A Randomized, Controlled, Evaluator-blinded, Split Face Study to Evaluate the Performance and Safety of GP0045 for Correction of Moderate to Severe Nasolabial Folds
Phase: NA
Conditions: Nasolabial Fold, Safety
Sponsor: Galderma R&D

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Title Page
A randomized, controlled, evaluator-blinded, split face study to evaluate 
the performance and safety of GP0045 for correction of moderate to 
severe nasolabial folds
Study products:
Investigational product: GP0045
Comparator product: 
Clinical trial number (CTN):
43FE1630 
Principal Investigator:
Sponsor:
Q-Med AB
Confidentiality Statement
This study protocol contains confidential information belonging to Q-Med AB. Except as 
may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree 
to hold such information in confidence and neither disclose it to any third parties (except 
where required by applicable law) nor use it for any other purpose than in relation to the 
clinical study described herein. 
 
  
 
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Summary of Changes in Clinical Study Protocol 43FE1630 from version 2.0 to 
version 3.0
 
 
  
 
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Summary of Changes in Clinical Study Protocol 43FE1630 from version 1.0 to 
version 2.0
 
 
  
 
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Investigators and Study Administrative Structure
Principal Investigator:
Treating Investigator:
Investigational Site
Sponsor:
Q-Med AB
Medical expert:
 
  
 
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Clinical Project Manager:
Statistician:
Clinical research organisation 
(CRO):
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
Clinical Project Manager, Q-Med AB
Statistician, Q-Med AB
Medical Expert, Q-Med AB
 
  
 
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Signed Agreement of the Clinical Study Protocol
CTN:
43FE1630 
Title of the CSP:
A randomized, controlled, evaluator-blinded, split face study to 
evaluate the performance and safety of GP0045 for correction of 
moderate to severe nasolabial folds
We, the undersigned, have read and understand the CSP specified above, and agree on the 
contents. The CSP, the clinical trial agreement (CTA) and the additional information given in the 
Investigator’s brochure (IB) 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 randomized, controlled, evaluator-blinded, split face study to evaluate the 
performance and safety of GP0045 for correction of moderate to severe 
nasolabial folds
Clinical Trial Number: 
43FE1630
Country, number of 
subjects 
Sweden, Up to 20 subjects
Principal Investigator:
Treating Investigator
Primary Objective 
Objective
To evaluate the performance following injection of GP0045 in the treatment of 
NLF 
 at 6 months post treatment.
Endpoint
The response rate based on 
 live assessment by the blinded evaluator, 
at 6 months post treatment. The response rate is defined as percentage of 
subjects with at least 1 grade improvement 
Secondary Objectives 
Objective
To evaluate the performance following injection of GP0045 in the treatment of 
NLF 
 at 2 weeks, 3, 9, 12, 15 and 18 
months post treatment.
Endpoint
The response rate based on 
 live assessment by the blinded 
evaluator, at 2 weeks, 3, 9, 12, 15 and 18 months post treatment. The response 
rate is defined as percentage of subjects with at least 1 grade improvement 
 
 
 
Safety Objective
Objective
To evaluate the safety of GP0045 
Endpoints

Incidence, intensity, duration and onset of adverse events (AEs) collected 
during 18 months post treatment

Incidence, intensity, and duration of pre-defined expected post-treatment 
events collected using a subject diary during 2 weeks post treatment
Study Design:
This is an 18 months, randomized, evaluator-blinded, comparative, single-
centre study to assess the performance and safety of GP0045 
 
in the treatment of NLF. A split face design will be 
used, i.e. subjects will be randomized to treatment with either GP0045 in the 
right NLF 
; or 
 
 GP0045 in the left NLF.
 
  
 
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GP0045 
 will be administered by the treating 
Investigator. For the initial injection, a maximum volume of 2.0 mL per NLF 
will be injected, and for the optional touch-up injection a maximum of 2.0 mL 
per NLF will be injected.
 
After the screening, eligible subjects are given the initial injection at the 
baseline visit and contacted by telephone on Day 3 following the injection. A 
second, optional injection (touch-up) may be given at Week 2 to subjects who 
have not achieved optimal correction from the initial injection. Subjects who 
receive a touch-up injection will be contacted by phone on Day 3 following the 
touch-up injection. Following the last injection (initial or touch-up), there is a 
follow-up period of 18 months. Subjects will be in the study for up to 
20 months, including the screening period.
At each physical follow-up visit, 
 assessments will be 
performed and photographs of the NLFs will be taken.
The subjects will be provided with a 2-weeks diary in which to report pre-
defined, expected post-treatment events daily, starting on the day of the injection 
(separate diaries are provided for each post-injection period). AEs will be 
recorded throughout the study and device deficiencies will be evaluated after 
each injection.
Inclusion criteria: 
1. Ability to adequately understand the verbal explanations and the written 
subject information provided in local language and ability to give consent to 
participate in the study
2. Signed and dated informed consent to participate in the study, including 
photo consent 
 
 
 
5. Subjects with intent to undergo correction of both nasolabial folds 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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Exclusion criteria:
1.
Known/previous allergy or hypersensitivity to any injectable HA gel
2.
Known/previous allergy or hypersensitivity to local anesthetics, e.g. 
lidocaine or other amide-type anesthetics,
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 3 and Vitamin E 
are acceptable only as part of a standard multivitamin 
 
  
 
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16. Any condition (medical or other) that, in the opinion of the Investigator, 
would make the subject unsuitable for inclusion (e.g. a chronic, relapsing 
or hereditary disease that may interfere with the outcome of the study)
 
 
18. Participation in any other clinical study with an investigational product
within 30 days before treatment
Investigational product, 
dose and mode of 
administration:
 
 
 
 
 
 
Reference therapy, dose 
and mode of 
administration
 
 
 
 
 
Duration of treatment 
and follow-up: 
Following screening and treatment (initial and optional touch-up at 2 weeks) 
there is a follow-up period of 18 months,
 
 
 
  
 
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Performance 
Assessments:
Safety Assessments:

Adverse Events

Subject Diary

Device deficiencies
Statistical Methods: 
Statistical analysis will be descriptive and presented by study product and visit, 
as appropriate.
Continuous data will be summarized using standard statistical measures such 
as n (number of subjects), mean, median, standard deviation, minimum, and 
maximum.
Categorical data will be summarized in frequency tables presenting absolute 
(n) and relative (%) frequencies.
All adverse events will be summarized and listed by system organ class (SOC) 
and preferred term (PT) assigned to the event using MedDRA.
 
  
 
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Abbreviations and Definitions of Terms
AE
Adverse event 
Blinded 
evaluator
An evaluator responsible for independent evaluation of treatment
result(s). The evaluator must not be involved in the treatment of the
subject. The evaluator must have a medical background and be trained in 
the scales used in the study.
CE
French: Conformité Européenne
CFR
Code of Federal Regulations
Comparator
Medical device, therapy (e.g. active control), placebo or no treatment, 
used in the reference group in a study
CRF
Case report form
CRO
Contract research organisation
CSP
Clinical study protocol
CTA
Clinical trial agreement
CTN
Clinical trial number
CV
Curriculum vitae
DCF
Data clarification form
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
First subject in
First subject screened, i.e. who signs the informed consent form
First subject out
First subject who completed his/her last study visit
G
Gauge
GCP
Good clinical practice
GMP
Good manufacturing practice
HA
Hyaluronic acid
IB
Investigator’s brochure, i.e. compilation of the current clinical and non-
clinical information on the investigational product, relevant to the 
clinical study
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
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”.
 
  
 
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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
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
NLF
Nasolabial fold
NSAID
Non-steroidal anti-inflammatory drugs
PI
Principal Investigator; qualified person responsible for conducting the 
study at a study site
PT
Preferred term
QA
Quality assurance
RA
Regulatory authority
SAE
Serious adverse event
SAP
Statistical analysis plan
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
TW
Thin wall (needle)
WHO
World Health Organization
 
  
 
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Table of Contents
TITLE PAGE
1
SUMMARY OF CHANGES IN CLINICAL STUDY PROTOCOL 43FE1630 FROM VERSION 
2.0 TO VERSION 3.0
2
SUMMARY OF CHANGES IN CLINICAL STUDY PROTOCOL 43FE1630 FROM VERSION 
1.0 TO VERSION 2.0
3
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
4
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
7
SYNOPSIS
8
ABBREVIATIONS AND DEFINITIONS OF TERMS
13
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
Study products description
19
2.2.1
Hyaluronic acid gel description
19
2.2.2
Investigational product description
20
2.2.3
Comparator product description
20
2.3
Previous experience
20
2.3.1
Non-clinical documentation
20
2.3.2
Clinical documentation
21
2.4
Study rationale and justification for design
21
2.5
Risks and benefits
22
3.
OBJECTIVES AND ENDPOINTS
24
3.1
Objectives and endpoints
24
3.1.1
Primary objective and endpoints
24
3.1.2
Secondary objectives and endpoints
24
3.1.3
Safety objective and endpoints
24
4.
DESIGN OF THE STUDY
25
4.1
General outline
25
4.2
Number of subjects
26
4.3
Duration of subject participation
26
4.4
Randomization
26
4.4.1
Randomization
26
4.4.2
Blinding
26
4.4.3
Emergency unblinding
26
 
  
 
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4.5
Medical history
26
4.6
Concomitant therapies
27
4.6.1
Definition
27
4.6.2
Categories
27
4.6.3
Recording
27
4.6.4
Authorized concomitant therapies
27
4.6.5
Prohibited concomitant therapies
27
4.7
Schedule of events
29
4.8
Visits
30
4.8.1
Screening visit (Day -30 to Day 0)
30
4.8.2
Day 0, Baseline visit
30
4.8.12
Month 18 (±15 days) following last injection
32
5.
SUBJECTS
33
5.1
Subject information and informed consent
33
5.2
Inclusion criteria
34
5.3
Exclusion criteria
34
5.4
Screening and subject numbers
35
5.5
Withdrawal of subjects
36
6.
STUDY PRODUCTS
37
6.1
Additional products and material
37
6.2
Packaging, labelling, and storage
38
6.2.1
Investigational product
38
6.2.2
Comparator product
38
6.3
Product accountability
39
6.4
Treatment
39
6.4.1
Treatment procedure
39
6.4.2
Treatment regimen (dose and interval)
40
6.4.3
Post-treatment care
41
6.4.4
Post-trial provisions
41
6.4.5
Case report form recordings
41
6.4.6
Treatment compliance
41
7.
PERFORMANCE ASSESSMENTS
41
 
  
 
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7.1
General information
41
7.4
Photography
43
8.
SAFETY ASSESSMENTS
44
8.2
Laboratory assessments
44
8.3
Adverse events
44
8.3.1
Definition of an adverse event
44
8.3.2
Definition of a serious adverse event
45
8.3.3
Recording instructions
45
8.3.4
Reporting of adverse events
46
8.3.5
Reporting of serious adverse events
46
8.3.6
Follow-up of unresolved events ongoing at termination of the study
47
8.3.7
Reporting and follow-up of events occurring after subject termination of the study
48
8.3.8
Pregnancy
48
8.4
Device deficiencies
48
8.4.1
Definition of a device deficiency
48
8.4.2
Recording instructions
48
8.4.3
Reporting of device deficiencies
49
9.
DATA HANDLING AND MANAGEMENT
49
9.1
Data management
49
9.2
Paper case report forms
50
9.2.1
Correction of recorded data
50
9.3
Source documents
50
9.4
Record keeping and access to source data
51
9.5
Document and data retention
51
10.
STATISTICAL METHODS
51
10.1
General
51
10.2
Analysis populations
52
10.3
Demographics, baseline assessments, and subject characteristics
52
10.4
Performance analysis
52
10.4.1
Primary analysis
52
10.4.1
Secondary analysis
52
10.5
Safety analysis
53
10.5.1
Adverse Events
53
10.5.2
Pre-defined expected post-treatment events
53
10.6
Handling of missing data
53
10.7
Interim analysis
53
10.8
Withdrawals and deviations
53
 
  
 
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10.9
Sample size
53
11.
PROTECTION OF PERSONAL DATA
53
12.
QUALITY CONTROL AND QUALITY ASSURANCE
54
12.1
Quality control
54
12.2
Quality assurance
54
12.3
Changes to the clinical study protocol
54
12.3.1
Amendments
54
12.3.2
Deviations
55
13.
FINANCING, INDEMNIFICATION, AND INSURANCE
55
14.
PUBLICATION POLICY
55
15.
SUSPENSION OR PREMATURE TERMINATION
55
16.
APPENDICES
57
List of Tables
Table 1.
Schedule of events.....................................................................................................29
Table 2.
Description and Usage of the Study Products...........................................................37
List of Appendices
Appendix 1
Declaration of Helsinki .........................................................................................57
 
 
  
 
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1. Ethical Considerations
1.1
Statement of ethical compliance
The study shall be conducted in compliance with the clinical trial agreement (CTA), the clinical 
study protocol (CSP), good clinical practice (GCP), and applicable regional or national 
regulations. The international standard for clinical investigation of medical devices for human 
subjects – Good clinical practise, ISO 14155:2011, shall be followed. The International Council
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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 study requires application for approval from the RA. The study will not be started until the 
Sponsor has received written approval. The Sponsor will provide the PI with a copy of the 
relevant document.
The collection, access to, processing, and transfer of protected health information or sensitive 
personal data shall be carried out in accordance with applicable rules and regulations.
2. Background Information
2.1
Indication and population description
GP0045 is being developed as an injectable hyaluronic acid (HA) gel
 
In this study, GP0045 is 
intended for the correction of 
nasolabial folds (NLFs) in men and women 
over the age of 18.
2.2
Study products description
 
 
 
 
                                                
1 Greene JJ, Sidle DM. The Hyaluronic Acid Fillers; Current Understanding of the Tissue Device Interface. Facial 
Plast Surg Clin N Am 2015:23:423–32.
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.
 
  
 
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2.2.2
Investigational product description
 
 
 
 
2.2.3
Comparator product description
The comparator product is 
 a CE-marked HA gel
 
 
 
2.3
Previous experience
 
 
 
 
 
 
 
                                                
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.
 
  
 
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2.4
Study rationale and justification for design
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                
5 Cohen J, Dayan S, Brandt F, Nelson D, Axford-Gatley R, Theisen M and Narins R. Systemic review of clinical 
trials of small- and large-gel-particle hyaluronic acid injectable fillers for aesthetic soft tissue augmentation. 
Dermatol Surg 2013; 39:2015-231
6 Day DJ, Littler CM, Swift RW, Gottlieb S. The wrinkle severity rating scale. Am J Clin Dermatol 2004;5(1):49-52
 
  
 
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2.5
Risks and benefits
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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3. Objectives and Endpoints
3.1
Objectives and endpoints
3.1.1
Primary objective and endpoints
The primary objective is to evaluate the performance following injection of GP0045 in the 
treatment of NLF 
 at 6 months post treatment.
Endpoint
The response rate 
, as assessed by the blinded evaluator, at 6 months post 
treatment.
The response rate is defined as percentage of subjects with at least 1 grade improvement 
 
 
3.1.2
Secondary objectives and endpoints
The secondary objectives are:
-
To evaluate the performance following injection of GP0045 in the treatment of NLF 
 at 2 weeks, 3, 9, 12, 15 and 18 months post 
treatment.
Endpoint
The response rate 
, as assessed by the blinded evaluator, at 2 weeks, 3, 
9, 12, 15 and 18 months post treatment.
The response rate is defined as percentage of subjects with at least 1 grade improvement 
.
 
3.1.3
Safety objective and endpoints
The safety objective is to evaluate the safety of GP0045 
Endpoints
-
Incidence, intensity, duration and onset of adverse events (AEs) collected during 18 
months post treatment
-
Incidence, intensity, and duration of pre-defined expected post-treatment events collected 
using a subject diary during 2 weeks post treatment
 
  
 
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4. Design of the Study
4.1
General outline
This is an 18 months, randomized, evaluator-blinded, comparative, single-centre study to assess 
the performance and safety of GP0045 
 in the treatment of 
NLF. A split face design will be used, i.e. subjects will be randomized to treatment with either 
GP0045 in the right NLF 
 or
 
 GP0045 in the left NLF. GP0045 and 
 
will be administered by the treating Investigator. 
After the screening, eligible subjects are given the initial injection by the treating Investigator at 
the baseline visit and contacted by telephone on Day 3 following the injection. A second, 
optional injection (touch-up) may be given by the treating Investigator at Week 2 to subjects who 
have not achieved optimal correction from the initial injection. Subjects who receive a touch-up 
injection will be contacted by phone on Day 3 following the touch-up injection. Following the 
last injection (initial or touch-up), there is a follow-up period of 18 months.
 
Subjects will be in the study for up to 19.5 months, including the screening period.
At each physical follow-up visit, 
 assessments will 
be done and photographs of the NLFs will be taken (Section 7.4).
The subjects will be provided with a 2-weeks diary in which to report pre-defined, expected 
post-treatment events daily, starting on the day of the injection (separate diaries are provided for 
each post-injection period). AEs will be recorded throughout the study and device deficiencies 
will be evaluated after each injection (Figure 4-1).
 
  
 
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4.2
Number of subjects
Up to twenty (20) subjects will be recruited at a single site in Sweden. The duration of the 
enrolment period is expected to be 4 weeks.
4.3
Duration of subject participation
The total duration of the study is expected to be approximately 20 months. Each subject will be 
involved in the study for up to 19.5 months, including the screening period.
End of study is when enrolment has reached the target number of subjects and all subjects have 
completed the last study visit.
4.4
Randomization 
4.4.1
Randomization
Up to twenty (20) subjects will be randomized to treatment with either GP0045 in the right NLF 
; or
 
GP0045 in the left NLF.
Before starting the study, a computer generated randomization list will be prepared under the 
supervision of a designated statistician from the Sponsor. Each subject will be assigned a 
consecutive subject number at the treatment visit when all inclusion criteria and exclusion 
criteria have been verified. Each subject number is linked to the specific treatment sequence to 
be administered according to the randomization list. All treatment information will be kept by 
the Investigator during the study.
4.4.2
Blinding
This is an evaluator-blinded study. Due to the differences in the physical characteristics 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.
Because the method of administration is similar, the treatment can be masked from the subjects 
by simply preventing them from viewing the syringes during administration of the study 
products. This will be done by placing an opaque drape or patch over the subject’s eyes during 
the injection procedure.
The blinded evaluator shall not be allowed to retrieve study supplies or to be present during 
opening of the study supplies or injections. The treating Investigator is not allowed to discuss 
treatments with the blinded evaluator or the subjects. All documents with information on study 
products shall be kept in a separate binder not available to the blinded evaluator. The blinded 
evaluator should not have access to CRF pages with study product information.
4.4.3
Emergency unblinding
Not applicable as the treating Investigator is unblinded.
4.5
Medical history
History of surgical events and medical conditions that are judged as relevant by the Investigator
shall be documented in the case report form (CRF) using medical terminology.
History of dermal fillers and other cosmetic procedures shall be documented in the CRF.
 
  
 
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4.6
Concomitant therapies
4.6.1
Definition
Concomitant therapies are defined as follows:

any existing therapies ongoing at the time of the Screening visit,

any changes to existing therapies (such as changes in dose or formulation) during the
course of the study, or

any new therapies received by the subject since the Screening visit
4.6.2
Categories
The following two categories are to be considered for concomitant therapies:

Drugs/therapies including but not limited to, prescription, over-the-counter (OTC), birth 
control pills/patches/hormonal devices, vitamins, herbal medicines/supplements, and 
homeopathic preparations

Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers, X-rays, etc.
4.6.3
Recording
Concomitant therapies administered during the study are to be recorded on the dedicated forms
in the CRF. Any concomitant therapies reported in the subject diary during the first 14 days shall 
be transferred into the concomitant therapies page/module in the CRF at the 2-week follow-up 
visit(s). Concomitant therapies are to be recorded, reviewed, and updated at each visit. 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 CRF. Any new concomitant therapy or 
modification of an existing therapy may be linked to an AE. A corresponding AE form must be 
completed to account for the change in therapy, except in some cases such as therapy used for 
prophylaxis, dose modification for a chronic condition, etc.
4.6.4
Authorized concomitant therapies
Except as noted below, concomitant medications or other treatments or procedures may be 
utilized when the Investigator or his/her authorized designee considers it medically necessary.
 
 
 
 
 
 
  
 
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If a subject receives prohibited therapy during the study, a protocol deviation should be 
documented. The Sponsor must be notified to discuss the pertinence. The subject should, for 
safety reasons, continue in the study for the scheduled follow-up visits.
 
  
 
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4.7
Schedule of events
Title 
Doc id  
Clinical Study Protocol GP0045 43FE1630
MA-34391
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4.8
Visits
 
  
 
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5. Subjects
5.1
Subject information and informed consent
The PI or his/her authorized designee must always use the IEC-approved subject information and 
informed consent form and it must not be changed without prior discussion with the Sponsor and 
approval from the applicable IEC.
It is the responsibility of the PI or his/her authorized designee to give each subject prior to 
inclusion in the study, full and adequate verbal and written information regarding all aspects of 
the clinical study that are relevant to the subject’s decision to participate throughout the study, 
e.g. explain the purpose and procedures of the study, the duration and number of expected 
participants, possible risks involved, and the opinion of the IEC. The subject shall be informed 
that the participation is confidential and voluntary and that the subject has the right to withdraw 
from the study at any time, without any consequences to his/her future medical care, treatment or 
benefits to which the subject is otherwise entitled. The information shall be provided in a 
language clearly and fully understandable to the 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. The consent includes information that data will be 
collected, recorded, processed, and may be transferred to other countries. The data will not 
contain any information that can be used to identify any subject.
Full face photographs collected during the study will be stored in a database by the Sponsor. The
subjects are recognisable on the photographs, however their names will not be disclosed.
All signed informed consent forms shall be filed in the Investigator file. The subject shall be 
provided with a copy of the signed and dated informed consent form and any other written 
information.
The Investigator shall ensure that important new information is provided to new and existing 
subjects throughout the study.
 
  
 
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5.2
Inclusion criteria
1. Ability to adequately understand the verbal explanations and the written subject information 
provided in local language and ability to give consent to participate in the study
2. Signed and dated informed consent to participate in the study, including photo consent 
 
5. Subjects with intent to undergo correction of both nasolabial folds 
 
 
 
 
 
 
 
 
5.3
Exclusion criteria
1. Known/previous allergy or hypersensitivity to any injectable HA gel
2. Known/previous allergy or hypersensitivity to local anesthetics, e.g. lidocaine or other 
amide-type anesthetics, 
 
  
 
 
 
 
  
 
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16. Any condition (medical or other) that, in the opinion of the Investigator, would make the 
subject unsuitable for inclusion (e.g. a chronic, relapsing or hereditary disease that may 
interfere with the outcome of the study)
 
18. Participation in any other clinical study with an investigational product within 30 days 
before treatment
5.4
Screening and subject numbers
Each subject who has signed the informed consent form will be assigned a screening number and 
shall be listed on a subject screening and inclusion log. The screening number will consist of 
“SCR” followed by two (2) digits and start with 01 and followed by 02, 03, etc. in consecutive 
order.
 
  
 
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A “screening failure” is defined as a subject who does not fulfil the eligibility criteria. For 
screening failures, the CRF screening visit shall be completed to an extent that makes it clear 
which assessments have been made and the reason why the subject did not fulfil the eligibility 
criteria. The reason for excluding a subject from entering the study shall also be specified in the 
subject screening and inclusion log. When the Investigator has confirmed that all inclusion 
criteria and no exclusion criteria are met, each subject will be assigned a subject number in a 
consecutive order, starting with 01.
The subject number, subject name, and other information sufficient to link the CRF to the 
medical records (e.g. national identification number, chart number, etc.) shall be recorded on a 
subject identification list. The subject identification list shall only be available at the site, both 
throughout and after the study.
5.5
Withdrawal of subjects
Each subject shall be advised in the informed consent form that he/she has the right to withdraw 
from the study at any time, for any reason, without prejudice. Subjects may also be discontinued 
from this study if the Investigator determines that it is in the subject’s best interest to do so, and 
may be withdrawn at the Investigator's discretion at any time.
 
 
 
 
 
 
 
 
 
The reason and date for withdrawal shall be documented in the CRF. When possible, an 
explanatory comment shall be added in the early termination page to further explain the reason 
for withdrawal. If withdrawal of a subject occurs during a regular study visit, the CRF for that 
specific visit shall be completed as far as possible together with the study termination CRF page. 
If withdrawal of a subject occurs between regular study visits the subject should when possible 
(irrespective of the reason for withdrawal) be scheduled for a termination visit to document 
subject outcome for the primary and secondary endpoints. In these cases the CRF for early 
termination 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 reason for withdrawal is “subject request” or “other”, the subject shall be questioned to rule 
out the possibility of an AE.
 
  
 
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If an AE which, according to the Investigator’s assessment, is related to the use of any of the 
study products and is still ongoing at the time of the withdrawal, the Investigator shall follow up 
the subject until the AE resolves, is assessed as chronic or stable, or for three months (see 
Section 8.3.6).
6. Study Products
The term “study products” refers to both the investigational product (GP0045) and the 
comparator product
Study products are provided by the 
Sponsor.
 
 
 
6.1
Additional products and material
 
 
  
 
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6.2
Packaging, labelling, and storage
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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6.3
Product accountability
The study products will be released to the PI or his/her authorized designee after study approvals 
have been received from the IEC and RA and the CTA has been signed by all parties.
The PI must ensure that the study products are kept in a secure location, with access limited to 
those authorized by the PI.
The study products must be traceable from the manufacturer to their use in subjects until 
disposal. It is therefore important that the PI maintains accurate product accountability records, 
i.e. documentation of the physical location of all study products and delivery of study products 
between the Sponsor and the PI, and documentation of administration of product to the subject. 
A shipping record shall be kept of all study products received from the Sponsor; including the 
product name, date received, lot number, expiration date, and amount received. In addition, 
dispensing logs shall be maintained including the product name, dispense date, the number of 
syringes used/amount dispensed, the subject receiving study product, and number of syringes left 
in stock at the site.
When the study is completed, all unused or expired study product at each study site shall be 
destroyed locally at the site, with proper documentation, after agreement with the Sponsor. Any 
malfunctioning study products shall be reported as described in Section 8.4.3.
Products deliberately or accidentally destroyed during shipment or at a study site shall be 
accounted for and documented. Used syringes, disposable needles, and any opened unused 
material must be discarded immediately after the treatment session and must not be reused due 
to risk for contamination of the unused material and the associated risks including infections 
according to standard procedures at the site. Disposal of hazardous material, i.e. syringes and 
needles must conform to applicable laws and regulations. The study products must not be used 
outside the study. 
6.4
Treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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7. PERFORMANCE ASSESSMENTS
7.1
General information
The methods for collecting performance data include assessment 
 
, and photography (Section 7.4). 
 
  
 
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To avoid inter-observer variability, every effort should be made to ensure that preferably the 
same individual who made the initial baseline determinations completes all corresponding 
follow-up evaluations.
7.2
 a validated photograph-based outcome instrument that is designed specifically for 
quantifying facial folds (Table 3). Scoring of fold severity is based on visual assessment of the 
length and apparent depth of the NLF at a certain time-point and the result is not based on a 
comparison to the baseline or pre-treatment appearance. Each score 
 is exemplified 
by a photograph of NLFs (Appendix 3)
Live assessments will be performed through-out the study.
The blinded evaluator will evaluate 
 to verify the wrinkle severity inclusion criteria before 
the initial treatment. The 
 will also be assessed by the blinded evaluator at each follow-up 
visit for performance assessment. At the Week 2 follow-up visit after the initial treatment, the 
 assessment will be used for treatment guidance, e.g., to decide if touch-up treatment 
should be performed. A clinically significant improvement is defined as ≥1 grade improvement 
 
Each NLF (right/left) will be evaluated separately, thus generating two wrinkle severity score 
results per subject. A subject should preferably be assessed by the same blinded evaluator 
throughout the entire study.
When treatment is administered at the same visit as the 
 assessment, it is important to 
asses wrinkle severity prior to injection. 
 
  
 
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.
7.4
Photography
Photographs will be taken of each subject pre-treatment at visits when treatment is performed 
and at each follow-up visit. The photographs will be used to document condition at baseline, for 
 evaluation and to document AEs in the treated area. Note that no covering make-up should 
be used on the photographs. 
The Investigator and other study site personnel designated to take photographs shall be 
thoroughly trained in the equipment and techniques before study start. The same photographic 
equipment and standardized setting must be used at each visit (e.g., distance, light, facial position 
and expression). For further details, please see the instruction of image procedures in the photo 
user guide
All photos should be taken from a straight frontal view with full face frame. The subject shall 
have a neutral facial expression.
 
  
 
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Each photograph shall be labeled with:
-
Study number (43FE1630)
-
Subject number
-
Visit number 
-
Date
In order to maintain confidentiality, the photographs must not include any information that may 
reveal the subject’s identity. 
8. Safety Assessments
8.1
Pre-defined, expected, post-treatment events
The subject shall evaluate pre-defined, expected, post-treatment events in a 14-day diary, starting 
on the day of treatment. The presence and maximum intensity of pre-defined expected post-
treatment events, i.e. bruising, redness, swelling, pain, tenderness, and itching shall be assessed 
for each treated area individually (Table 5). AEs that have not been pre-defined as expected post-
treatment events in the diary may also be recorded in the diary.
 
8.2
Laboratory assessments
No laboratory assessments are performed.
8.3
Adverse events
8.3.1
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 persons7, whether or 
not related to the study product. 
This definition includes:
a) events related to the investigational product or the reference product
b) events related to the procedures involved
                                                
7 For users or other persons, this definition is restricted to events related to the investigational product.
 
  
 
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8.3.2
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-threatening8 illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalisation9, 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 8.3.4).
8.3.3
Recording instructions
 
 
 
 
 
 
 
                                                
8 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).
9 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: ISO 14155:2011).
 
  
 
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8.3.3.1
Intensity
Intensity will be recorded for each reported AE. The following definitions of intensity are to be 
used:
Mild:
Awareness of symptoms or signs, but easily tolerated (acceptable)
Moderate:
Enough discomfort to interfere with usual activity (disturbing)
Severe:
Incapacity to work or to do usual activity (unacceptable)
If the intensity changes within one day, the maximum intensity of the AE during that day shall 
be recorded.
8.3.3.2
Causal relationship and seriousness
Each AE, serious as well as non-serious, shall be assessed by the Investigator for causal 
relationship with the study product and its use (the injection procedure) and for seriousness (Yes
or No) of the event. 
A two-point scale (Yes or No response) shall be used for the causality assessments. The 
Investigators shall be asked to indicate a response to each of the following questions in the CRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?”, and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product injection procedure?”
If any of these questions is answered Yes, the AE is considered related.
Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in order to 
fulfil regulatory requirements. 
8.3.4
Reporting of adverse events 
 
8.3.5
Reporting of serious adverse events
 
 
 
 
  
 
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8.3.6
Follow-up of unresolved events ongoing at termination of the study
 
 
 
  
 
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8.3.7
Reporting and follow-up of events occurring after subject termination of the study
 
 
 
 
 
 
 
 
 
8.3.8
Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy during the study period the subject must be withdrawn from any 
following study treatment, but should continue to be followed for safety within the study and the 
outcome of pregnancy must be reported even if the delivery occurs after study completion.
 
 
 
 
 
 
 
8.4
Device deficiencies
8.4.1
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, safety10, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
8.4.2
Recording instructions
 
 
 
 
 
                                                
10 Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
 
  
 
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8.4.3
Reporting of device deficiencies
 
 
 
 
9. Data Handling and Management 
9.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to enter 
clinical data information into a database, efficiently and avoiding errors. The data management 
routine includes procedures for handling CRFs, database set-up and management, data entry and 
verification, data validation, and documentation of the performed activities including 
information of discrepancies in the process. The data management process will be described in 
detail in the data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the CSP
and the CRF. 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 CRFs and entered in the 
database is as correct and complete as possible, the clinical database will be locked. Study data 
will be transferred to SAS datasets which thereafter will be write-protected. Statistical analyses 
will be generated in SAS using data from the locked datasets.
 
  
 
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9.2
Paper case report forms
A CRF is required and shall be completed for each screened (screening visit CRF) and included 
subject (CRF sections for subsequent completed visits). The completed original CRFs are 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. 
All original CRFs shall be kept in the Sponsor file. A copy of all CRFs shall be kept as a part of 
the Investigator file.
Any delegation of completion/entering of data shall be specified in a signature and delegation 
log. All information recorded by the Investigator (or delegated person) in the CRFs shall be in 
English. The CRFs must be signed and dated by the Investigator, who, by signing, takes 
responsibility for the accuracy, completeness and legibility of the data reported to the Sponsor in 
the CRFs. Forms to be completed by the subject, i.e. subject diary, shall be translated into local 
language.
The name and address of the subjects must not be registered in the CRFs or in the database. The 
subjects’ identity must always remain confidential.
9.2.1
Correction of recorded data
Correction in the original CRF at site shall be made by crossing a single line through the 
incorrect data, leaving the wrong data clearly visible. The accurate data shall be recorded next to 
the inaccurate data and must be dated and signed (and explained if necessary). Correction fluid 
must not be used. 
During the monitoring the monitor shall collect the original CRF at the study sites and leave a 
copy as a part of the Investigator file. Discrepant data identified after the original CRF has left 
the clinic is generally compiled in a query report generated in connection with data entry and 
printed from the database. Alternatively, a data clarification form (DCF) may be used e.g. when 
discrepant data is identified at the site. The query report/DCF shall state the question or data to 
be changed together with the correct data. Each query report/DCF shall be dated and signed by 
the Investigator. The original query report/DCF shall be handled as the original CRF and a copy 
of the query report/DCF shall be retained together with the copies of the CRF as a part of the 
Investigator file. 
During data entry from the original CRF page the Sponsor may make corrections in the data in 
the clinical database if the corrections qualify as self-evident. A self-evident change (SEC) is 
defined as a change or correction made to discrepant data without requiring prior 
query/documentation from the study site. Self-evident changes permit the Sponsor to update or 
accept reported values in the clinical database according to agree upon data handling procedures. 
A summary of all such changes in the clinical database will be printed and sent to the PI at the 
end of the study for signature. The original SEC report shall be handled as the original CRF and 
be returned to the Sponsor and a copy of the report shall be retained together with the copies of 
the CRF in the Investigator file. 
9.3
Source documents
The CRF 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.
 
  
 
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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 
CRF for each subject for whom signed informed consent has been collected. All supportive 
documentation submitted with the CRF, 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.
9.4
Record keeping and access to source data
The PI/Institution shall permit study-related monitoring, audits, IEC review, and RA inspections 
and shall provide direct access to the source data/medical record including the identity of all 
participating subjects (sufficient information to link records, i.e. CRF, diaries, medical records, 
original signed informed consent forms and detailed records of study product accountability). 
The records shall be retained by the PI as required by local legislation and international 
guidelines. Any transfer of responsibility for storage of the records shall be documented and the 
Sponsor shall be informed in writing.
The Sponsor shall verify that each subject has consented in writing to direct access to the 
original medical record/source data (by the use of written subject information and signed 
informed consent). The data recorded in the CRFs 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 CRF serves as the source. Such 
data only need to be recorded in the CRF and are typically associated with study-specific 
procedures and not with normal clinical care practice. For this type of study data the Investigator 
would not be expected to duplicate the information into the medical record. 
9.5
Document and data retention
All records pertaining to the conduct of the study, including signed CRFs, informed consent 
forms, study product accountability records, source documents, and other study documentation
must be retained for 15 years after study completion or longer if required by national legislation. 
Sponsor will inform the site(s) as to when these documents no longer needs to be retained. 
Measures shall be taken to prevent accidental or premature destruction of these documents (e.g. 
protection against damage and unauthorised access, preferably by storage in a fire-proof 
cabinet). Refer to the CTA.
It is the PI’s responsibility to inform the Sponsor in writing if the Investigator file is moved or if 
the responsibility for the documents is transferred to someone else.
10. Statistical Methods
10.1 General
 
 
 
 
 
  
 
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10.2 Analysis populations
The following populations will be defined:

Safety

Full Analysis Set (FAS)
 

Per Protocol (PP)
 
The FAS population is the primary population for all performance analyses. If there are any CSP 
deviations considered to have a substantial impact on the performance outcome at the 6 months 
follow-up visit, a PP population excluding those subjects will be defined. A detailed list 
containing such deviations will be included in the SAP. Safety analysis is performed based on 
the safety population set.
10.3 Demographics, baseline assessments, and subject characteristics
Demographic data, baseline assessments and subject characteristics will be presented using 
descriptive statistics.
 
 
 
 
 
 
 
 
 
  
 
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10.6 Handling of missing data
No imputation of missing data will be performed.
10.7 Interim analysis
Not applicable.
10.8 Withdrawals and deviations
All withdrawn subjects will be listed individually, including at least subject number, date and 
reason for withdrawal, and last visit performed.
Deviations from the statistical analysis plan (SAP) will be documented in the Clinical Study 
Report.
10.9 Sample size
 
 
11. Protection of personal data
The study shall include collection and processing of personal data as specified in Directive 95/46
EC on the protection of individuals with regard to the processing of personal data and on the free 
movement of such data. For the purposes of the study, Sponsor will be considered the data 
controller, and Institution and PI will both be considered data processors.
All processing of personal data must be carried out in accordance with national legislation 
concerning the protection of personal data. The Institution and the PI are responsible for 
complying with all requirements pursuant to national legislation in the country in which the 
 
  
 
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Institution and the PI are located. The Sponsor will ensure that all requirements are complied 
with for data processing, which is carried out in Sweden by the Sponsor.
The informed consent form shall contain information about what personal data to be collected in 
the study and that this will be kept confidential. The provided information shall be sufficient to
enable all subjects to give their consent not only to the participation in the study, but also to the 
processing of personal data. Such information includes information regarding the purposes of the 
collecting, processing, data transfer to countries not having same high level of security for 
processing of personal data than Sweden and EU, and the length of time during which personal 
data will be stored. The subject shall have the right of access to stored personal data, and the 
right to correction of incorrect information. If a subject decides to terminate the study 
prematurely, data collected before withdraw of consent will be used in the evaluation of the 
study, however no new data may be collected. Authorised representatives from the Sponsor, 
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 CRF. Data and information shall be handled strictly confidential.
12. Quality Control and Quality Assurance
12.1 Quality control
On-site monitoring of the study will be arranged by the Sponsor according to GCP guidelines to 
verify that the rights and well-being of the subjects are protected, the reported data are accurate, 
complete, verifiable from source documents, and that the conduct of the study complies with the 
approved CSP, subsequent amendment(s), GCP and the applicable regulatory requirements. 
12.2 Quality assurance
The study site may be subject to quality assurance audit by the Sponsor as well as inspection by 
appropriate RA. It is important that the PI and other relevant study site personnel are available 
during the monitoring visits, possible audits, and inspections, and that sufficient time is devoted 
to the monitoring process.
Each participating member of the study site team shall provide a curriculum vitae (CV) or 
equivalent that demonstrates their qualifications to conduct the study. The CV shall give name, 
date of birth, address and place of work, and shall show the training, appointments and, for the 
PI, any other information that will confirm the suitability of the PI to be responsible for the 
study. 
It is the responsibility of the PI to ensure that all personnel involved in the study are fully 
informed of all relevant aspects of the study, including detailed knowledge of and training in all 
procedures to be followed. All Investigators and other responsible persons shall be listed 
together with their function in the study on the signature and delegation log.
12.3 Changes to the clinical study protocol
12.3.1 Amendments
The PI and other site personnel involved in the study must not implement any changes to the 
CSP without agreement with the Sponsor and prior review and documented approval from the 
IEC 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 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.
 
  
 
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12.3.2 Deviations
The PI is not allowed to deviate from the CSP. However, under emergency circumstances, 
deviations from the CSP to protect the rights, safety and well-being of the subjects may proceed 
without prior approval of the Sponsor and the IEC 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. 
13. Financing, Indemnification, and Insurance
The CTA outlines the compensation and payment terms of the study. The CTA must be signed 
before the first subject is screened in the study. If there are differences between the CTA and the 
CSP regarding certain rights and obligations, the CTA is the prevailing document. The Sponsor’s
obligations in this clinical study are covered by Galderma’s global general liability program. An
insurance certificate will be provided upon request. The Institution/PI is obligated to maintain 
insurance coverage for their obligations in the clinical study according to the CTA.
14. Publication Policy
The PI’s, Institution’s, and the Sponsor’s obligations regarding intellectual property rights,
confidentiality, and publications are described in detail in the CTA.
The results of this study could be submitted to a medical journal for publication of the results. 
Everyone who is to be listed as an author of the results 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 resolved11. 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 the 
Sponsor to take primary responsibility for the overall work as primary author.
15. Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IEC or RA, or if it is 
judged that the subjects are subjected to unreasonable risks, or for valid scientific or 
administrative reasons.
                                                
11 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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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, the Sponsor will provide information on the handling of 
currently enrolled subjects who have not completed the study.
 
  
 
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16. Appendices
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 
 
  
 
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responsibility for the protection of research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given consent.
10.
Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration.
11.
Medical research should be conducted in a manner that minimises possible harm to the environment.
12.
Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional.
13.
Groups that are underrepresented in medical research should be provided appropriate access to participation 
in research.
14.
Physicians who combine medical research with medical care should involve their patients in research only to 
the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has 
good reason to believe that participation in the research study will not adversely affect the health of the patients who 
serve as research subjects.
15.
Appropriate compensation and treatment for subjects who are harmed as a result of participating in research 
must be ensured.
Risks, Burdens and Benefits
16.
In medical practice and in medical research, most interventions involve risks and burdens.
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects.
17.
All medical research involving human subjects must be preceded by careful assessment of predictable risks 
and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them 
and to other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the researcher.
18.
Physicians may not be involved in a research study involving human subjects unless they are confident that 
the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19.
Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm.
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
 
  
 
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21.
Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.
22.
The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.
Research Ethics Committees
23.
The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its functioning, 
must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in which the research is to be 
performed as well as applicable international norms and standards but these must not be allowed to reduce or 
eliminate any of the protections for research subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to the 
protocol may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the study’s findings and 
conclusions.
Privacy and Confidentiality
24.
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information.
Informed Consent
25.
Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable 
of giving informed consent may be enrolled in a research study unless he or she freely agrees.
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.
 
  
 
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27.
When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In 
such situations the informed consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship.
28.
For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a research 
study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden.
29.
When a potential research subject who is deemed incapable of giving informed consent is able to give assent 
to decisions about participation in research, the physician must seek that assent in addition to the consent of the 
legally authorised representative. The potential subject’s dissent should be respected.
30.
Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent is 
a necessary characteristic of the research group. In such circumstances the physician must seek informed consent 
from the legally authorised representative. If no such representative is available and if the research cannot be 
delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects 
with a condition that renders them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon 
as possible from the subject or a legally authorised representative.
31.
The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never 
adversely affect the patient-physician relationship.
32.
For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage 
and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for 
such research. In such situations the research may be done only after consideration and approval of a research ethics 
committee.
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
 
  
 
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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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SIGNATURES PAGE
 
  
 
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