TERMS
13
LIST OF FIGURES
18
LIST OF TABLES
18
LIST OF APPENDICES
18
1.
ETHICAL CONSIDERATIONS
19
1.1
Statement of ethical compliance
19
1.2
Application to independent ethics committee and/or regulatory authorities
19
2.
BACKGROUND INFORMATION
19
2.1
Indication and population description
19
2.2
Investigational product description
20
2.3
Reference product description
21
2.4
Previous experience
21
2.4.1
Non-clinical documentation
21
2.4.2
Clinical documentation
21
2.5
Study rationale
22
2.6
Justification for the design of the study
22
2.7
Risks and benefits
22
2.8
Objectives and endpoints
23
2.8.1
Effectiveness objectives and endpoints
23
2.8.2
Safety objectives and endpoints
23
3.
DESIGN OF THE STUDY
24
3.1
General outline
24
3.2
Study flow chart
25
3.3
Number of subjects
25
3.4
Duration of subject participation
25
3.5
Blinding
25
3.5.1
Treatment allocation
25
3.5.2
Blinding
25
3.5.3
Emergency unblinding
26
3.6
Medical history
26
3.7
Concomitant medications, treatments, and procedures
26
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3.8
Schedule of events
27
3.9
Visits
28
3.10
Demographics, screening and baseline assessments
30
4.
SUBJECTS
31
4.1
Subject information and informed consent
31
4.2
Inclusion criteria
32
4.3
Exclusion criteria
32
4.4
Screening and subject numbers
34
4.5
Withdrawal of subjects
35
5.
STUDY PRODUCTS
36
5.1
Investigational products
36
5.2
Reference product
36
5.3
Additional products and material
36
5.4
Packaging, labelling, and storage
36
5.4.1
Investigational products
36
5.5
Reference product
37
5.6
Product accountability
37
5.7
Treatment
38
5.7.1
Determination of tissue thickness:
38
5.7.2
Treatment algorithm
38
5.7.3
Treatment procedure
39
5.7.4
Treatment area
39
5.7.5
Treatment regimen (volume and interval)
40
5.7.6
Post-treatment care
40
5.7.7
Post-trial provisions
40
5.7.8
Electronic case report form recordings
40
5.7.9
Treatment compliance
41
6.
EFFICACY ASSESSMENTS
41
6.1
General information
41
6.2
2D Photography
41
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6.6
Naturalness of treatment result
43
7.
SAFETY ASSESSMENTS
45
7.1
Pre-defined, expected, post-treatment events
45
7.2
Laboratory assessments
45
7.3
Adverse events
46
7.3.1
Definition of an adverse event
46
7.3.2
Definition of a serious adverse event
46
7.3.3
Recording instructions
46
7.3.4
Reporting of adverse events
48
7.3.5
Reporting of serious adverse events
48
7.3.6
Follow-up of unresolved events after termination of the study
49
7.3.7
Pregnancy
50
7.4
Device deficiencies
50
7.4.1
Definition of a device deficiency
50
7.4.2
Recording instructions
50
7.4.3
Reporting of device deficiencies
51
8.
DATA HANDLING AND MANAGEMENT
51
8.1
Data management
51
8.2
Electronic case report forms
51
8.2.1
Data entry
52
8.2.2
The query process
52
8.2.3
User identification
52
8.2.4
Audit trail
53
8.3
Source documents
53
8.4
Record keeping and access to source data
53
8.5
Document and data retention
54
9.
STATISTICAL METHODS
54
9.1
General
54
9.2
Analysis populations
54
9.3
Demographics, screening/baseline assessments, and subject characteristics
54
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9.4
Effectiveness analysis
55
9.5
Safety analysis
55
9.6
Handling of missing data
56
9.7
Interim analysis
56
9.8
Withdrawals and deviations
56
9.9
Sample size
56
10.
PROTECTION OF PERSONAL DATA
56
11.
QUALITY CONTROL AND QUALITY ASSURANCE
57
11.1
Quality control
57
11.2
Quality assurance
57
11.3
Changes to the clinical study protocol
57
11.3.1
Amendments
57
11.3.2
Deviations
58
12.
FINANCING, INDEMNIFICATION, AND INSURANCE
58
13.
PUBLICATION POLICY
58
14.
SUSPENSION OR PREMATURE TERMINATION
59
15.
REFERENCES
60
List of Figures
Figure 1   
Flow chart .......................................................................................................................................................... 25
Figure 2   
Treatment algorithm........................................................................................................................................... 38
Figure 3   
Treatment area ................................................................................................................................................... 39
List of Tables
Table 1.
Schedule of events ............................................................................................................................................. 27
Table 7.
Grading for bruising, redness, swelling, pain (including burn), tenderness, and itching.................................... 45
List of Appendices
Appendix 1
Declaration of Helsinki...................................................................................................................................... 61
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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 and/or regulatory authorities
It is the responsibility of the Principal Investigator (PI) to obtain approval of the 
CSP/CSP amendment(s) from the independent ethics committee (IEC). The study shall not 
begin until the required favourable opinion from the IEC has been obtained. The PI shall file 
all correspondence with the IEC in the Investigator file and copies of IEC approvals shall be 
forwarded to the Sponsor. Any additional requirements imposed by the IEC or regulatory 
authorities (RA) shall be followed. 
The collection, access to, processing, and transfer of protected health information or sensitive 
personal data shall be carried out in accordance with applicable rules and regulations.
2. Background Information
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.3
Reference product description
Not applicable.
 
 
 
 
 
 
 
 
 
 
 
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2.8
Objectives and endpoints
2.8.1 Effectiveness objectives and endpoints
1.
To evaluate improvement of midface 
 
2.
To evaluate midface fullness 
 
 
 
4.
To evaluate naturalness of  treatment result 
 
2.8.2 Safety objectives and endpoints
1.
To evaluate local tolerability by direct questioning to subject at 4 weeks after 
first treatment and touch-up
2.
To evaluate Adverse Events (AEs) collected throughout the study
 
 
 
 
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3.
Design of the Study
3.1
General outline
This is a 24-week evaluator-blinded, multi-center study to evaluate the safety and 
effectiveness of midface treatments with Restylane Volyme, Restylane Defyne, or Restylane 
Lyft Lidocaine, using an individualized treatment approach and treatment algorithm.
Approximately 90 subjects requiring volumization, lifting and/or contouring of midface and 
fulfilling all eligibility criteria will be enrolled in the study. Approx. 30 subjects should be 
allocated to each treatment group. The aim is to include 20% male subjects in the study. 
Product selection for treatment of midface will be based on Investigator assessment of subject 
tissue coverage and main treatment goal; volumizing, lifting or contouring. Based on those 
parameters, one of the products Restylane Volyme, Restylane Defyne or Restylane Lyft
Lidocaine will be used according to a defined treatment algorithm. Blinding will be 
accomplished by using a treating Investigator to administer the treatments and a blinded 
evaluator, to whom treatment allocation is concealed, to conduct assessments.
 
 
 
 
After screening and first treatment there is a 24-week follow-up period 
 
 
Information about the subject’s tissue thickness and rationale for product choice will be 
collected as well as treatment procedure, e.g. product used, injection technique, depth, 
injection volume, use of cannula/needle and anaesthesia used.
Photographs will be taken before treatment and at follow-up visits to be used for effectiveness 
assessments.
 
 
Safety will be followed by AE and device deficiency reporting throughout the study. A 
question regarding local tolerability will be asked 4 weeks after first treatment and touch-up, 
for collection of injection-related events.
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3.2
Study flow chart
3.3
Number of subjects
Approximately 90 subjects will be recruited at approximately 2-5 sites. The duration of 
enrolment is expected to approximately 3 months.
Approximately 15-45 subjects will be enrolled per site. The aim is to include 20% male 
subjects in the study. 
3.4
Duration of subject participation
A subject will be involved in the study for 24-27 weeks.
End of study is when enrolment has reached the target number of subjects and all subjects
have completed the last study visit.
3.5
Blinding
3.5.1 Treatment allocation
Treatment allocation will be assessed by the treating Investigator according to a treatment
algorithm (see section 5.7.2 ).
All treatment information will be kept by the treating Investigator during the study not to be 
disclosed to the blinded evaluator.
3.5.2 Blinding
Due to the differences in the physical characteristics (viscosity) of the study products, it is not 
possible to truly double-blind the study, and the treatment assignment cannot be obscured 
from the treating Investigator.
The blinded evaluator shall not be allowed to retrieve study supplies or to be present during 
opening of the study supplies or be present during the injection procedure. The treating 
Investigator and the subjects are not allowed to discuss treatments with the blinded evaluator. 
All documents with information on study products shall be kept in a separate binder not 
available to the blinded evaluator. 
The site personnel (except blinded evaluator), the subjects, Sponsor and the Sponsor 
representative shall not be blinded to treatment assignment during the study.
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3.5.3 Emergency unblinding
Not applicable as the treating Investigator is not blinded to treatment assignment. 
3.6
Medical history
History of surgical events and medical conditions that are judged as relevant by the 
Investigator shall be documented in the electronic case report form (eCRF) using medical 
terminology.
3.7
Concomitant medications, treatments, and procedures
Except as noted below, concomitant medications or other treatments or procedures may be 
utilised when the PI or his/her authorised designee considers it medically necessary. 
Information regarding any use of concomitant medications, including over-the-counter 
medications administered during the study are to be recorded in the eCRF. The generic name 
or the trade name of all concomitant medication or a description of the procedure and the 
reason for its use shall be documented in the eCRF.
 
 
 
 
 
 
 
 
 
 
 
 
Participation in any other clinical study is prohibited.
If a subject receives prohibited therapy during the study, a protocol deviation should be
documented. The subject shall continue in the study for the scheduled follow-up visits unless 
otherwise instructed by the Sponsor.
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3.8
Schedule of events
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3.9
Visits
 
 
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4. Subjects
4.1
Subject information and informed consent
The PI or his/her authorised designee must always use the IEC-approved subject 
information and informed consent form and it must not be changed without prior 
discussion with the Sponsor and approval from the applicable IEC.
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It is the responsibility of the PI or his/her authorised designee to give each subject, prior to 
enrolment in the study, full and adequate verbal and written information regarding all 
aspects of the clinical study that are relevant to the subject’s decision to participate 
throughout the study, e.g. explain the purpose and procedures of the study, the duration 
and number of expected participants, possible risks involved, and the opinion of the IEC. 
The subject shall be informed that the participation is confidential and voluntary and that
the subject has the right to withdraw from the study at any time, without any effect on 
his/her future medical care, treatment or benefits to which the subject is otherwise entitled. 
The information shall be provided in a language clearly and fully understandable to the
subject. The subject shall be given sufficient time to read and understand the informed 
consent form and to consider participation in the study. Before any study-related activities 
are performed, the informed consent form shall be personally signed and dated by the 
subject and the PI or his/her authorised designee responsible for conducting the informed 
consent process. The consent includes information that data will be collected, recorded, 
processed, and 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.
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.
4.2
Inclusion criteria
1.
Male/Female 25 to 55 years old.
2.
Subjects needing lifting, contouring or volumization of the midface.
 
 
 
5.
Signed and dated informed consent to participate in the study.
4.3
Exclusion criteria
1.
Known/previous allergy or hypersensitivity to any injectable HA gel.
2.
Known/previous allergy or hypersensitivity to lidocaine or other amide-type 
anaesthetics, or topical anaesthetics or nerve blocking agents (if such products are 
intended to be used for that subject).
 
4.
Previous use of any permanent (non-biodegradable) or semi-permanent (i.e., calcium 
hydroxylapatite or Poly-L-Lactic acid) facial tissue augmentation therapy or 
contouring with, lifting threads, permanent implants, or autologous fat in the 
treatment area.
5.
Previous use of any hyaluronic acid or collagen based facial tissue augmentation 
therapy in the facial area within 12 months before treatment
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6.
Previous use of any neurotoxin in the facial area within 6 months before treatment.
 
 
 
 
 
 
 
8.
Previous facial surgery (including aesthetic facial surgical therapy or liposuction) in 
the facial area. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19. Any medical condition that in the opinion of the Investigator would make the subject 
unsuitable for inclusion (e.g. a chronic, relapsing or hereditary disease that may 
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affect the general condition or may require frequent medical treatment, any abnormal 
screening laboratory value or ECG, or psychiatric disorders).
 
 
 
 
 
 
4.4
Screening and subject numbers
Each subject who has signed the informed consent form will be assigned a subject 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 eCRF screening visit shall be completed to an extent that makes it 
clear which assessments have been made and the reason why the subject did not fulfil the 
eligibility criteria. The reason for excluding a subject from entering the study shall also be 
specified in the subject screening log.
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.
Screening will include ensuring that the subject is eligible based on product allocation and 
subject gender. Treatment assignment, i.e. product selection, will be based on a treatment 
algorithm as assessed by the treating Investigator.
 
 
 
Once the product selection has been made, the study site must verify that the subject 
based on product selection is eligible to enroll.
                                                
 
 
 
 
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4.5
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 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 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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5. Study Products
The term “study products” refers to Restylane Volyme, Restylane Defyne and Restylane 
Lyft Lidocaine.
5.1
Investigational products
Restylane Volyme is a sterile, biodegradable, transparent gel of non-animal cross-linked 
hyaluronic acid with the addition of lidocaine hydrochloride 3 mg/mL. The gel is supplied 
in a prefilled plastic syringe. The syringe contains 1 mL gel. The investigational product is 
for single use only.
Restylane Defyne is a sterile, biodegradable, transparent gel of non-animal cross-linked
hyaluronic acid with the addition of lidocaine hydrochloride 3 mg/mL. The gel is supplied 
in a prefilled plastic syringe. The syringe contains 1 mL gel. The investigational product is 
for single use only.
Restylane Lyft Lidocaine is a sterile, transparent, biodegradable gel of stabilized 
hyaluronic acid of non-animal origin with the addition of 0.3% lidocaine hydrochloride. It 
is supplied in a glass syringe. The syringe contains 1 mL gel. The investigational product 
is for single use only.
Detailed product information is provided in the applicable instructions for use (IFU).
5.2
Reference product
Not applicable.
5.3
Additional products and material
The study site will provide pregnancy tests (urinary human chorionic gonadotropin; U-
HCG) and needles/cannulas as needed
Local anaesthesia (topical or infiltration) 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 Investigator shall provide adequate equipment in case of emergency.
The sponsor will provide photo equipment as agreed when needed. 
 
 
 
 
 
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5.5
Reference product
Not applicable.
5.6
Product accountability
The investigational products will be released to the PI or his/her authorised designee after 
study approvals have been received from the IEC and the CTA has been signed by all 
parties.
The PI must ensure that the study products are kept in a secure location, with access 
limited to those authorised by the PI.
The investigational products 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 
investigational products, deliveries, and return of investigational products between the 
Sponsor and the PI, and documentation of administration of product to the subject. A 
shipping record shall be kept of all investigational 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 product at each study 
site shall be returned to the Sponsor for destruction, if not otherwise instructed by Sponsor 
in writing. Any malfunctioning investigational products shall be reported as described in
section 7.4.3.
Products deliberately or accidentally destroyed during shipment or at a study site shall be 
accounted for and documented. Used syringes, disposable needle or blunt cannula, 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 products must not be used outside the study. 
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5.7
Treatment
 
 
 
 
 
 
 
 
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5.7.9 Treatment compliance
No other measurements of treatment compliance shall be made. 
6. Efficacy Assessments
6.1
General information
The methods for collecting efficacy data include 2D photography (section 6.2), 
 
assessment of naturalness of  
treatment results (section 6.6), 
 
 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial screening or baseline determinations completes all 
corresponding follow-up evaluations.
6.2
2D Photography
Photographs shall be taken prior to the first injection of the investigational product and at
follow-up visits in order to document treatment effect.
Note that no covering make-up shall be used on the photographs
At visits where injections are performed the photographs shall be taken prior to the 
injections.
Instructions for photography are provided in a separate photography manual. Each 
photograph shall be labelled with the subject number, and the visit number at which the 
photograph was taken. In order to maintain confidentiality, the photographs must not 
include any information that may reveal the subject’s identity. The photographs should be 
used in the assessment of 
 naturalness, 
 and to document AEs..
The photographs shall be presented on a computer monitor (preferably the same monitor 
throughout the study).
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6.3
The 
is a qualitative 5-graded scale evaluating aesthetic improvement (Table 4).
While 
 is neither an objective measurement tool nor a validated tool, 
 
improvement has been commonly accepted by the medical community in Europe and the 
United States as clinical meaningful scale to assess visible aesthetic results. The 
 
can be used not only by the Investigator and blinded evaluator, but is also a useful tool 
for subject’s self-assessment.
The subject, Investigator and blinded evaluator shall, independently of each other, rate the 
midface for aesthetic change by comparing the appearance at follow-up against a 
photograph taken before treatment. The photographs shall be presented on a computer 
monitor (preferably the same monitor throughout the study). Live assessment may help the 
investigator and the blinded evaluator and a mirror may help the subject. The following 
question will be asked: ”How would you describe the subject’s/your aesthetic 
appearance of the midface, i.e. the treated area, compared to the photographs taken 
before treatment?” The subject shall rate according to the left column in Table 4 
and the Investigator and blinded evaluator shall rate according to the right column in 
Table 4.
A clinically significant improvement is defined as a score of improved; much improved; or 
very much improved. The 
 assessments shall as far as possible be performed by the 
same Investigator or blinded evaluator throughout the study.
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6.4
 a 4-grade scale (Table 5) to assess the fullness of the midface from Fairly Full 
(1) to Substantial Loss of Fullness (4) as described below. 
 
 
 
 
 
 
 
6.6
Naturalness of treatment result
 assess naturalness of the treatment result 
based on review of baseline photographs and live assessment by responding to the 
question: “Are the subject’s treatment results natural looking?”
Strongly agree
Agree
Neither agree nor disagree
Disagree
Strongly disagree





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7. Safety Assessments
7.1
Pre-defined, expected, post-treatment events
The subject shall evaluate local tolerability at the visit 4 weeks after the first treatment and
touch-up. A question regarding the presence and maximum intensity of pre-defined
expected post-treatment events, i.e. bruising, redness, swelling, pain (including burn), 
tenderness, and itching shall be assessed for the treated area (Table 7). These events shall
not be reported as adverse events (AEs) if fully recovered during the first 2 weeks.
Any sign or symptom of pre-defined expected post-treatment events (as specified above)
that are still ongoing 2 weeks post-treatment shall also be reported separately as AEs. The 
events shall be transferred to an AE page in the eCRF and thereafter followed as AEs. The 
start date of these events shall be the first time point when it was first experienced, and the 
intensity shall be the maximum intensity of the sign or symptom experienced.
7.2
Laboratory assessments
No laboratory assessments should be performed.
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7.3
Adverse events
7.3.1 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 persons3, 
whether or not related to the investigational product. 
This definition includes:
a) events related to the investigational product or the reference product
b) events related to the procedures involved
7.3.2 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-threatening4 illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalisation5, or
4. medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function,
c) led to foetal distress, foetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such (see section 7.3.4).
7.3.3 Recording instructions
The study site personnel should question each subject about AEs at each study visit 
following the signature of informed consent. The following question should be asked at 
each visit: ”Since your last clinical visit have you had any health problems?”, and all AEs 
provided should be recorded. 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 deteriorates (in intensity or frequency) shall be reported as AEs. 
                                                
3 For users or other persons, this definition is restricted to events related to the investigational product.
4 The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe. (Source: ICH-E2A clinical safety data management: definitions and standards for 
expedited reporting).
5 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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When an AE is related to a device deficiency (refer to section 7.4), 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) 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 7.3.3)
f)
Seriousness (serious or not serious, according to definition in section 7.3.2)
g) Causal relationship to investigational product or investigational 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.
The pre-defined, expected post-treatment events shall be assessed separately. These events 
shall be collected by direct questioning to subjects at a visit 4 weeks after the first
treatment, and touch-up. Any ongoing sign or symptom still persistent 2 weeks after
treatment shall be recorded as an AE in the AE module for continued follow-up.
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.
7.3.3.1 Causal relationship and seriousness
Each AE, serious as well as non-serious, shall be assessed by the Investigator for causal 
relationship with the investigational 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:
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
“Do you consider that there is a reasonable possibility that the event may have been 
caused by the investigational product?”, and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the device 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. 
7.3.4 Reporting of adverse events 
Adverse event reporting on each subject shall start at the baseline visit. 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.
7.3.5 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 made via the eCRF system by 
completing the SAE module. Via the eCRF-system, the SAE-report will be automatically 
sent to Sponsor. If there are difficulties accessing the eCRF, an SAE paper form can be 
completed and sent via fax or e-mail to Sponsor (see contact details below).
In case of difficulty to obtain all the required information within 24 hours, an initial report 
can be submitted, with the following information as a minimum, irrespective of whether 
some of it is regarded as preliminary:

Clinical Trial Number

Subject identification (age, gender, subject number)

Adverse event description

Date when AE occurred

Date when AE became serious

Name of PI and original reporter (if other than the PI)

Name of investigational product 

Treatment specification
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.
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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 or pregnancy reporting:
Fax number for SAE reporting:
________________________________________________________________________
E-mail for device deficiency reporting:
For non urgent complementary information about SAEs or device deficiencies not possible 
to send by e-mail or fax, please use surface mail.
_________________________________________________________________________
Surface mail for providing complementary information:
 
________________________________________________________________________
The SAE form must be signed and dated by the Investigator. Information about 
investigational products must not be disclosed to the blinded evaluator. If the initial 24-
hour SAE report does not contain full information or if it is made without using the SAE
module/form the fully completed and signed SAE module/form shall be sent 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 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.
7.3.6 Follow-up of unresolved events after termination of the study
All serious as well as non-serious AEs with a causal relationship to the investigational
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. Follow-up information shall be reported on 
the AE follow-up form.
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7.3.7 Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy during the study period the subject must continue to be followed 
within the study and the outcome of pregnancy must be reported even if the 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 and be submitted to the Sponsor
according to contact details specified in section 7.3.5. The report can be prospective or 
retrospective. Follow-up shall be conducted to obtain outcome information on all 
prospective reports. 
Cases that led to foetal distress, foetal death or a congenital abnormality or birth defect are 
to be regarded as SAEs and shall be reported on the exposure in utero report form to the 
Sponsor immediately but no later than 24 hours after the Investigators awareness (see 
contact details in section 8.3.5). These events shall be handled as SAEs during data 
processing. Other complications during the pregnancy that are related to the pregnant 
woman and fulfils any serious criteria, such as pre-eclampsia requiring hospitalisation, 
shall be reported and handled as SAEs. Elective abortions without complications shall not 
be reported as AEs.
7.4
Device deficiencies
7.4.1 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, safety6, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
7.4.2 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 investigational product shall be reported as 
applicable. If an injury has occurred, an AE module or an SAE module/form shall be 
completed as applicable (refer to section 7.3). 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. 
                                                
6 Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
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7.4.3 Reporting of device deficiencies
The Investigator shall send the completed clinical study complaint form to the Sponsor via 
eCRF using the contact details specified in section 7.3.5. If there are difficulties accessing 
the eCRF, a paper form can be completed and sent via fax or e-mail to Sponsor. A device 
deficiency that led to a SAE and any device deficiency that could have led to a SAE shall 
be reported within 24 hours after the Investigator’s awareness in accordance to section
7.3.5. 
In order to fulfil regulatory reporting requirements, all deficiencies with the investigational
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 if required by national regulations and the PI is 
responsible for reporting it to the IEC if required by national regulations.
The deficient investigational product shall be kept by the study site until the QA 
complaints group has confirmed whether the product shall be returned to Sponsor for 
further study or if it can be destroyed at the study site.
8. Data Handling and Management 
8.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter clinical data information into a database, efficiently and avoiding errors. The data 
management routine includes procedures for handling eCRFs, database set-up and 
management, data entry and verification, data validation, and documentation of the 
performed activities including information of discrepancies in the process. The data 
management process will be described in detail in the data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the 
CSP and the eCRF. 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 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.
8.2
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 enrolled subjects (subsequent visits). 
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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 enrolment 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.
8.2.1 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.
8.2.2 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 authorised designee. The monitor cannot enter data in the eCRFs. 
Once study data have been submitted to the central server via the eCRF, corrections to the 
data fields will be audit trailed, meaning that the reason for change, the name of the person 
who made the change, together with time and date will be logged. Roles and rights of the 
site personnel responsible for entering study data into the eCRF shall be determined in 
advance. If discrepant data is detected during review of the data, either by the Sponsor or 
its representatives, the responsible data manager or monitor shall raise a query in the 
electronic data capture application. The query shall state the question or data to be changed 
and shall be resolved in the system by the PI or his/her authorised designee. The 
appropriate study site personnel shall answer the queries in the eCRF. This will be audit 
trailed by the electronic data capture application meaning that the name of study site
personnel, time, and date is logged.
8.2.3 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 
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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. 
8.2.4 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.
8.3
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.
8.4
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 
investigational 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. 
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. 
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8.5
Document and data retention
All records pertaining to the conduct of the study, including signed eCRFs, informed 
consent forms, investigational 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.
It is the PI’s responsibility to inform Q-Med AB in writing if the Investigator file is moved 
or if the responsibility for the documents is transferred to someone else.
9. Statistical Methods
9.1
General
 
 
 
 
 
 
 
 
9.2
Analysis populations
The following populations will be defined:

Safety

Modified Intention-to-
treat (MITT)
 
All effectiveness analyses will be based on the MITT population. Safety analysis will be
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.
9.3
Demographics, screening/baseline assessments, and subject characteristics
Demographic endpoints and subject characteristics will be presented by investigational
product using descriptive statistics.
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9.4
Effectiveness analysis
 
 
the proportion of improved subjects (assessed as very much improved, much improved or 
improved) will be presented together with a 95% confidence interval (based on the 
binomial distribution).
 
 
 
the proportion of improved midfaces
(1 grade decrease on the scale) and subjects (both midfaces improved) will be presented 
together with a 95% confidence interval (based on the binomial distribution). 
 
 
 
 
 
 
Evaluation of naturalness after treatment 
 
will be presented descriptively by treatment group and visit.
 
.
 
 
 
 
 
 
 
9.5
Safety analysis
Adverse events will be summarised in frequency tables by study product, containing 
number of subjects with no AEs, number of subjects with at least one AE, and number of 
events,
 All AEs will be summarised 
and listed by system organ class (SOC) and preferred term (PT) assigned using MedDRA. 
 
 
 
 
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9.6
Handling of missing data
Study data will be presented based on observed cases, i.e. no imputation of missing values
will be performed.
9.7
Interim analysis
Not applicable. 
Since this is an open study, available data may be analysed prior to study completion.
9.8
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. 
Deviations from the statistical plan will be documented in the statistical report.
 
 
 
10. Protection of personal data
The study shall include collection and processing of personal data as specified in the 
Regulation (EU) 2016/679 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 
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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, clinical research organisation 
(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.
11. Quality Control and Quality Assurance
11.1 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.
11.2 Quality assurance
The study site may be subject to quality assurance audit by the Sponsor as well as 
inspection by appropriate RA. It is important that the PI and other relevant study site 
personnel are available during the monitoring visits, possible audits, and inspections, and 
that sufficient time is devoted to the monitoring process.
Each participating member of the study site team shall provide a curriculum vitae (CV) or 
equivalent that demonstrates their qualifications to conduct the study. The CV shall give 
name, 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.
11.3 Changes to the clinical study protocol
11.3.1 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 and RA, if applicable, 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. For non-substantial changes not affecting 
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the rights, safety and well-being of the subjects or not related to the clinical objectives or 
endpoints, a simple notification to the IEC and RA, if applicable, can be sufficient.
11.3.2 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 and RA. Such deviations 
should be documented and reported to the IEC and RA 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 hrs following detection) as well 
as the IEC if required. 
12. 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.
13. 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 resolved7. 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.
                                                
7 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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14. 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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15. References
1.
Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol 2006 May-Jun; 19(3):141-50.
2.
Gold M. The science and art of hyaluronic acid dermal filler use in esthetic applications. J Cosmet Dermatol 
2009 Dec; 8(4):301-7.
3.
Pons-Guiraud A. Classification des produits de comblement disponsible en France. Ann Dermatol Venerol 
2008;135:I S27-34.
4.
Ascher B et al. Chapter 34: Hyaluronic acids. In: Ascher B ed. Injection Treatment in Cosmetic Surgery. Informa 
UK Ltd. 2009.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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. 
11.
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. 
12.
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.
13.
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.
14.
Weiss RA et al. Effectiveness and Safety of Large Gel Particle Hyaluronic Acid with Lidocaine for Correction of 
Midface Volume Deficit or Contour Deficiency. Dermatol Surg. 2016 Jun; 42(6):699-709.
15.
Cartier H et al. Perioral rejuvenation with a range of customized hyaluronic acid fillers: efficacy and safety over 
six months with a specific focus on the lips. J Drugs Dermatol 2012;11(1)(suppl):17-26.
16.
Kestemont,P et al. Sustained efficacy and high patient satisfaction after cheek enhancement with a new 
hyaluronic acid dermal filler. J Drugs Dermatol 2012. 11, s9-16.
17.
Rzany,B., et al. Full-face rejuvenation using a range of hyaluronic acid fillers: efficacy, safety, and patient 
satisfaction over 6 months. Dermatol. Surg 2012a. 38, 1153-1161.
18.
Segura S et al. A complete range of hyaluronic acid filler with distinctive physical properties specifically 
designed for optimal tissue adaptations. J Drugs Dermatol 2012;11(1)(suppl):5-8.
19.
Lorenc ZP, Bank D, Kane M, Lin X, Smith S. Validation of a Four Point Photographic Scale for the Assessment 
of Midface Volume Loss and/or Contour Deficiency. Plast Reconstr Surg 2012 Dec; 130(6):1330-6.
20.
Day DJ, Littler CM, Swift RW, Gottlieb S. The wrinkle severity rating scale. Am J Clin Dermatol 2004;5(1):49-
52.
21.
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. 
Dermatol Surg 29;6:2003.
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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.
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10.
Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm to the environment.
12.
Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional.
13.
Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research.
14.
Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not adversely affect 
the health of the patients who serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured.
Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and burdens.
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects.
17.
All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with foreseeable 
benefits to them and to other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20.
Medical research with a vulnerable group is only justified if the research is responsive to the health needs 
or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 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 
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subjects and information regarding provisions for treating and/or compensating subjects who are harmed 
as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must 
be duly qualified. It must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to 
the protocol may be made without consideration and approval by the committee. After the end of the 
study, the researchers must submit a final report to the committee containing a summary of the study’s 
findings and conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she freely 
agrees.
26.
In medical research involving human subjects capable of giving informed consent, each potential subject 
must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential 
subject must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information.
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study.
27.
When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship.
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 
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consent is a necessary characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorised representative. If no such representative is available 
and if the research cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the subject or a 
legally authorised representative.
31.
The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee.
Use of Placebo
33.
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.
In advance of a clinical trial, sponsors, researchers and host country governments should make provisions 
for post-trial access for all participants who still need an intervention identified as beneficial in the trial. 
This information must also be disclosed to participants during the informed consent process.
Research Registration and Publication and Dissemination of Results
35.
Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject.
36.
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication.
Unproven Interventions in Clinical Practice
37.
In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.
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