A Randomized, Evaluator-blinded, Parallel Group, No-treatment Controlled, Multi-center Study to Evaluate the Safety and Effectiveness of Restylane-L® for Correction of Infraorbital Hollows
Phase: NA
Conditions: Infraorbital Hollows
Sponsor: Galderma R&D

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A randomized, evaluator-blinded, parallel group, no-treatment controlled, 
multi-center study to evaluate the safety and effectiveness of Restylane-L®
for correction of Infraorbital Hollows
Study products:
Restylane-L
Clinical trial number (CTN):
43USTT1904
Sponsor:
Q-Med AB, a Galderma affiliate.
Seminariegatan 21
SE-752 28 Uppsala, Sweden
Telephone:
+46 18 474 90 00
Facsimile:
+46 18 474 90 01
Confidentiality Statement
This study protocol contains confidential information belonging to Q-Med AB, a Galderma 
affiliate. Except as may be otherwise agreed to in writing, by accepting or reviewing these 
materials, you agree to hold such information in confidence and neither disclose it to any 
third parties (except where required by applicable law) nor use it for any other purpose than 
in relation to the clinical study described herein.
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Investigators and Study Administrative Structure
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.
Sponsor:
Q-Med AB
Seminariegatan 21
SE-752 28 Uppsala, Sweden
Telephone: +46 18 474 90 00
Galderma Research and Development, LLC
14501 N. Freeway
Fort Worth, Texas 76177
Telephone: 817-961-5000
Senior Medical Expert:
:
Sponsor’s Clinical Project 
Manager:
Sponsor’s Statistician:
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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.
, Galderma R&D, LLC
Senior Medical Expert, Q-Med AB
Statistician, Q-Med AB
Clinical Project Manager, Galderma R&D, LLC
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Signed Agreement of the Clinical Study Protocol
CTN:
43USTT1904
Title of the CSP:
A randomized, evaluator-blinded, parallel group, no-treatment 
controlled, multi-center study to evaluate the safety and effectiveness 
of Restylane-L® for correction of Infraorbital Hollows
We, the undersigned, have read and understand the CSP specified above, and agree on the 
contents. The CSP, the clinical trial agreement (CTA) and the additional information given in 
the Instructions for use (IFU) and Report of Prior Investigations (ROPI) 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, evaluator-blinded, parallel group, no-treatment controlled, multi-
center study to evaluate the safety and effectiveness of Restylane-L® for 
correction of Infraorbital Hollows
Clinical Trial Number:
43USTT1904
Study population:
Subjects over 21 years of age with moderate or severe Infraorbital Hollows and 
with the intent to undergo correction of both infraorbital hollows.
Countries involved:
United States
Number of sites:
Approximately 18 sites: approximately half of the sites using needle for injection 
and the other sites using cannula for injection.
Number of subjects:
Approximately 329 subjects will be included (
) to treatment (using needle or 
cannula) or to no treatment group.
Approximately 9 sites will be treating subjects using needle and approximately 
9 sites will be treating subjects using cannula.
Within each site subjects will be randomized to treatment versus no treatment.
At least 36 subjects will be Fitzpatrick skin type (FST) IV - VI, with at least 18
of those subjects with FST V – VI. The aim is for equal distribution of subjects 
for the above referred Fitzpatrick skin types between sites using needle versus 
cannula.
Study Design:
This is a prospective, randomized, evaluator-blinded, no-treatment controlled, 
parallel group, multi-center US study. 
In the treatment group approximately 146 subjects will get injections using 
needle and approximately 136 subjects using cannula.
Approximately 47 subjects will be randomized to no-treatment at baseline.
Effectiveness and safety data will be collected for 12 months following the first 
injection. 
At the month 12 visit, the no-treatment comparator subjects will be offered an 
optional Restylane-L® treatment. The subjects who received Restylane-L at the 
baseline visit will also be offered an optional additional treatment if optimal 
aesthetic improvement is not maintained (as determined by the Treating 
Investigator and subject). 
For subjects receiving optional treatment at month 12, the effectiveness and 
safety data will be collected for another 6 months. A subject will be involved in 
the study for up to 19 months, including 30-day screening period and 6-month 
follow-up after optional treatment at month 12. 
The study visits are illustrated in Figure 1.
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Primary Effectiveness 
Objective and Endpoint:
The primary objective of the study is to evaluate the effectiveness of 
Restylane-L (injected using needle or cannula) versus no-treatment control in 
the correction of Infraorbital Hollows.
Endpoint: 
Responder rate based on the Blinded Evaluators’ live assessment of the 
Galderma Infraorbital Hollows Scale (GIHS), at 3 months after baseline.
A responder is defined as a subject with at least 1 point improvement from 
baseline, on both sides of the face concurrently.
Secondary Effectiveness
Objective(s) and 
Endpoint(s):
To evaluate the effectiveness of Restylane-L (injected using needle or cannula) 
versus no-treatment control in the correction of Infraorbital Hollows.
Endpoints:
1.
Responder rate based on the Blinded Evaluators’ live assessment of 
the GIHS, at 6, 9, and 12 months after baseline and at 3 and 6 months 
after optional treatment.
A responder is defined as a subject with at least 1 point improvement 
from baseline, on both sides of the face concurrently, at each of the 
timepoints.
2.
Proportion of subjects having at least “Improved” on the Global 
Aesthetic Improvement Scale (GAIS), as assessed live by the Subject 
and Treating Investigator separately at all follow-up visits after 
baseline. 
Safety Objectives and 
Endpoints:
To evaluate Adverse Events (AEs) at all visits, and pre-defined, expected post-
treatment events reported during the first 28 days after each treatment as 
recorded in the subject diary.
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Clinical Study Duration:
The planned clinical study duration (from FSFV to LSLV) is approximately 23
months. One month is defined as 4 weeks in the study.
The planned duration of recruitment (from FSFV to LSFV) is approximately 4
months.
Duration of Subject 
Participation:
Clinical study participation for each subject is approximately 19 months,
including 30 days screening period and 6 months follow-up after optional 
treatment at month 12.
Inclusion criteria: 
The subjects must meet all the following criteria to be eligible for the study:
1.
Subject is willing to comply with the requirements of the study 
including being photographed, following post-treatment care 
instructions, completing the diary, attending all study visits and 
providing a signed written informed consent.
2.
Moderate or severe (Grade 2 or 3 on the GIHS) infraorbital hollows 
with no more than one grade difference between the left and right side 
at baseline as assessed by the blinded evaluator.
3.
Visual function assessment tests without findings according to treating 
investigator.
4.
Males or non-pregnant, non-breastfeeding females, over the age of 21.
5.
Subject is willing to abstain from any other facial plastic surgical or 
cosmetic procedure(s) during the duration of the study (e.g. laser or 
chemical resurfacing, needling, facelift, radiofrequency).
6.
Intent to undergo correction of both orbital hollows.
7.
If the subject is a female of childbearing potential, she agrees to use an 
acceptable form of effective birth control for the duration of the study 
and is willing to take a urine pregnancy test (UPT) at the 
screening/enrollment visit and prior to treatment. Acceptable forms of 
effective birth control include:
a)
Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm 
or 
cervical 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository.
b)
Bilateral tubal ligation.
c)
Combined oral contraceptives (estrogens and progesterone), 
implanted or injectable contraceptives on a stable dose for at least 
28 days prior to Day 1.
d)
Hormonal or copper intra uterine device (IUD) inserted at least 28 
days prior to Day 1.
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e)
Vasectomized partner (in monogamous relationship) for at least 3 
months prior to screening.
f)
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).
8.
Negative urine pregnancy test for females of childbearing potential at 
screening and all injection visits.
Exclusion criteria:
The presence of any of the following exclusion criteria excluded a subject from 
enrollment in the study:
1.
Known/previous allergy or hypersensitivity to any injectable 
hyaluronic acid (HA) gel or to gram positive bacterial proteins.
2.
Known/previous allergy or hypersensitivity to local anesthetics, e.g. 
lidocaine or other amide-type anesthetics.
3.
Active or a history of recurrent or chronic infraorbital edema or rosacea 
or uncontrolled severe seasonal allergies.
4.
Previous or present multiple allergies or severe allergies, such as 
manifested by anaphylaxis or angioedema, or family history of these 
conditions.
5.
Previous superficial facial dermal therapies (i.e. microderm abrasion, 
superficial chemical peels) to the periorbital or malar region within the 
past 6 months or plans to receive such treatment during participation in 
the study.
6.
Previous deep facial dermal therapies (i.e. facial ablative or fractional 
laser, deep chemical peels, non-invasive skin-tightening [e.g. 
Ultherapy, Thermage]) to the periorbital or malar region within the past 
12 months or plans to receive such treatment during participation in the 
study.
7.
Prior lower-eyelid surgery, including orbital or midface surgery, or has 
a permanent implant or fat grafting or fat injections in the mid-facial 
region or tattoo (including microblading of eyebrow or eyeliner) that 
could interfere with effectiveness assessments or plans to have it during 
the study. 
8.
Lower lid retraction or exophthalmos.
9.
Pigmentation abnormalities around the eyes and/or dark circles under 
the eyes due to pigmentation changes and not from infraorbital hollow 
shadowing.
10. Ectropium, entropion, or trichiasis of the lower eyelid or eye diseases 
that lead to reddening and tendency of watering of the eye.
11. Has gained or lost ≥2 body mass index (BMI) units within the 
previous 90 days or has the intention to gain or lose a significant amount 
of weight during the study.
12. Received lower periorbital and/or malar region treatments with any 
absorbable or temporary fillers such as porcine-based collagen fillers, 
HA products, RADIESSE®, poly L-lactic acid (PLLA) or received 
mesotherapy treatment to the area within the past 24 months or plans to 
receive such treatments during participation in the study.
13. Received neurotoxin treatment to the periorbital region, Forehead Lines 
(FL), Lateral Canthal Lines (LCL) or glabella, within the past 6 months 
or plans to receive such treatment during participation in the study.
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14. Any current or history of uncontrolled retinal disease or detached retina 
or any other condition with the potential to cause a decline of visual 
acuity (e.g. uncontrolled diabetes).
15. Tendency to accumulate eyelid edema, has developed festoons, or has 
large and/or herniating infraorbital fat pads.
16. Skin or fat atrophy, other than age-related, in the mid-facial and/or 
perio-orbicular regions or has been diagnosed with a connective tissue 
disorder.
17. Skin laxity or sun damage beyond typical for the subject’s age.
18. A history of recurrent herpetic eruption in the mid-facial region, 
excluding the lips, within 12 months.
19. Subjects typically experiencing occasional migraines (≥ 8 per year).
20. History of radiation damage, cancerous or pre-cancerous lesions (e.g. 
actinic keratosis) near the area close to be treated.
21. Scars or deformities, active skin disease, inflammation, or related 
conditions such as infection, perioral dermatitis, seborrheic dermatitis, 
eczema, rosacea, acne, psoriasis, and herpes zoster near or in the area 
to be treated.
22. Subjects with dental or oral status on visual inspection that, in the 
opinion of the Investigator, would make the subject unsuitable for 
inclusion, or Subjects with dental, oral or sinus surgery within past 12 
months prior to the treatment visit or planned surgery, including dental 
implants, tooth extractions, orthodontia, during the study period.
23. Inflammation, active or chronic (e.g. in the mouth, dentals, head and 
neck region).
24. History of or active autoimmune disease or connective tissue diseases 
such as systemic lupus erythematosus, rheumatoid arthritis, 
polymyositis, dermatomyositis, or localized or systemic scleroderma.
25. Tendency to form keloids, hypertrophic scars, or any other healing 
disorder.
26. History of bleeding disorders or treatment with anticoagulants or 
inhibitors of platelet aggregation e.g. aspirin or other non-steroid anti-
inflammatory drugs (NSAIDs), Omega-3, or vitamin E within 2 weeks 
before treatment.
27. Treatment 
with 
chemotherapy, 
immunosuppressive 
agents, 
immunomodulatory therapy (e.g., monoclonal antibodies, antiviral 
treatment for HIV or hepatitis);
systemic or topical (facial) 
corticosteroids within 3 months before treatment (inhaled corticoids are 
allowed).
28. Any prescription skin-irritating topical preparations, or pigmenting 
agents (e.g., self-tanning or bleaching agents) in the periorbital area
within the past 2 weeks.
29. Concomitant treatment with prescribed topical (facial) retinoids within 
3 months, or systemic retinoids within 6 months before treatment,or 
plan to receive such treatment during participation in the study.
30. Any medical condition that in the opinion of the Investigator would 
make the subject unsuitable for inclusion (e.g., porphyria, 
methemoglobinemia,
hemoglobinopathy, thalassemia, glucose-6-
phoshate dehydrogenase deficiency, a chronic, relapsing or hereditary 
disease that may affect the general condition or may require frequent 
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medical treatment, any abnormal screening laboratory value or ECG, or 
psychiatric disorders).
31. Women who are pregnant or breast feeding, or women of childbearing 
potential who are not practicing adequate contraception or planning to 
become pregnant during the study period.
32. Study site personnel, close relatives of the study site personnel (e.g. 
parents, children, siblings, or spouse), employees, or close relatives of 
employees at the Sponsor Company.
33. Participation in any other clinical study within 30 days before 
treatment.
Investigational product:
Restylane-L 0.5 mL syringe, co-packed 29G x ½" Thin Wall (TW) needle, or 
commercially available TSK Steriglide 25G x 1½" and TSK Steriglide 27G x 
1½" cannulas. The co-packed needle should be used as incision needle with each 
cannula. 
The sterilized gel contains 20mg/mL stabilized HA and 3 mg/mL lidocaine 
hydrochloride in a physiological buffer.
Reference therapy:
No treatment control group
Treatment regimen and 
location of treated area:
One treatment at baseline and one optional touch-up treatment at 1 month. 
Subjects who received Restylane-L at the baseline visit will be offered an 
optional additional treatment at month 12 if optimal aesthetic improvement was 
not maintained (as determined by the Treating Investigator and subject). The no-
treatment comparator subjects will also be offered an optional Restylane-L 
treatment at 12 months.
Detailed information regarding the injection procedure, pre- and post-treatment 
care and patients instructions are provided in the IFU. Restylane-L will be placed 
at the junction of the lower eyelid and midface along the inferior orbital rim in 
the supraperiosteal plane. The injection technique is at the discretion of the 
Investigator. For needle serial puncture is recommended and for cannula fanning 
technique is recommended. Slow injection is recommended and overcorrection 
should be avoided.
Approximately half of the sites will be selected to use needle for injection and 
the other sites will use cannula.
Allowed maximum injection volume for initial injection, touch-up, and optional 
treatment is 1,0 mL per side at each treatment session. 
Prior to injection, Vision Function Assessment tests including the Visual Snellen 
visual acuity test, Extraocular muscle function test and Confrontation visual 
field, will be assessed by the treating investigator.
Effectiveness
Assessment(s):

Blinded evaluator GIHS

Treating Investigator GIHS

Treating Investigator GAIS 

Subject reported GAIS
Safety Assessment(s):
Adverse Event reporting: AEs will be obtained from signs and symptoms 
reported by the subject or detected during each examination.
Device deficiencies will be assessed at treatment visits.
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All incidences of visual disturbances, regardless of relationship to study product 
or seriousness, are considered Adverse Events of Special Interest (AESIs) and 
include but are not limited to the following: any change in vision, any loss of 
vision, blurry vision, double vision, pain in or around the eye, blind spot or 
shadow in the visual field, trouble moving eyes, any change in Snellen visual 
acuity including change of one line or greater.
Vision Function Assessment tests will be performed prior to and 30 minutes post 
injection of the study product.
A subject diary will be dispensed to all subjects for daily completion over the 
first 28 days after each treatment to record the following pre-identified 
symptoms: bruising, redness, pain, tenderness, lumps/bumps, itching, swelling.
Any other symptoms outside the pre-identified should also be recorded in the 
diary. The diary will also include instructions for the subject to:

Contact an eye doctor (retinal specialist or ophthalmologist) if they 
experience changes in vision (i.e. vision loss, blurriness, double vision, 
pain in or around eye, blindness, blind spots, problems moving your 
eyes), change in skin color, or crusty/scabby skin around the eyelids

Call 911 and seek immediate medical attention if signs of stroke or 
subject experience dizziness, confusion, weakness, or numbness in 
face, arms or legs, changes to consciousness or alertness, difficulty 
speaking/speech impairment, face droop
Stopping rules
Enrollment and treatment in the study will be temporarily halted if an SAE 
occurs for a vascular embolic event that leads to skin necrosis, vision loss, or 
stroke, and is determined by the Investigator to be directly or possibly related to 
the investigational device or injection procedure. The SAE will be investigated 
by the Sponsor.
Statistical Methods: 
Analysis populations:

Modified Intention-to-treat (mITT) population includes all subjects 
who are randomized and will be analyzed according to the 
randomization scheme; subjects with a GIHS month 3 assessment via 
a remote visit will be excluded from the mITT

Intention-to-treat (ITT) population will include all subjects who are 
randomized and will be analyzed according to the randomization 
scheme

Per-protocol (PP) population will include all subjects in ITT who 
complete 3 months after baseline visit without any deviations 
considered to have substantial impact on the primary effectiveness 
outcome

Safety population will include all subjects who were treated with 
Restylane-L or randomized to the control group, and will be analyzed 
according to as-treated principle
Primary effectiveness analysis:
Responder rate based on the GIHS, as assessed live by the Blinded Evaluator at 
Month 3 after baseline, will be the primary effectiveness endpoint. A responder 
will be defined as a subject with at least 1 point improvement from baseline on 
both sides of the face concurrently. For a significant result, the two-sided p-value 
of the comparison of responder rates between the treated and untreated subjects 
at Month 3, using the Cochran-Mantel-Haenszel (CMH) test stratified by 
injection tool, must be smaller than 0.05. 
The null hypothesis will be that there is no relationship between responder rate 
and treatment group (i.e. the responder rate is the same in both groups). The 
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alternative hypothesis will be that there is a relationship between responder rate 
and treatment group (i.e. the responder rate is different in the two groups).
The estimates of the responder rate in each treatment group will be presented as 
well as the difference in responder rates. Corresponding confidence intervals for 
responder rates and the difference in responder rates along with the p-value for 
the difference will also be presented.
Secondary effectiveness 
:
Responder rates (defined as at least 1 point improvement from baseline on both 
sides of the face concurrently) based on the GIHS as assessed by the Blinded 
Evaluator at month 6, 9, and 12 after baseline and at 3 and 6 months after optional 
treatment will be analyzed in the same way as the primary effectiveness 
endpoint. No correction for multiplicity will be done; p-values obtained for any 
endpoint other than the primary will only be provided for ease of interpretation 
of the results.
All other secondary effectiveness analyses will be done descriptively, as 
appropriate. 
Safety analysis will be descriptive only.
Handling of drop-outs and missing data
Number of missing values will be summarized and reported as appropriate.
For mITT analysis of the Blinded Evaluator GIHS responder rate at month 3 
after baseline (primary endpoint),
 
 Impact of missing data on the primary 
endpoint will be evaluated by performing sensitivity analysis based on the 
baseline observation carried forward (BOCF) method, and the observed cases in 
the ITT set.
All other effectiveness endpoints will be evaluated based on the observed cases 
in ITT.
Descriptive statistics of all safety data will be performed on observed cases in 
the Safety population.
Sample size
Due to the public health emergency related to the COVID-19 pandemic during 
2020, steps have been taken to ensure patient and practitioner safety in alignment 
with FDA Guidance dated May 11, 2020 (Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency). Most 
notably, in partnership with clinical sites and the IRB, optional remote 
assessment procedures for efficacy and safety endpoints has been implemented 
to ensure safety and respect localized and elective restrictions. Therefore, the 
sample size has been increased during the conduct of the study to ensure a 
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sufficient number of subjects in the mITT population used in the assessment of 
the primary effectiveness endpoint.
The study was initially planned to enroll a total sample size of approximately 
238 subjects; approximately 204 randomized to treatment with Restylane-L 
(~102 injected using needle, and ~102 injected using cannula) and 
approximately 34 randomized to no treatment.
Based on information on missing data and the number of remote visits performed 
at study sites so far, the study is now planned to enroll approximately 329
subjects; approximately 282 will be randomized to treatment with Restylane-L 
(~146 will be injected using needle, and ~136 will be injected using cannula) 
and approximately 47 will be randomized to no treatment in order to achieve the 
required number of mITT subjects in each stratum.
Previous data
Since the primary endpoint will be based on a new scale, no existing data is 
available.
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Abbreviations and Definitions of Terms
AE
AESI
Adverse Event
Adverse Events of Special Interest
Blinded evaluator
An evaluator responsible for independent evaluation of treatment 
result(s). The evaluator must not be involved in the treatment of 
the subject.
CFR
Childbearing Potential
Code of Federal Regulations
A female (including pre-menopausal subjects) capable of 
becoming pregnant; this includes women on oral, injectable, or 
mechanical contraception or women whose male partners have 
been vasectomized or are utilizing mechanical contraceptive 
devices
CMH test
Cochran-Mantel-Haenszel test
CRO
Contract research organization
CSP
Clinical Study Protocol
CTA
Clinical trial agreement
CTN
Clinical trial number
CV
Curriculum vitae
Device deficiency
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance (includes 
malfunctions, use errors, and inadequate labelling)
DMP
Data management plan
eCRF
EOS
ET
Electronic case report form
End of Study
Early termination
FDA
United States Food and Drug Administration
FL
Forehead Lines
FSFV
FST
First Subject First Visit, i.e. first subject who signs the 
informed consent form
Fitzpatrick Skin Type
G
Gauge
GAIS
Global Aesthetic Improvement Scale
GCP
Good clinical practice
GDPR
General Data Protection Regulation
GIHS
Galderma Infraorbital Hollows Scale
TW
Thin walled (needles)
HA
HIPAA
ICF
Hyaluronic acid
Health Insurance Portability and Accountability Act
Informed Consent Form
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ICH
International Conference on Harmonization
IFU
Instructions for use
Investigational product
Medical device being assessed for safety or performance in a 
study. “Investigational product” is the same as “study device”, 
“investigational device”, or “investigational medical device.”
Institution
Any public or private entity or agency or medical or dental 
facility where a clinical study is conducted.
Investigator
The Principal Investigator (PI) or other qualified person, i.e. sub-
Investigator, designated and supervised by the PI at a study site 
to perform critical study-related procedures or to make important 
study-related decisions as specified on the signature and 
delegation log
Investigator file
Essential documents relating to a clinical study as defined in 
applicable GCP guidance document and maintained by the 
Investigator.
IRB
Institutional review board
ISO
International Organization for Standardization
ITT
LCL
Intention-to-treat
Lateral Canthal Lines
LSFV
Last Subject First Visit
LSLV
Last Subject Last Visit
MedDRA
Medical Dictionary for Regulatory Activities
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
ROPI
Report of Prior Investigations, i.e. compilation of the current 
clinical and non-clinical information on the investigational 
product, relevant to the clinical study
SAE
SAP
SDV
Serious Adverse Event
Statistical Analysis Plan
Source data verification
SEC
Self-evident change
SOC
System organ class
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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
TC
Institution or site where the study is carried out
Telephone Call
Touch-up
Tx
Repeated injection to be performed after treatment, if necessary 
to achieve optimal correction 
Treatment
U-HCG
Urinary human chorionic gonadotropin
WHO
World Health Organization
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Table of Contents
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
2
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
4
SYNOPSIS
5
ABBREVIATIONS AND DEFINITIONS OF TERMS
14
LIST OF TABLES
20
LIST OF APPENDICES
20
1.
ETHICAL CONSIDERATIONS
21
1.1
Statement of ethical compliance
21
1.2
Application to institutional review board; IRB and/or regulatory authorities
21
2.
BACKGROUND INFORMATION
21
2.1
Indication and population description
21
2.2
Study Product Profile
21
2.2.1
Investigational product description
21
2.2.2
Reference product description
22
2.3
Study rationale and justification for design
22
2.4
Risks and benefits
23
3.
OBJECTIVE(S) AND ENDPOINT(S)
24
3.1
Objectives and endpoints
24
3.1.1
Primary objective and endpoint
24
3.1.2
Secondary objectives and endpoints
24
3.1.3
Safety objectives and endpoints
25
4.
DESIGN OF THE STUDY
25
4.1
General outline
25
4.2
Number of subjects
28
4.3
Duration of subject participation
28
4.4
Randomization and blinding
28
4.4.1
Randomization
28
4.4.2
Blinding
28
4.4.3
Emergency unblinding
28
4.5
Medical history
28
4.6
Prior and concomitant therapies
29
4.6.1
Definition
29
4.6.2
Recording
29
4.6.3
Authorized concomitant therapies
29
4.6.4
Prohibited concomitant therapies
29
4.7
Visits
33
4.7.1
Visit 1 a: Screening (Day -30 to Day 1)
33
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4.7.2
Visit 1b: Baseline/Day 1 (Initial Treatment)
33
4.7.3
Visit 2: Follow up 72 hour (±24 hours) telephone call after Baseline/Day 1
34
4.7.4
Visit 3: Follow up visit 14 days (± 3 days) after Baseline/Day 1
35
4.7.5
Visit 4: Follow-up visit 1 month (+ 7 days) after Baseline/Day 1/ Optional touch-up
35
4.7.6
Visit 4a: Follow-up 72 hour (± 24 hours) telephone call after optional touch-up performed
36
4.7.7
Visit 4b: Follow up visit 14 days (± 3 days) after optional touch-up performed
36
4.7.8
Visit 4c: Follow up visit 1 month (+ 7 days) after optional touch-up performed
37
4.7.9
Visits 5-7: Follow-up visit 3 months, 6 months  and 9 months (± 7 days), after Baseline/Day 1
37
4.7.10
Visit 8: Follow-up visit 12 months (± 7 days) after Day 1 / Optional treatment / End of Study (EOS) /Early 
Termination Visit (ET)
37
4.7.11
Visit 8a: Follow-up 72 hour (± 24 hours) telephone call after optional treatment
38
4.7.12
Visit 8b: Follow up visit 14 days (± 3 days) after optional touch-up performed
39
4.7.13
Visit 8c: Follow up visit 1 month (+7 days) after optional treatment
39
4.7.14
Visit 8d: Follow up visit 3 months (+7 days) after optional treatment
39
5.
SUBJECTS
40
5.1
Subject information and informed consent
40
5.2
Inclusion criteria
41
5.3
Exclusion criteria
42
5.4
Subject number
44
5.5
Withdrawal of subjects
44
6.
STUDY PRODUCTS
45
6.1
Investigational product
46
6.2
Additional products and materials
46
6.3
Labelling and storage
46
6.4
Product accountability
46
6.5
Treatment
47
6.5.1
Pre-Treatment procedure
47
6.5.2
Treatment Regimen (dose and interval)
47
6.5.3
Post-treatment care
48
6.5.4
Post-trial provisions
48
6.5.5
Treatment compliance
48
7.
EFFECTIVENESS ASSESSMENTS
48
7.1
General information
48
7.2
Galderma Infraorbital Hollows Scale (GIHS)
48
7.3
Global Aesthetic Improvement Scale (GAIS)
49
50
50
50
7.7
Photography
50
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50
8.
SAFETY ASSESSMENTS
50
8.1
Assessment of AEs by direct question to subject and evaluation of subject
50
8.1.1
Adverse Events of special interest
51
8.2
Vision function assessment
51
8.2.1
Snellen visual acuity test
51
8.2.2
Extraocular muscle function test
51
8.2.3
Confrontation visual field
52
8.3
Subject Diary Data
52
8.4
Laboratory assessments
52
8.5
Adverse Events
53
8.5.1
Definition of an Adverse Event
53
8.5.2
Definition of a Serious Adverse Event
53
8.5.3
Definition of unanticipated adverse effect
53
8.5.4
Recording instructions
53
8.5.5
Reporting of Adverse Events
55
8.5.6
Reporting of Adverse Events of special interest (AESIs)
55
8.5.7
Reporting of serious Adverse Events
56
8.5.8
Stopping Rule
57
8.5.9
Reporting of unanticipated adverse device effects
57
8.5.10
Follow-up of unresolved events ongoing at termination of the study
57
8.5.11
Reporting and follow-up of events occurring after subject termination of the study
57
8.5.12
Pregnancy
57
8.5.13
Anticipated Adverse Events
58
8.6
Device deficiencies
58
8.6.1
Definition of a device deficiency
58
8.6.2
Recording instructions
58
8.6.3
Reporting of device deficiencies
58
9.
DATA HANDLING AND MANAGEMENT
59
9.1
Data management
59
9.2
Electronic case report forms
59
9.2.1
Data entry
60
9.2.2
The query process
60
9.2.3
User identification
60
9.2.4
Audit trail
60
9.3
Source documents
60
9.4
Record keeping and access to source data
61
9.5
Document and data retention
61
10.
STATISTICAL METHODS
61
10.1
General
61
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10.2
Analysis populations
62
10.3
Demographics, baseline assessments, and subject characteristics
62
10.4
Effectiveness analysis
62
10.4.1
Primary effectiveness analysis:
62
10.4.2
Secondary effectiveness analysis:
63
10.5
Safety analysis
63
64
10.6.1
Effectiveness
64
10.6.2
Safety
64
10.7
Handling of drop-outs and missing data
64
10.8
Interim analysis
65
10.9
Data monitoring committee
65
10.10
Withdrawals and deviations
65
10.11
Sample size
65
11.
PROTECTION OF PERSONAL DATA
66
12.
QUALITY CONTROL AND QUALITY ASSURANCE
66
12.1
Quality control
66
12.2
Quality assurance
67
12.3
Changes to the clinical study protocol
67
13.
FINANCING, INDEMNIFICATION, AND INSURANCE
67
14.
PUBLICATION POLICY
67
15.
SUSPENSION OR PREMATURE TERMINATION
68
16.
REFERENCES
69
List of Tables
Table 1: Schedule of events.....................................................................................................31
Table 2: Fitzpatrick Skin Types (FST) ....................................................................................33
Table 3: Global Aesthetic Improvement Scale (GAIS) ...........................................................49
List of Appendices
Appendix 1
Declaration of Helsinki....................................................................................70
Appendix 2
Galderma Infraorbital Hollows Scale (GIHS) .................................................75
....................................76
....................................77
Appendix 5
Summary of changes to the clinical study protocol.........................................78
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1. Ethical Considerations
Statement of ethical compliance
The study shall be conducted in compliance with the clinical trial agreement (CTA), the 
Clinical Study Protocol (CSP), good clinical practice (GCP), and applicable regional or 
national regulations. The study shall be conducted in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki (1964, and its amendments in force at the 
initiation of the study) insofar as such revisions are consistent with US treaty obligations and 
in accordance with US law.
The study shall follow the international standard for clinical study of medical devices for 
human subjects, ISO14155:2011 as applicable for US regulations and the International 
Conference on Harmonization (ICH) guideline for GCP (E6) as applicable for medical device.
Application to institutional review board; IRB and/or regulatory authorities
It is the responsibility of the Principal Investigator (PI) to obtain approval of the 
CSP/CSP amendment(s) from the institutional review board (IRB). The study shall not begin 
until the required favorable opinion from the IRB has been obtained. The PI shall file all 
correspondence with the IRB in the Investigator file and copies of IRB approvals shall be 
forwarded to the Sponsor. Any additional requirements imposed by the IRB or regulatory 
authorities (RA) shall be followed. 
The study requires application for approval from the US Food and Drug Administration (FDA). 
The study will not be started until the Sponsor has received written approval or until the
statutory waiting period from the appropriate authority has elapsed. 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
Indication and population description
Restylane-L is in this study intended for correction of infraorbital hollows in subjects over the 
age of 21.
The study will include at least 36 subjects with Fitzpatrick Skin Types (FST) IV-VI with at 
least 18 of those subjects with FST V-VI.
Study Product Profile
Investigational product description
The currently marketed Restylane-L 0,5 mL syringes will be used in the study. For injection 
either needle or cannula will be used. 
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2.2.1.2
Clinical documentation
Please refer to the Restylane-L study-specific Instructions for Use (IFU) which summarizes the 
Adverse Events (AEs) experienced with HA injections along with precautions that can 
minimize these potential complications.
For intravascular complications or embolic event, the treating physician should provide prompt 
medical attention and follow relevant clinical practice guidelines 1 for handling these 
symptoms. The treating physician should also review the Intravascular Treatment Protocol
provided separately in the Investigator file, as a supportive tool. 
Please refer to the study ROPI for a description of performed clinical studies and clinical data 
from literature with Restylane-L in the periorbital area.
Reference product description
Not applicable. The reference in this study is a no-treatment control. 
Study rationale and justification for design
A result of the aging process is development of noticeable concave deformity in the area under 
the eyes, resulting in a tired and noticeable aged appearance of the face. Although many 
anatomical and physiological contributing factors must be considered for the cause of 
infraorbital hollowing, subjects with an inherent level of volume loss may benefit from filler 
augmentation treatment of the infraorbital hollows.
The rationale of performing this study is to obtain evidence of safety and effectiveness of 
Restylane-L for correction of infraorbital hollows to support a future US marketing application. 
The Galderma Infraorbital Hollows Scale (GIHS) was created to allow for a quantitative 
assessment of the infraorbital hollow area in clinical trials. In order for the GIHS to be 
considered a reliable and valid tool for assessing aesthetic improvements, live subjects were 
rated by an independent panel review at two sessions separated at least two weeks apart in order 
to assess the intra- and inter-rater reliability. Based on the validation results GIHS was 
determined to be fit-for-purpose to be used in the clinical setting to detect changes to treatment 
by improving the level of hollowing as a result of volume correction.
The purpose of this study is to evaluate the effectiveness of Restylane-L in the treatment for 
correction of infraorbital hollows by demonstrating superiority in responder rates (defined as 
at least 1 point improvement from baseline on the Galderma Infraorbital Hollows Scale
(GIHS)) relative to no treatment. No treatment has been chosen as control as there are no other 
HA products approved in the US for the same intended use.
                                                
1 Alam M, Gladstone H, Kramer EM, et al.  ASDS guidelines of care: injectable fillers.  Dermatol Surg.  2008; 
34 (suppl 1): S115-S148.
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The study will also assure that Restylane-L used in the infraorbital hollows will not impact
the safety of the product in an ethnically diverse population by including at least 36
subjects with FST IV, V, or VI with at least 18 of those subjects with FST V-VI.
Risks and benefits
Restylane-L has been proven safe and well tolerated in animal studies as well as in human 
clinical trials, with high levels of aesthetic improvement and sustained optimal correction of 
moderate to severe, deep facial wrinkles and fold such as nasolabial folds and for lip 
augmentation in patients over the age of 21 . The safety or effectiveness of Restylane and 
Restylane-L for the treatment of anatomic regions nasolabial folds and lips have been 
established in controlled clinical studies.
The primary benefit of the study is a perceived improvement of the treated area. Infraorbital 
Hollows is a major concern for many individuals seeking periorbital rejuvenation. Prominent 
Infraorbital Hollows gives a fatigued appearance despite adequate rest, and is refractory to 
attempts at cosmetic concealment. Restylane-L is less invasive than surgical options and offers 
less down time from swelling and bruising, adding volume in the Infraorbital Hollows to 
improve the patient satisfaction and restoring the harmony of the periorbital area.
As all other injectable medical devices, Restylane-L has the potential to cause complications. 
Most events are related to the injection volume and injection technique, though some could be 
associated with properties or constitutes of the gel itself. After the injection with Restylane-L, 
some common injection-related reactions might occur, such as swelling, erythema, tenderness, 
pain, bruising, and itching. These reactions consist mainly of short-term minor or moderate 
symptoms starting early after treatment that generally resolve spontaneously within one to two 
weeks after injection. The intensity and duration of these events are usually considered 
tolerable by a majority of subjects. 
Although most AEs occur within days to weeks following the implant procedure, some AEs 
such as swelling and serious infections/abscess have been reported several weeks to months 
after the injection.  Vascular occlusion resulting in ischemia/necrosis and visual disturbances 
including blindness have been reported following injection of any soft tissue filler in the face 
especially in the nose, glabella, periorbital areas, nasolabial folds and cheek, with a time to 
onset ranging from immediate to a few weeks following injection. Vascular compromise may 
occur due to an inadvertent intravascular injection or as a result of vascular compression 
associated with implantation of any injectable product. This may manifest as blanching, 
discoloration, necrosis or ulceration at the implant site or in the area supplied by the blood 
vessels affected; or rarely as ischemic events in other organs due to embolisation. Isolated rare 
cases of ischemic events affecting the eye (leading to visual loss) and the brain (resulting in 
cerebral infarction) following facial aesthetic treatments have been reported. Reported 
treatments included anticoagulant, epinephrine, aspirin, hyaluronidase, steroid treatment, 
analgesics, antibiotics, local wound care, drainage, surgery and hyperbaric oxygen. Outcome 
of the events ranged from resolved to ongoing at the time of last contact.  In many of the events 
requiring medical intervention, the patient was injected into the highly vascularized areas of 
the glabella, nose, and periorbital area. 
According to published literature AEs are mostly described as injection site reactions minor 
such as including some degree of bruising, erythema, local swelling, contour irregularity, and 
color change. 
Post-market surveillance reporting with device location defined as Tear trough alone or in 
combination with other locations (cheek, glabella, nasolabial folds, jaw lines, temple, eye lid, 
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or oral commission) are generally in line with the overall reporting pattern for Restylane. To 
date, no unacceptable risks have been identified for Restylane-L treatment. Any potential 
concerns related to the clinical study have been assessed and the remaining risks are disclosed 
in the study specific IFU.
Lidocaine can, in rare cases, give allergic reactions, and therefore subjects with known allergy 
or hypersensitivity to local anesthetics should not be included in the study.
Additional information about reported AEs and anticipated risks are included in the product 
specific IFUs and ROPI. 
To mitigate these risks, only study Investigators qualified by education and experience, and 
who are skilled in the use of dermal fillers from their clinical practice and involvement in 
clinical research, and with a firm knowledge of the vascular anatomy and understanding of the 
depth and plane of injection as well as knowledge of the signs and symptoms and management 
of potential complications will be chosen in order to assure proper device implantation and 
management of study risk. Visual function assessments will be performed before and after gel 
injection; an Intravascular Treatment Protocol is available for reference would an intravascular 
event occur; and the subject diary includes instructions in case of severe intravascular events. 
The study protocol also defines a stopping rule, see section 8.5.8.
Based on the open-label clinical studies sponsored by the company as well as published 
literature and spontaneously reported Adverse Events from the market, it is concluded that 
there is reasonable assurance from a safety perspective for conducting an IDE clinical trial in 
the USA, using Restylane-L for injection into the infraorbital hollow (tear trough) area in 
subjects over the age of 21.
Given the anticipated low level of transient and acceptable AEs in connection with the 
injection, the protocol required safety assessments, and the training being provided on the 
injection technique, it was determined the risk-benefit assessment for use of Restylane-L for
correction of infraorbital hollows offer a clinical benefit at reasonable risk.  
3. Objective(s) and Endpoint(s)
Objectives and endpoints
Primary objective and endpoint
The primary objective of the study is to evaluate the effectiveness of Restylane-L (injected 
using needle or cannula) versus no-treatment control in the correction of Infraorbital Hollows.
Endpoint: Responder rate based on the Blinded Evaluators’ live assessment of the Galderma 
Infraorbital Hollows Scale (GIHS), at 3 months after baseline.
A responder is defined as a subject with at least 1 point improvement from baseline, on both 
sides of the face concurrently.
Secondary objectives and endpoints
The secondary objectives are to evaluate the effectiveness of Restylane-L(injected using needle 
or cannula) versus no-treatment control in the correction of Infraorbital Hollows.
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Endpoints:
1. Responder rate based on the Blinded Evaluators’ live assessment of the GIHS, at 6, 9, 
and 12 months after baseline and at 3 and 6 months after optional treatment.
A responder is defined as a subject with at least 1 point improvement from baseline, on 
both sides of the face concurrently, at each of the timepoints.
2. Proportion of subjects having at least “Improved” on the Global Aesthetic Improvement 
Scale (GAIS), as assessed live by the Subject and Treating Investigator separately at all 
follow-up visits after baseline. 
Safety objectives and endpoints
The safety objectives and endpoints are:

To evaluate AEs at all visits, and pre-defined, expected post-treatment events reported 
during the first 28 days after treatment as recorded in the subject diary.
4. Design of the Study
General outline
This is a prospective, randomized, evaluator-blinded, no-treatment controlled, parallel group, 
multi-center US study to evaluate the effectiveness and safety of Restylane-L for correction of 
Infraorbital Hollows. Approximately 329 subjects will be included (
) to treatment (using 
needle or cannula) or to no treatment group. In the treatment group approximately 146 subjects 
will get injections using needle and approximately 136 subjects using cannula. Approximately 
47 subjects will be randomized to no-treatment at baseline. The sites will be selected to use 
either needle or cannula for injection of all subjects randomized to treatment at their particular 
site. Approximately half of the sites will be using needle and the other using cannula for 
injection.
All randomized subjects’ will have a GIHS score of 2 (Moderate) or 3 (Severe) with no more 
than one grade difference between the left and right side at baseline.
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Investigator blinding will be accomplished by using a Treating Investigator to administer the 
treatments and a Blinded Evaluator, to whom randomization and treatment are concealed, to 
conduct the blinded assessments. In addition, the Blinded Evaluator should not be allowed to 
retrieve study supplies or be present during the opening of the study supplies or injection 
procedure. All documents with information regarding study products and randomization 
assignment should be kept in a separate binder not available to the Blinded Evaluator. Safety 
assessments will be performed by non-blinded personnel.
Eligible subjects randomized to receive treatment will be injected by the Treating Investigator 
at Day 1. Optional touch-up treatment may be administered after 1 month of initial treatment, 
if deemed necessary by Treating Investigator and subject to obtain optimal aesthetic 
improvment. Optimal aesthetic improvement is defined as at least 1 grade improvement, from 
baseline, on the GIHS and best correction that can be achieved as agreed by the Treating 
Investigator and the subject. If optional touch-up is performed, a 72 hours telephone call, 14 
day and 1 month follow-up visits should be scheduled.  
Effectiveness and safety data will be collected for 12 months following the first injection. 
At the month 12 visit, the no-treatment comparator subjects will be offered an optional 
Restylane-L treatment. The subjects who received Restylane-L at the baseline visit will also be 
offered an optional additional treatment if optimal aesthetic improvement is not maintained (as 
determined by the Treating Investigator and subject). For subject receiving optional treatment 
at month 12 the effectiveness and safety data will be collected for another 6 months. A subject 
will be involved in the study for up to 19 months including 30 days screening and 6 months
follow-up after optional treatment at month 12. The study visits are illustrated in Figure 1.
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Number of subjects
Approximately 329 subjects will be enrolled in approximately 18 sites in the USA. The 
duration of the enrollment period is expected to 4 months. Approximately 15 to 25 subjects
will be included and treated per site.
Duration of subject participation
The total duration of the study is approximately 19 months including 30 days screening period 
and 6 months follow-up after optional treatment at month 12. One month is defined as 4 weeks 
in the study.
End of study is when enrolment has reached the target number of subjects and all subjects have 
completed the last study visit.
Randomization and blinding
Randomization
Approximately 329 subjects will be randomized in a 
 ratio to treatment with Restylane-L or
no treatment. Before starting the study, a computer generated randomization list will be 
prepared under the supervision of a designated statistician from the Sponsor. The 
randomization list will be stratified by FST group (I-III, IV, and V-VI). The FST I-III group 
will be further stratified by study site. The FST IV and FST V-VI groups will be further 
stratified at needle or cannula level (needle sites pooled into a needle stratum, and cannula sites 
pooled into a cannula stratum). Randomization numbers will be allocated in ascending 
sequential order to each subject. Randomization will be performed using an Interactive 
Response System by assigning each subject to Restylane-L or no treatment according to the 
randomization list.
Blinding
The Treating Investigator will not be blinded to study treatments. 
A Blinded Evaluator, to whom randomization and treatment are concealed, will conduct the 
blinded assessments. The Blinded Evaluator is not allowed to be present during the injections
or to discuss treatments with the Treating Investigator or subjects. No study related documents 
that contain information regarding the treatment of subjects should be available to the Blinded 
Evaluator. 
Safety assessment will be performed by non-blinded personnel as treatment-related AEs are 
expected to occur during a few days after treatment, thereby revealing which subjects has 
received the study product. 
Emergency unblinding
Not applicable as the treating Investigator is not blinded to treatment. 
Medical history
History of relevant surgical events and medical conditions should be documented (including
any prior dermatological procedures or implants) in the electronic case report forms (eCRF)
using medical terminology.
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Prior and concomitant therapies
Definition
Prior therapies are defined as therapies that have been used within 30 days preceding the 
Screening visit or within the timelines specified in the Inclusion/Exclusion criteria, and then 
stopped prior to the Screening visit.
Concomitant therapies are defined as follows:

any existing therapies ongoing at the time of the Screening visit,

any changes to existing therapies (such as changes in dose or formulation) during the
course of the study, or

any new therapies received by the subject since the Screening visit
Recording
Prior and concomitant therapies are to be recorded on the appropriate form in the eCRF.
Concomitant therapies are to be recorded, reviewed, and updated at each visit.
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.
Authorized concomitant therapies
Unless listed in prohibited concomitant therapies (section 4.6.4), all therapies are authorized.
Prohibited concomitant therapies
The following therapies are prohibited during the study because they may interfere with the 
efficacy and/or safety assessment of the study product(s) and/or injection procedure:

Anticoagulants or inhibitors of platelet aggregation (e.g. aspirin, non-steroidal anti-
inflammatory drugs [NSAIDs]), Omega-3 or Vitamin E should not be used within 2
weeks before any treatment to avoid increased bruising or bleeding at injection sites.
Omega 3 and Vitamin E are acceptable only as part of a standard multivitamin 
formulation.

The study product contains lidocaine, but additional local anesthesia may be used. 
Lidocaine should however be used with caution in subjects receiving other local
anesthetics or agents structurally related to amide-type anesthetics, e.g. certain
antiarrhythmics, as the systemic toxic effects can be additive.

Concomitant 
treatment 
with 
chemotherapy, 
immunosuppressive 
agents, 
immunomodulatory therapy (e.g. monoclonal antibodies, antiviral treatment for HIV or 
Hepatitis) is prohibited.

Any prescription skin-irritating topical preparations, or pigmenting agents (e.g., self-
tanning or bleaching agents) in the periorbital area.

Immunosuppressive medications or systemic steroids (except intranasal/inhaled 
steroids) or prescription topical steroids (face). 

Topical (facial) prescription retinoids or systemic retinoids.
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
Superficial facial dermal therapies (e.g. microderm abrasion, superficial chemical 
peels) or aesthetic facial plastic surgery or cosmetic procedures (i.e., facial ablative or 
fractional laser, deep chemical peels, threads, non-invasive skin-tightening [e.g., 
Ultherapy, Thermage]) to the periorbital or malar region.

Lower eyelid surgery, including orbital or midface surgery, or permanent implant or fat 
grafting in the midfacial region or tattoo (including microblading of eyebrow or 
eyeliner) 

Neurotoxin treatment to the periorbital region, LCL, forehead lines or glabella lines.

Lower periorbital and/or malar region treatments with absorbable or temporary dermal 
fillers (e.g., collagen, fat, hyaluronic-acid products, calcium-hydroxylapatite, poly L-
lactic acid products, etc.) and/or mesotherapy.

Facial treatments with any permanent dermal fillers and/or permanent implant.

Planned surgery including dental implants, tooth extractions, orthodontia are 
prohibited.

Participation in any other clinical study during this study is prohibited.
If a prohibited therapy becomes a necessary treatment for the safety or best interest of the 
subject, the Sponsor Medical Expert should be notified, time permitting, to discuss possible 
alternatives prior to administration of a prohibited therapy.
If a subject receives prohibited therapy during the clinical study, the Sponsor should be notified 
to discuss the pertinence and the modalities for the subject to continue in the clinical study.
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Table 1: Schedule of events
Procedure
Visit 1a
Visit 1b
Visit 24
Visit 34
Visit 4
Visit 
4a4
Visit 4b4
Visit 4c4 Visit 5 -7
Visit 8 or 
EOS/ET
Visit 8a4
Visit 8b4
Visit 8c4
Visit 8d4
Visit 8e4
EOS for 
optional Tx
Visits may be 
combined if subject 
meets eligibility 
criteria
72 hrs 
after Tx
(±24 
hrs)
14 days 
after 
Baseline 
(±3 days)
1 month10
after
Baseline
(+7 days)
72 hrs 
after 
Option
al 
touch-
up
(±24 
hrs)
14 days 
after 
Optional 
touch-up 
(±3 days)
1 
month10
after 
Optional 
touch-up
(+7
days)
3, 6, & 9 
months10
after 
Baseline
(±7 days)
12 months10
(±7 days)
after 
Baseline
72 hrs
after 
optional 
Tx
(±24 hrs)
14 days 
after 
optional Tx 
(±3 days)
1 month 
after 
optional Tx 
(+7 days)
3 months10
after 
optional Tx
(±7 days)
6 months10
after 
optional Tx
(+7 days)
Screening
Day -30 to
1
Baseline/
Tx
Day 1
TC
Follow-up Follow-up
Optional 
TU
TC
Follow-up Follow-
up
Follow-up Follow-up
Optional
Tx
TC
Follow-up
Follow-up
Follow-up
Follow-up
Informed Consent
X
Med. Hx/prior therapies
X
X1,2
Demographics
X
Height/Weight6
X1,6
X6
X6
X6
X6
X6
X6
X6
X6
X6
X6
Inclusion/Exclusion Criteria
X
X1,2
X1,5
X1,5
Urine pregnancy test3
X
X1,2
X1,5
X1,5
Vision Function Assessments
X
X2,8,9
X
X5,8,9
X
X5,8
X
Randomization
X
Treatment with study product
X9
X5,9
X5
Evaluate device deficiencies
X
X9
X5
Dispense Subject Diary
X9
X5
X5
Collect / Review Subject Diary
X7
X
X9
X7
X
X
X7
X
X
2D Photography
X1
X
X1
X
X
X
X1
X
X
X
X
Concomitant Therapies
X
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treating Investigator Assessments
GAIS
X1
X
X
X1
X
X
X
GIHS
X
X1,2
X1
X1
Blinded Evaluator Assessments
GIHS
X
X1,2
X
X1
X
X
Subject Assessments
GAIS
X1
X
X
X1
X
X
X
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1Prior to any planned treatment
2Omitted if the screening and baseline visits occur on Day 1. Screening visit and baseline visit can be combined if no drug washout is needed
3For females of childbearing potential
4Visit is scheduled only if initial treatment, optional touch-up or optional treatment is performed
5Omitted if optional touch-up or optional treatment is not performed
6Subject self-reported. Height only needs to be collected at baseline
7Review diary with subject over the phone
8Performed prior and 30 minutes post injection of study product
9For subjects randomized to study treatment
10 One month is defined as 4 weeks in the study
ET = Early Termination
EOS = End of Study
GIHS = Galderma Infraorbital Hollows Scale
GAIS = Global Aesthetic Improvement Scale
TC= Telephone call
TU = Touch up
Tx = Treatment
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Visits
Visit 1 a: Screening (Day -30 to Day 1)
The following activities and screening assessments will be performed within 30 days prior 
to baseline/Day 1 visit:

Obtain Informed Consent.

Obtain demographic data: date of birth, gender, ethnicity, race, and FST.  For
determination of the FST, see Table 2.
Table 2: Fitzpatrick Skin Types (FST)
Skin type
Skin color
Skin characteristics
I
White; very fair; red or blond hair; blue eyes; 
freckles
Always burns, never tans
II
White; fair; red or blond hair; blue, hazel or green 
eyes
Usually burns, tans with difficulty
III
Cream white; fair with any eye or hair color; very 
common
Sometimes mild burn, gradually tans
IV
Brown; typical Mediterranean Caucasian skin
Rarely burns, tans with ease
V
Dark brown; Middle Eastern skin types
Very rarely burns, tans very easily
VI
Black
Never burns, tans very easily
FST is a skin classification system that categorizes different skin colors, and their reactions to ultraviolet 
light.2

Record the subject’s medical history (including any prior dermatological procedures 
or implants) and prior or concomitant therapies.

For all females of childbearing potential, perform UPT prior to treatment.  Test result 
must be negative for the subject to be eligible for treatment.

Assess GIHS – Treating Investigator and Blinded Evaluator

Assess eligibility (inclusion and exclusion criteria).

Schedule the Baseline/Day1 (initial treatment) visit or proceed to Day 1 activities if 
subject meets all eligibility criteria.
Visit 1b: Baseline/Day 1 (Initial Treatment)
The screening visit and baseline visit (Day 1) may be performed on the same day if a subject is 
deemed eligible by the Treating Investigator.   
If Screening visit and Baseline/Day 1 visit are not performed on the same day, the following 
procedures should be repeated at the Baseline/Day 1 visit:

Review for changes in medical history and concomitant therapies.

Re-confirm eligibility criteria.
                                                
2 Fitzpatrick T.B. (1988). The validity and practicality of sun-reactive skin types I through VI. Arch. Dermatol. 124, 869–
871.
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
Perform UPT for all females of childbearing potential (prior to treatment). Test result 
must be negative for the subject to be eligible for study treatment.

Assess GIHS – Treating Investigator and Blinded Evaluator

Evaluate the subject for AEs since screening visit.
Once the subject is deemed eligible for study treatment by the Treating Investigator, the 
following procedures should be completed:

Record subject’s height and weight.

Obtain pre-treatment photographs of the infraorbital hollows.

Randomize the subject to treatment (using needle or cannula according to what is agreed 
per site) or to no treatment. For subject randomized to treatment:
o
Perform Vision Function Assessments prior to injection.
o
Subjects will be injected with the study product.
o
Record all concomitant medications/procedures used during the injection 
session.
o
Record the number of syringes used and the volume of study product injected 
during the injection session.
o
Evaluate for device deficiencies. If deficiencies are noted, complete form as 
specified in section 8.6
o
Following 30 minutes after injection, perform Vision Function Assessments
o
Evaluate post-treatment AEs by Treating Investigator
o
Dispense Subject Diary and instruct subject on Diary completion. Remind the 
subject to bring the diary to next on-site study visit.
o
Schedule the 72 hours (±24 hours) follow-up phone call (Visit 2) and Visit 3, 
14 days (±3 days) after the Baseline visit (Visit 1b) for subjects randomized 
to treatment.

Schedule Visit 4, 1 month (+7 days) after the Baseline visit (Visit 1b).
Visit 2: Follow up 72 hour (±24 hours) telephone call after Baseline/Day 1
Visit conducted for subjects randomized to treatment only.

Interview subject regarding any concomitant therapies.

Interview subject regarding any AEs that have occurred since receiving treatment. If 
AEs are reported, notify the Investigator immediately and determine whether subject 
should return to the site for an unscheduled visit. The Investigator should assess all 
reported AEs in a timely manner.

Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind subject of the next scheduled on-site visit.
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Visit 3: Follow up visit 14 days (± 3 days) after Baseline/Day 1

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating 
Investigator (if randomized to treatment) that have occurred since the last visit.

Obtain photographs.

Perform Vision Function Assessments.

Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind subject of the next scheduled on-site visit.
Visit 4: Follow-up visit 1 month (+ 7 days) after Baseline/Day 1/ Optional touch-
up

Interview the subject regarding concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating 
Investigator (if randomized to treatment) that have occurred since the last visit.

Obtain photographs (if treatment is given, ensure photos are taken prior to injection)

Assessments to be performed, prior to optional touch-up:
o
GIHS – Treating Investigator
o
GAIS – Treating Investigator and Subject

Schedule Visit 5, 3 months (± 7 days) after the Baseline visit (Visit 1b).
For subjects randomized to treatment

Collect and review Subject Diary for subjects randomized to treatment:
o
Review diary entries for completeness and legibility.
o
If the subject handwrites entries on the diary pages, review these entries with 
the subject and clarify as needed. Record all clarifications on the subject’s 
source documents and record the Diary data into the eCRF.

Assess whether optimal aesthetic result has been achieved by subjects randomized to 
treatment (as agreed by the Treating Investigator and subject) and determine whether 
optional touch-up is appropriate.  
o
Subject must meet eligibility criteria for touch-up to be provided.  
o
Touch-up should not be provided if the subject has a disease or condition
described in the exclusion criteria, or an ongoing treatment-related AE that 
in the opinion of the Treating Investigator would be worsened by a touch-up.
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If touch-up is to be performed:

Prior to any treatment being provided, perform UPT for all females of childbearing 
potential. The test result must be negative for a subject to receive the touch-up 
treatment.
o
Perform Vision Function Assessments prior to injection.
o
Subjects will be injected with the study product.
o
Record all concomitant medications/procedures used during the injection 
session.
o
Record the number of syringes used and the volume of study product injected 
during the injection session.
o
Evaluate for device deficiencies. If deficiencies are noted, complete form as 
specified in Section 8.6.
o
Following 30 minutes after injection, perform Vision Function Assessments.
o
Dispense new Subject Diary and remind subject on Diary completion. Remind
the subject to bring the diary to next on-site study visit.
o
Schedule the 72 hours (± 24 hours) follow-up phone call (Visit 4a), Visit 4b, 
14 days (± 3 days) and Visit 4c, 1 months (+ 7 days) after optional touch-up.
Visit 4a: Follow-up 72 hour (± 24 hours) telephone call after optional touch-up 
performed 
This visit should only be conducted for subjects who received a touch-up treatment at 
Visit 4.

Interview subject regarding any concomitant therapies.

Interview subject regarding any AEs that have occurred since receiving treatment. If 
AEs are reported, notify the Investigator immediately and determine whether subject 
should return to the site for an unscheduled visit. The Investigator should assess all 
reported AEs in a timely manner.

Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind subject of the next scheduled on-site visit.
Visit 4b: Follow up visit 14 days (± 3 days) after optional touch-up performed
This visit should only be conducted for subjects who received a touch-up treatment at 
Visit 4.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating 
Investigator (if randomized to treatment) that have occurred since the last visit.

Obtain photographs.

Perform Vision Function Assessments.
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
Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind subject of the next scheduled on-site visit.
Visit 4c: Follow up visit 1 month (+ 7 days) after optional touch-up performed
This visit should only be conducted for subjects who received a touch-up treatment at 
Visit 4.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating 
Investigator that have occurred since the last visit.

Collect and review Subject Diary:
o
Review diary entries for completeness and legibility.
o
If the subject handwrites entries on the diary pages, review these entries with 
the subject and clarify as needed. Record all clarifications on the subject’s 
source documents and record the Diary data into the eCRF.

Assess GAIS – Treating Investigator and Subject

Obtain photographs

Remind subject of the next scheduled on-site visit.
Visits 5-7: Follow-up visit 3 months, 6 months and 9 months (± 7 days), after 
Baseline/Day 1

Interview the subject regarding concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs that have occurred since the last visit.

Obtain photographs

Assessments to be performed:
o
GIHS – Blinded Evaluator
o
GAIS assessment for all subjects – Treating Investigator and Subject

Schedule follow up visits for 6 months, 9 months and 12 months (± 7 days) after the 
Baseline visit (Visit 1b).
Visit 8: Follow-up visit 12 months (± 7 days) after Day 1 / Optional treatment /
End of Study (EOS) / Early Termination Visit (ET)

Interview the subject regarding concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs that have occurred since the last visit.

Obtain photographs (if treatment is given, ensure photos are taken prior to injection)
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
Assessments to be performed, prior to optional treatment:
o
GIHS - Treating Investigator and Blinded Evaluator
o
GAIS – Treating Investigator and Subject
For subjects receiving optional treatment

Assess whether optimal aesthetic result has been achieved by subjects randomized to 
treatment (as agreed by the Treating Investigator and subject) and determine whether 
optional treatment or if initial treatment is appropriate.
o
Subject must meet eligibility criteria for treatment to be provided.  
o
Treatment should not be provided if the subject has a disease or condition
described in the exclusion criteria, or an ongoing treatment-related AE that 
in the opinion of the Treating Investigator would be worsened by a treatment.
If treatment is to be performed:

Prior to any treatment being provided, perform UPT for all females of childbearing 
potential. The test result must be negative for a subject to receive the touch-up 
treatment.
o
Perform Vision Function Assessments prior to injection.
o
Subjects will be injected with the study product.
o
Record all concomitant medications/procedures used during the injection 
session.
o
Record the number of syringes used and the volume of study product injected 
during the injection session.
o
Evaluate for device deficiencies. If deficiencies are noted, complete form as 
specified in Section 8.6.
o
Following 30 minutes after injection, perform Vision Function Assessments.
o
Dispense new Subject Diary and remind subject on Diary completion. Remind 
the subject to bring the diary to next on-site study visit.
o
Schedule the 72 hours (± 24 hours) follow-up phone call (Visit 8a), Visit 8b, 
14 days (± 3 days) and Visit 8c, 1 months (+ 7 days) after optional treatment 
(Visit 8).
For subjects who do not receive an optional treatment:

Complete end of study form in the eCRF.
Visit 8a: Follow-up 72 hour (± 24 hours) telephone call after optional treatment 
This visit should only be conducted for subjects who received a treatment at Visit 8.

Interview subject regarding any concomitant therapies.
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
Interview subject regarding any AEs that have occurred since receiving treatment. If 
AEs are reported, notify the Investigator immediately and determine whether subject 
should return to the site for an unscheduled visit. The Investigator should assess all 
reported AEs in a timely manner.

Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind the subject of the next on-site visit.
Visit 8b: Follow up visit 14 days (± 3 days) after optional touch-up performed
This visit should only be conducted for subjects who received a treatment at Visit 8.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating 
Investigator (if randomized to treatment) that have occurred since the last visit.

Obtain photographs.

Perform Vision Function Assessments.

Interview subject regarding the Diary completion and reported events since receiving 
treatment. Remind subject to complete the Diary daily and bring it to the next on-site 
visit.

Remind subject of the next scheduled on-site visit.
Visit 8c: Follow up visit 1 month (+7 days) after optional treatment
This visit should only be conducted for subjects who received a treatment at Visit 8.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs, and post-treatment AEs by Treating
Investigator that have occurred since the last visit.

Collect and review Subject Diary:
o
Review diary entries for completeness and legibility.
o
If the subject handwrites entries on the diary pages, review these entries with 
the subject and clarify as needed. Record all clarifications on the subject’s 
source documents and record the Diary data into the eCRF.

GAIS assessment – Treating Investigator and Subject

Obtain photographs

Schedule Visit 8d, 3 months (± 7 days) after optional treatment (Visit 8).
Visit 8d: Follow up visit 3 months (± 7 days) after optional treatment 
This visit should only be conducted for subjects who received a treatment at Visit 8.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs that have occurred since the last visit.
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
Assessments to be performed:
o
GIHS – Blinded Evaluator
o
GAIS – Treating Investigator and Subject

Obtain photographs

Schedule Visit 8e, 6 months (+ 7 days) after optional treatment (Visit 8).
Visit 8e: Follow up visit 6 months (+7 days) after optional treatment 
This visit should only be conducted for subjects who received a treatment at Visit 8.

Interview subject regarding any concomitant therapies and record subject’s weight.

Interview subject and evaluate any AEs that have occurred since the last visit.

Assessments to be performed:
o
GIHS – Blinded Evaluator
o
GAIS – Treating Investigator and Subject

Obtain photographs

Remind subjects to contact the study site if any new AE occurs after study exit as 
subjects will be asked to return to the study site and be evaluated and receive treatment, 
if applicable.  

Complete end of study form in the eCRF
5. Subjects
Subject information and informed consent
The PI or his/her authorized designee must always use the IRB-approved subject information
and informed consent form and it must not be changed without prior discussion with the 
Sponsor and approval from the applicable IRB.
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 IRB. 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 
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consent form shall be personally signed and dated by the subject and the PI or his/her authorized
designee responsible for conducting the informed consent. The consent includes information 
that data will be collected, recorded, processed, and may be transferred to other countries. The 
data will not contain any information that can be used to identify any subject.
Photographs collected during the study will be analyzed and stored in a database by the Sponsor 
and its representatives in order to evaluate the effect of the treatment in the study. The subjects 
will be recognizable on the photographs, but their names will not be disclosed.
All signed informed consent forms shall be filed in the Investigator file. The subject shall be 
provided with a copy of the signed and dated informed consent form and any other written 
information.
The Investigator shall ensure that important new information is provided to new and existing 
subjects throughout the study.
Inclusion criteria
The subjects must meet all the following criteria to be eligible for the study:
1. Subject is willing to comply with the requirements of the study including being 
photographed, following post-treatment care instructions, completing the diary, 
attending all study visits and providing a signed written informed consent.
2. Moderate or severe (Grade 2 or 3 on the GIHS) infraorbital hollows with no more than 
one grade difference between the left and right side at baseline as assessed by the 
blinded evaluator.
3. Visual function assessment tests without findings according to treating investigator.
4. Males or non-pregnant, non-breastfeeding females, over the age of 21. 
5. Subject is willing to abstain from any other facial plastic surgical or cosmetic 
procedure(s) during the duration of the study (e.g. laser or chemical resurfacing, 
needling, facelift, radiofrequency).
6. Intent to undergo correction of both orbital hollows.
Inclusion criteria 7 - 8 apply to female subjects only
7. If the subject is a female of childbearing potential, she agrees to use an acceptable form 
of effective birth control for the duration of the study and is willing to take a urine 
pregnancy test (UPT) at the screening/enrollment visit and prior to treatment. 
Acceptable forms of effective birth control include:
a) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical 
caps) with spermicidal foam/gel/film/cream/suppository.
b) Bilateral tubal ligation.
c) Combined oral contraceptives (estrogens and progesterone), implanted or injectable 
contraceptives on a stable dose for at least 28 days prior to Day 1.
d) Hormonal or copper intra uterine device (IUD) inserted at least 28 days prior to Day 
1.
e) Vasectomized partner (in monogamous relationship) for at least 3 months prior to 
screening.
f)
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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8. Negative urine pregnancy test for females of childbearing potential at screening and all 
injection visits.
Exclusion criteria
The presence of any of the following exclusion criteria excluded a subject from enrollment in 
the study:
1. Known/previous allergy or hypersensitivity to any injectable hyaluronic acid (HA) gel
or to gram positive bacterial proteins.
2. Known/previous allergy or hypersensitivity to local anesthetics, e.g. lidocaine or other 
amide-type anesthetics.
3. Active or a history of recurrent or chronic infraorbital edema or rosacea or uncontrolled 
severe seasonal allergies.
4. Previous or present multiple allergies or severe allergies, such as manifested by 
anaphylaxis or angioedema, or family history of these conditions.
5. Previous superficial facial dermal therapies (i.e. microderm abrasion, superficial 
chemical peels) to the periorbital or malar region within the past 6 months or plans to 
receive such treatment during participation in the study.
6. Previous deep facial dermal therapies (i.e. facial ablative or fractional laser, deep 
chemical peels, non-invasive skin-tightening [e.g. Ultherapy, Thermage]) to the 
periorbital or malar region within the past 12 months or plans to receive such treatment 
during participation in the study.
7. Prior lower-eyelid surgery, including orbital or midface surgery, or has a permanent 
implant or fat grafting or fat injections in the mid-facial region or tattoo (including 
microblading of eyebrow or eyeliner) that could interfere with effectiveness 
assessments or plans to have it during the study. 
8. Lower lid retraction or exophthalmos.
9. Pigmentation abnormalities around the eyes and/or dark circles under the eyes due to 
pigmentation changes and not from infraorbital hollow shadowing.
10. Ectropium, entropion, or trichiasis of the lower eyelid or eye diseases that lead to 
reddening and tendency of watering of the eye.
11. Has gained or lost ≥ 2 body mass index (BMI) units within the previous 90 days or has 
the intention to gain or lose a significant amount of weight during the study.
12. Received lower periorbital and/or malar region treatments with any absorbable or 
temporary fillers such as porcine-based collagen fillers, HA products, RADIESSE®, 
poly L-lactic acid (PLLA) or received mesotherapy treatment to the area within the past 
24 months or plans to receive such treatments during participation in the study.
13. Received neurotoxin treatment to the periorbital region, Forehead Lines (FL), Lateral 
Canthal Lines (LCL) or glabella, within the past 6 months or plans to receive such 
treatment during participation in the study.
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14. Any current or history of uncontrolled retinal disease or detached retina or any other 
condition with the potential to cause a decline of visual acuity (e.g. uncontrolled 
diabetes).
15. Tendency to accumulate eyelid edema, has developed festoons, or has large and/or 
herniating infraorbital fat pads.
16. Skin or fat atrophy, other than age-related, in the mid-facial and/or perio-orbicular 
regions or has been diagnosed with a connective tissue disorder.
17. Skin laxity or sun damage beyond typical for the subject’s age.
18. A history of recurrent herpetic eruption in the mid-facial region, excluding the lips, 
within 12 months.
19. Subjects typically experiencing occasional migraines (≥ 8 per year).
20. History of radiation damage, cancerous or pre-cancerous lesions (e.g. actinic keratosis) 
near the area close to be treated.
21. Scars or deformities, active skin disease, inflammation, or related conditions such as 
infection, perioral dermatitis, seborrheic dermatitis, eczema, rosacea, acne, psoriasis, 
and herpes zoster near or in the area to be treated.
22. Subjects with dental or oral status on visual inspection that, in the opinion of the 
Investigator, would make the subject unsuitable for inclusion, or Subjects with dental, 
oral or sinus surgery within past 12 months prior to the treatment visit or planned 
surgery, including dental implants, tooth extractions, orthodontia, during the study 
period.
23. Inflammation, active or chronic (e.g. in the mouth, dentals, head and neck region).
24. History of or active autoimmune disease or connective tissue diseases such as systemic 
lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, or localized 
or systemic scleroderma.
25. Tendency to form keloids, hypertrophic scars, or any other healing disorder.
26. History of bleeding disorders or treatment with anticoagulants or inhibitors of platelet 
aggregation e.g. aspirin or other non-steroid anti-inflammatory drugs (NSAIDs), 
Omega-3, or vitamin E within 2 weeks before treatment.
27. Treatment with chemotherapy, immunosuppressive agents, immunomodulatory 
therapy (e.g., monoclonal antibodies, antiviral treatment for HIV or hepatitis), systemic 
or topical (facial) corticosteroids within 3 months before treatment (inhaled corticoids 
are allowed).
28. Any prescription skin-irritating topical preparations, or pigmenting agents (e.g., self-
tanning or bleaching agents) in the periorbital area within the past 2 weeks.
29. Concomitant treatment with prescribed topical (facial) retinoids within 3 months, or 
systemic retinoids within 6 months before treatment,or plan to receive such treatment 
during participation in the study.
30. Any medical condition that in the opinion of the Investigator would make the subject 
unsuitable for inclusion (e.g., porphyria, methemoglobinemia, hemoglobinopathy, 
thalassemia, glucose-6-phoshate dehydrogenase deficiency, a chronic, relapsing or 
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hereditary disease that may affect the general condition or may require frequent medical 
treatment, any abnormal screening laboratory value or ECG, or psychiatric disorders).
31. Women who are pregnant or breast feeding, or women of childbearing potential who 
are not practicing adequate contraception or planning to become pregnant during the 
study period.
32. Study site personnel, close relatives of the study site personnel (e.g. parents, children, 
siblings, or spouse), employees, or close relatives of employees at the Sponsor 
Company.
33. Participation in any other clinical study within 30 days before treatment.
Subject number
Prior to any study procedures being conducted, the subject must sign the informed consent 
form. Each subject who has signed the informed consent form will be assigned a screening 
number. Upon randomization, each subject will be assigned a subject number that will be 
allocated in ascending order within each center. A screen failure is a subject who signed the 
informed consent but never enrolled (i.e. was randomized and/or received treatment) in the 
study. For screen failures, the subject source documents should indicate which assessments 
have been made and the reason why the subject was determined to be a screen failure. A screen 
failure should not be re-entered in the study. A subject is considered enrolled when they have 
signed the Informed Consent Form (ICF) and are randomized and/or treated.
For the duration of the clinical study, each subject will be identified using the subject number 
for all documentation and discussion. A subject identification log is required to be kept in the 
Investigator file. 
Withdrawal of subjects
An investigator may decide to discontinue a subject from the clinical study for safety reasons.
Although the importance of completing the entire clinical study should be explained to the 
subject by the clinical study personnel, any subject is free to discontinue participation in this 
clinical study at any time and for whatever reason, specified or unspecified, and without any 
prejudice. No constraints are to be imposed on the subject, and when appropriate, a subject 
may be treated with other conventional therapy when clinically indicated. 
When a subject does not complete the clinical study, he/she will be fully assessed, if such 
assessment is possible. The procedures designated for the Early Termination (ET) visit should 
be completed for all subjects discontinuing the clinical study and the appropriate eCRF should 
be completed.
All discontinuations and the reason for discontinuation are to be documented by the 
investigator on the Exit form.
For discontinuation due to and AE, the Adverse Event form is to be completed. The investigator 
should also ensure that the subject receives suitable therapy for the AE.
A subject who has been randomized cannot be replaced by another subject if he/she 
discontinues the clinical study for any reason.
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Pregnancies occurring during the screening period are considered as screening failures; they 
should be recorded as such in the eCRF and no pregnancy form is to be completed. 
In case of a pregnancy occurring after the baseline visit, follow the procedures described in 
section 8.5.12. The subject may remain in the study, but no invasive procedure should be 
conducted.
The Sponsor may also decide to prematurely terminate or suspend a subject’s participation in 
the clinical study.
Potential reasons for discontinuation are defined below:
The withdrawal criteria are:
Medical Reasons
If the subject suffers from a medical condition and/or Adverse 
Events that, in the judgment of the Investigator makes it medically 
necessary to withdraw the subject. The specific rationale for 
Investigator-initiated withdrawal of a subject for medical reasons 
should document the specific condition for withdrawing the subject.
Withdrawal 
by 
Subject:
Includes consent withdrawal, subject relocation, schedule conflicts. 
A subject can withdraw their consent to participate in the study at 
their own request or be withdrawn from participation in the study at 
the request of their legally authorized representative at any time for 
any reason.
Lost to follow-up:
If a subject does not return for a scheduled visit, reasonable effort 
shall be made to contact that subject, confirm with three 
documented phone calls and a certified letter (delivery receipt 
requested) without answer before declaring the subject lost to 
follow-up.
Other:
This category is to be used for a subject who discontinues due to a 
reason other than as specified in the pre-defined categories above. 
Explain the reason for discontinuation.
If reason for discontinuation is “withdrawal by subject” or “other”, the subject will be 
questioned to rule out the possibility of an AE. If the AE led to discontinuation then “Adverse 
Event” should be chosen as the reason for discontinuation, rather than “withdrawal by subject” 
or “other”.
If an AE which, according to the Investigator’s assessment, is related to the use of any of the 
study products and is still ongoing at the time of the withdrawal, the Investigator shall follow-
up the subject until the AE resolves, is assessed by the Investigator to be “chronic” or “stable”
or subject is lost to follow up. Follow-up information shall be reported on the AE follow-up 
form.
6. Study Products
The term “study products” refers to Restylane-L. The study product will be provided by the 
Sponsor.
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Investigational product
The investigational device (i.e. study product) is Restylane-L injectable gel. The sterilized gel 
contains 20mg/mL stabilized HA and 3 mg/mL lidocaine hydrochloride in a physiological 
buffer. Each syringe contains 0.5 mL gel.
Restylane-L is supplied sterile, 0.5 mL filled in a disposable glass syringe with a luer lock 
fitting. Restylane-L is co-packed with one sterilized Thin Wall (TW) needle as indicated on the 
carton (29 G x ½").
Additional products and materials
The sponsor will provide Urine Pregnancy Tests, cotton wisps, and monofilaments to each 
study site.
Topical or local anaesthesia may be used at the discretion of the treating Investigator before 
the treatment. If used, the anaesthesia shall be supplied by the study site. Type of anaesthesia, 
administration route, product name, and quantity used must be recorded in the eCRF.
Small blunt tip commercially available cannulas TSK Steriglide 25G x 1½" and TSK Steriglide
27G x 1½" will be supplied by the study sites (for sites using cannula). The co-packed needle 
should be used as incision needle with each cannula.
Labelling and storage
Labelling will be performed according to United States Code of Federal Regulations (CFR) 
21 CFR 812.5: Labelling of investigational devices. The carton will be labeled with the lot 
number as well as expiration date and the CTN and the following:
"CAUTION - Investigational Device. Limited by US Law to Investigational Use.”
The syringes should be stored in their original packaging at a temperature up to 25°C (77°F), 
protected from sunlight and freezing. Opened packages or partially used devices should not be 
reused. Detailed product information is provided in the IFU.
Product accountability
The study products will be released to the Investigator or his/her authorized designee after
study approvals have been received from the FDA and IRB and the CTA has been signed by
all parties.
The Investigator must ensure that the study products are kept in a secure location, with access
limited to those authorized by the Investigator.
The study products must be traceable from the manufacturer to their use in subjects until
return or disposal. It is therefore important that the Investigator maintain accurate product 
accountability records, i.e. documentation of the physical location of all study products, 
deliveries, and return of study products between the Sponsor and the Investigator, and
documentation of administration of product to the subject.
When the study is completed, all unused or expired study product at each study site
should be returned to the Sponsor representative for destruction, or be destroyed locally at the
site if documented as agreed with Sponsor.
Any malfunctioning study products should be reported as described in section 8.6.
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Products deliberately or accidentally destroyed during shipment or at a study site should be 
accounted for and documented.  Used syringes, needles, and any 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.
Treatment
The investigational product is reserved for use by Treating Investigators who are experienced
in infraorbital injection procedures. Before treatment the subject will be informed about the
expected post-treatment events that should be recorded in the Subject Diary and potential risks 
involved with the treatment and when to contact the Investigator in case of emerging
symptoms. The investigator must be trained on, and have at hand, the relevant clinical practice 
guidelines1 and the actions to be taken if visual disturbances occur. The investigator should 
also have reviewed the Intravascular Treatment Protocol supportive tool provided separately 
in the Investigator file.
Pre-Treatment procedure
A visual function assessment should be performed prior to injection of the investigational 
product, see section 8.2.
The study product contains lidocaine hydrochloride, but additional topical or local anesthesia
or ice pack may be used at the discretion of the Treating Investigator to enhance the experience
of the subject. Any additional topical or local anesthesia used should be recorded in the source
documentation and on the eCRFs
Treatment Regimen (dose and interval)
Detailed information regarding the injection procedure, pre- and post-treatment care and 
patients instructions are provided in the IFU.
Restylane-Lis to be placed in the supraperiosteal plane. The infraorbital treatment area is at the 
junction of the lower eyelid and midface where a volume deficit has formed. This area is 
bordered by the nasal sidewall medially, the temporal region of the bony orbit laterally, the 
bulk of the lower eyelid superiorly, and the superior aspect of the mid-face inferiorly. 
The injection technique is at the discretion of the Investigator. For needle serial puncture is
recommended and for cannula fanning technique is recommended. The injection should be 
performed with a constant low-to-moderate pressure on the plunger. Slight elevation of the skin 
should be observed without significant blanching of the skin. To avoid visible lumps and/or 
discoloration, avoid injection of Restylane-L superficially. When the injection is complete, the 
treated area may be gently massaged, if necessary.
                                                
1 Alam M, Gladstone H, Kramer EM, et al.  ASDS guidelines of care: injectable fillers.  Dermatol Surg.  2008; 
34 (suppl 1): S115-S148.
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Allowed maximum injection volume for initial injection, touch-up and end of study treatment 
is 1,0 mL per side at each treatment session. Slow injection is recommended and overcorrection 
should be avoided.
For the optional treatment at 12 months sites will continue to use needle or cannula for injection
based on the initial selection for each particular site.
Post-treatment care
Post treatment procedures with ice pack or gentle massage are allowed as per investigator 
normal procedure. Ice pack can be applied for a short period if the treated area is swollen. 
Gentle massage can be applied for any irregularities.
After the injection, some common injection-related reactions might occur. These reactions 
include erythema, swelling, pain, itching, bruising or tenderness at the implant site. Typically, 
resolution is spontaneous within one week after injection into the skin.
Post-injection Vision Function Assessment tests including the Snellen visual acuity test, 
Extraocular muscle function test and Confrontation visual field, by the treating investigator 
will be repeated 30 minutes after injection, see section 8.2.
Acetaminophen may be taken if instructed by the physician. Any medication or therapy used 
by the subject must be recorded in the CRF.
The subject must avoid exposing the treated area to heat (sun bathing, sauna, steam baths, etc.) 
or extreme cold until any signs of initial swelling and redness have disappeared. 
Post-trial provisions
In time, the implant will be degraded in the body and additional treatments will be necessary 
to maintain the aesthetic result.  Subjects will be offered optional treatment at the 12 months
follow-up visit. The same procedure as described in section 6.5.1 and 6.5.2 should be followed.
After the final study visit, the Sponsor will not supply any more treatments to the subjects, even 
if the result does not persist.
Treatment compliance
Not applicable; the treatment will be administered by the injector at the investigational site.
7. Effectiveness Assessments
General information
The methods for collecting efficacy data are described in the following sections. To minimize 
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.
Galderma Infraorbital Hollows Scale (GIHS)
The GIHS is a 4 point scale for assessment of Infraorbital Hollows (Appendix 2). Each score 
in the GIHS is exemplified by Photographic images of the scale. The blinded evaluator and 
treating investigator will perform live assessment of the subject´s left and right Infraorbital 
Hollow separately.
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The blinded evaluator will perform GIHS assessments at:

screening and baseline

3, 6, 9 and 12 months after randomization

3 and 6 months after optional treatment.  The evaluator is considered unblinded as these 
assessments are performed for all subjects receiving the optional treatment.
The treating investigator will perform GIHS assessment at:

screening and baseline

1 and 12 months after randomization
Global Aesthetic Improvement Scale (GAIS)
The 7-graded GAIS will be used to live assess the aesthetic improvement of the Infraorbital 
Hollows by the Treating Investigator and the subject, by comparing to a photograph taken at 
the baseline visit before the first treatment. The Treating Investigator and the subject will, 
independently of each other, respond to the question: “How would you describe the aesthetic 
improvement of your tear troughs today compared to the photograph taken before treatment?” 
by using the respective categorical scale below.
GAIS will be assessed at 1, 3, 6, 9 and 12 months after randomization, at 1 month after optional 
touch-up and at 1, 3, and 6 months after optional treatment.
Table 3: Global Aesthetic Improvement Scale (GAIS)
Rating (Treating 
Investigator and 
Subject
Definition (only for Treating Investigator)
Very Much
Improved
Optimal aesthetic result for the implant for this subject.
Much Improved
Marked improvement in appearance from the initial
condition, but not completely optimal for this subject.
Improved
The appearance is improved from the initial condition.
No Change
The appearance is essentially the same as baseline.
Worse
The appearance is worse than the initial condition.
Much Worse
Marked worsening in appearance from the initial condition.
Very Much Worse
Obvious worsening in appearance from the initial condition.
The Treating Investigator and Subject shall independently rate their assessment for aesthetic 
change comparing the appearance at follow-up visits to baseline photographs (obtained prior 
to injection at baseline
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Photography
Photographs will be taken prior to treatments with study product and at every follow-up visit
in order to document treatment effect. Photographs may also be taken to document AEs at 
the Treating Investigator’s discretion.  Baseline photographs may be used as a reference in
the GAIS assessment by the Treating Investigator and subject. Site personnel will be 
thoroughly trained in the photographic equipment and techniques before study start.
Camera equipment will be provided by the Sponsor or their designee and standardized
photographs should be achieved.  Further details regarding photography procedure will be 
specified in a separate user guide.
8. Safety Assessments
Assessment of AEs by direct question to subject and evaluation of subject
Safety evaluations for this study include an interview of the subjects at each visit to obtain 
information about any medical occurrence that meets the definition of an AE.  Each subject 
should be questioned about AEs at each study visit following the screening visit.  The question 
should be asked: “Since your last clinical visit have you had any health problems?”  
Information on AEs can also be obtained from signs and symptoms detected during each 
examination by the Investigator or designee, which should include visual inspection of the 
treatment area.
AEs must be documented in the source document and eCRF without regard for cause or relation 
to investigational product.  If in the process of the interview, additional information regarding 
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medical history or pre-planned medical or surgical procedures is revealed, it must be 
documented in the source document(s) and eCRF.  
It is the responsibility of the Investigator to determine severity of the AE and relatedness of the 
event to the study product.  
Adverse Events of special interest
All incidences of visual disturbances, regardless of relationship to study product or seriousness, 
are considered Adverse Events of Special Interest (AESIs) and include but are not limited to 
the following: any change in vision, any loss of vision, blurry vision, double vision, pain in or 
around the eye, blind spot or shadow in the visual field, trouble moving eyes, any change in 
Snellen visual acuity including change of one line or greater. 
AESIs should be reported (using the Adverse Event Clarification Form) within 24 hours of 
awareness to the Sponsor (following the instructions in section 8.5.6) via email to 
drugsafetypv@advancedclinical.com .  Appropriate follow up should be conducted in order to 
determine the cause, severity, seriousness, outcome, and relationship to the study product or 
procedures.
Vision function assessment
Vision function assessments will be performed both prior to and 30 minutes post injection of 
the study product at baseline and optional touch-up and optional treatment. These assessments 
include Snellen visual acuity, extraocular muscle function, and confrontation visual field 
testing.
Snellen visual acuity test
A Snellen Eye Chart will be used to assess visual acuity for distance vision.  Visual Acuity will 
be conducted using the subject’s best distance correction (e.g. contacts or eye glasses) at a 
distance of approximately 6 feet from the chart.  Each eye will be measured separately by either 
using an occluder or having the subject cover each eye.  The subject will be asked to start 
reading the letters at the top of the chart working their way to the bottom.  The smallest row of 
letters that the subject can read will indicate their visual acuity listed on the chart. Snellen 
Visual Acuity will be recorded in their source documentation and eCRF.  If there is one or 
more visual acuity line changes during the course of study, these should be reported to the 
Sponsor within 24 hours of awareness as an AESI. These events should be reviewed and 
assessed by the Investigator as an Adverse Event.
Extraocular muscle function test
Extraocular muscle function testing examines the function of the eye muscles.  This test 
observes the movement of the eyes in six specific directions to evaluate weakness or other 
problem in the extraocular muscles.  The subject will be asked to sit or stand with their head 
up and looking straight ahead.  The assessor will hold a pen or other object approximately 16 
inches in front of the subject’s face.  The assessor will then move the object in several directions 
and ask the subject to follow it with their eyes, without moving their head.  Normal or 
Abnormal will be recorded in the source documentation and eCRF.  Changes in movement of 
the eyes during the course of the study should be reviewed and assessed by the Investigator for 
a potential Adverse Event.
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Confrontation visual field
The Confrontation Visual Field test will be used to assess the subject’s peripheral vision.  The 
examiner will sit facing the subject, about 3 to 4 feet away from the subject and ask the subject 
to fix their gaze on the examiner’s eye.  The examiner will hold their arms straight out to the 
side and bring their hands into the subject’s visual field from the sides in each quadrant.  The 
subject will signal as soon as the hand is seen.  Each quadrant will be recorded as normal or 
abnormal in the source documentation and eCRF. Changes in the visual field of the eyes during 
the course of the study should be reviewed and assessed by the Investigator for a potential 
Adverse Event
Subject Diary Data
The subject shall evaluate local tolerability in a 28 days diary, starting on the day of each 
treatment. The presence and maximum intensity of pre-defined, expected post-treatment 
events, i.e. bruising, redness, pain, tenderness, lumps/bumps, itching and swelling shall be 
assessed for the treated area. The Subject Diary will also have an area for the subject to report
any other symptoms outside the pre-identified. Especially symptoms like change in vision 
change in skin color or crusty/scabby skin around the eyelids, dizziness, confusion, weakness 
or numbness in arms or legs, changes to consciousness or alertness, difficulty speaking/speech 
impairment, face droop, headache and fever should be recorded. The diary will also include 
instructions for the subject to:

Contact an eye doctor (retinal specialist or ophthalmologist) if they experience change 
in vision (i.e. vision loss, blurriness, double vision, pain in or around eye, blindness, 
blind spots, problems moving your eyes), change in skin color or crusty/scabby skin 
around the eyelids

Call 911 and seek immediate medical attention if signs of stroke or subject experience 
dizziness, confusion, weakness or numbness in face, arms or legs, changes to 
consciousness or alertness, difficulty speaking/speech impairment, face droop
The Investigator or study staff should review the diary for completion and clarify any events 
as needed.  For events that are ongoing at the time of diary completion, the Investigator should 
follow them and record resolution in the subject’s study file and eCRF. Diary data will be 
analyzed and displayed separately from AE data.
Laboratory assessments
Pregnancy Test
For all women of childbearing potential, including those currently using contraception, a urine 
pregnancy test is required prior to receiving any study treatment (Day 1, optional touch-up, or 
o treatment). The test result must be negative for the subject to receive any treatment with 
study product. The test result will be documented in the subject’s file and eCRF.
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Adverse Events
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 personsI, 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
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-threateningII illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalizationIII, 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 fetal distress, fetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such (see section 8.5.7).
Definition of unanticipated adverse effect
An unanticipated adverse device effect is any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, the investigational product, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence, or any other unanticipated serious problem associated with a device that relates to 
the right, safety or welfare of the subject (see US requirement CFR 812.3 (s). 
Recording instructions
Each subject should be questioned about AEs at each study visit following signing of informed 
consent. The question asked should be: ”Since your last clinical visit; have you had any health 
problems?”. Information on AEs can also be obtained from signs and symptoms detected 
                                                
I For users or other persons, this definition is restricted to events related to the investigational product.
II 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).
III Planned hospitalization for a pre-existing condition, or a procedure required by the CSP, without serious 
deterioration in health, is not considered a SAE. (Source: ISO14155:2011).
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during each examination or from a laboratory test, observations made by the study site
personnel, subject diaries, or spontaneous reports from the subjects or their relatives. 
When an AE is related to a device deficiency (refer to section 8.6), 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 provided separately 
in the Investigator file. 
Investigators, or other study site personnel, shall record all AEs in the eCRF, including:
a) Event term (recorded in standard medical terminology and avoiding abbreviations)
b) Affected area
c) Start date (first day with symptoms)
d) Stop date (last day with symptoms)
e) Intensity (mild, moderate, or severe according to definition in section 8.5.4.1)
f)
Seriousness (serious or not serious, according to definition in section 8.5.4.2)
g) Causal relationship to study product or study product injection procedure (yes or no)
h) Action taken (none, medication treatment, non-pharmacological treatment, or other 
procedures/tests, subject withdrawn)
i)
Outcome of the AE (ongoing, recovered, recovered with sequelae, death, chronic/ 
stable, not recovered at the end of the study)
The AE form/module in the eCRF must be signed and dated by the Investigator.
The pre-defined, expected post-treatment events shall be assessed separately. These 
events shall be collected by direct questioning to subjects in a diary used daily for 28
days after each treatment.
8.5.4.1 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.
8.5.4.2 Causal relationship and seriousness
Each AE, serious as well as non-serious, shall be assessed by the Investigator for causal 
relationship with the study product and its use (the injection procedure) and for seriousness
(Yes or No) of the event. 
A two-point scale (Yes or No response) shall be used for the causality assessments. The 
Investigators shall be asked to indicate a response to each of the following questions in the 
eCRF:
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
“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. 
Reporting of Adverse Events 
Adverse Event reporting on each subject shall start once a subject is enrolled (i.e., randomized 
and/or treated) in the study. All other events that occur after the subject signs the ICF but before 
enrollment will be recorded in the subject’s medical history. 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.
Reporting of Adverse Events of special interest (AESIs)
AESIs should be reported (using the AE Clarification Form) within 24 hours of awareness to 
the Sponsor at the email address drugsafetypv@advancedclinical.com. In case of difficulty to 
obtain all the required information within 24 hours, an initial report can be submitted with 
follow up information provided within 24 hours of awareness of the new information.
The following information should be provided when reporting an AESI: 

Subject identification (subject number and initials)

Event description including observed symptoms

Medical history related to event

Event onset date and time

Depth of injections

Interventions implemented to treat event

Event outcome (with resolution date and time if applicable)

Relatedness to study product or procedure

Seriousness of event

Study treatment information (number of injections, date of injections, name of product 
injected, volume injected, etc.)
If the Investigator assesses an AESI to be serious, an SAE report should be submitted as 
specified in section 8.5.7.
Upon receipt of the AESI report, the Medical Monitor and Sponsor will review the information 
provided, assess the event, and report to RA within 24 hours and to the IRB as applicable.
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Reporting of serious Adverse Events
The Investigator shall report any SAE to the Sponsor immediately but not later than 24 hours 
of awareness of the event. This initial report can be made via e-mail or submitted via the 
eCRF. 
In case of difficulty to obtain all the required information within 24 hours, an initial report can 
be submitted, with the following information as a minimum, irrespective of whether some of it 
is regarded as preliminary:

Subject identification (age, gender, initials, subject number)

Adverse Event description

Date when AE occurred

Name of PI

Name of study product 
Follow-up information and data missing in the initial SAE reporting shall be gathered as soon 
as possible and reported to the Sponsor immediately but not later than 24 hours of awareness
of the new data. Complete and adequate information on each SAE is required. All attempts to 
obtain this information, including dates for follow-up activities, must be documented by the 
Investigator.
Supporting documentation to be provided with the SAE report:

Concomitant therapies form/list

AE form/list

Medical history form/list

Any other relevant supporting documentation (e.g. hospital notes, death certificate, autopsy 
reports etc.)
___________________________________________________________________________
E-mail for SAE reporting:
drugsafetypv@advancedclinical.com
E-Fax number for SAE reporting:
+888–493–0910 
___________________________________________________________________________
For non-urgent complementary information that is not possible to send by e-mail or fax, please 
use surface mail.
___________________________________________________________________________
Surface mail for providing
Advanced Clinical
complementary information:
ATTN: Pharmacovigilance and Safety Monitoring
Building 2, Ground Floor 
Guildford Business Park
Guildford Surrey GU2 8XH
United Kingdom
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The SAE form must be signed and dated by the Investigator. If the initial 24-hour SAE report 
does not contain full information or if it is made without using the SAE form the fully 
completed and signed SAE form shall be e-mailed or faxed to the Sponsor. A copy of the fully 
completed SAE form shall be kept at the site. The blinded evaluator should perform live 
effectiveness assessments only and not discuss the treatment or any potential Adverse Events 
with the patient.
In addition, the PI shall report SAEs to the responsible IRB without undue delay. The PI is 
responsible for checking what reporting procedures are applicable for his/her IRB 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.
Stopping Rule
Enrollment and treatment into the study will be temporarily halted if the Sponsor receives a 
SAE for a vascular embolic event that lead to skin necrosis, vision loss, or stroke and is 
determined by the Investigator to be directly or possibly related to the study device or injection 
procedure.  The SAE will be investigated by the Sponsor. If the Sponsor’s investigation 
concludes:
The SAE was unanticipated, directly related to the study product or device injection 
procedure, and presents an unreasonable risk to study subjects, the study will be 
terminated and the Investigators notified.  The IRB and RA will also be notified if the 
study is prematurely terminated due to safety concerns.  

If the SAE does not meet the above criteria, then enrollment in the study will continue.  
Reporting of unanticipated adverse device effects
The Investigator shall submit to the sponsor and to the reviewing IRB a report of any 
unanticipated adverse device effect occurring during the study as soon as possible (see US 
requirement 21 CFR 812:150 (a.), for contact details, see section 8.5.7.
Follow-up of unresolved events ongoing at termination of the study
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure and ongoing at study end, shall be followed up after the subject's 
participation in the study is over. Such events shall be followed-up after the last study visit 
until resolved, assessed as chronic or stable, or subject is lost to follow up. Follow-up 
information shall be reported on the AE follow-up form.
Reporting and follow-up of events occurring after subject termination of the study
All Adverse Events with a causal relationship to the study products or treatment procedure that 
the Investigator becomes aware of, serious as well as non-serious, with onset after the study 
termination (subject’s last study visit) shall be reported to the Sponsor by email to safety.q-
med@galderma.com. The Investigator shall follow the subject until the event as resolved.
Pregnancy
Pregnancy itself is not regarded as an AE.
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If there is a pregnancy during the study period the subject must be withdrawn from any 
following study treatment, but should continue to be followed within the study and the outcome 
of pregnancy must be reported even if the delivery occurs after study completion.
A pregnancy confirmed during the study period must be reported by the Investigator on a 
pregnancy report form immediately upon acknowledge be submitted to the Sponsor according 
to contact details specified in section 8.5.7. The report can be prospective or retrospective. 
Follow-up shall be conducted to obtain outcome information on all prospective reports. 
Cases that led to fetal distress, fetal death or a congenital abnormality or birth defect are to be 
regarded as SAEs and shall be reported on the exposure in utero report form to the Sponsor 
immediately but no later than 24 hours after the Investigators awareness. These events shall be
handled as SAEs during data processing. Other complications during the pregnancy that are 
related to the pregnant woman and fulfils any serious criteria, such as pre-eclampsia requiring 
hospitalization, shall be reported and handled as SAEs. Elective abortions without 
complications shall not be reported as AEs.
Anticipated Adverse Events
Information regarding anticipated AEs for Restylane-L is included in the study specific IFU.
Device deficiencies
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, safetyIV, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
Recording instructions
When a device deficiency is discovered, Part A of the clinical study complaint form shall be 
completed by the Investigator. The type of complaint shall be described and injury to the 
subject or user or unintended exposure to study product shall be reported as applicable. If an 
injury has occurred, an AE or an SAE form shall be completed as applicable (refer to sections 
8.5.5 and 8.5.7). 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. 
Reporting of device deficiencies
The Investigator shall send the completed clinical study complaint form to the Sponsor.
E-mail for device deficiencies reporting:
drugsafetypv@advancedclinical.com
Fax number for device deficiencies reporting:
+888–493–0910
                                                
IV Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
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A device deficiency that led to a SAE and any device deficiency that could have led to a SAE 
shall be reported to the Sponsor within 24 hours after the Investigator’s awareness (for contact 
information, see section 8.5.7). 
If the Investigator or the Sponsor assesses that the device deficiency could have led to a SAE 
the Sponsor is responsible for reporting the device deficiency to RA and the PI is responsible 
for reporting it to the IRB.
The deficient study product shall be kept by the study site until the Sponsor has confirmed 
whether the product shall be returned to Sponsor for further study or if it can be destroyed at 
the study site.
9. Data Handling and Management 
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to enter 
clinical data information into a database, efficiently and avoiding errors. The data management 
routine includes procedures for database set-up and management, data entry and verification, 
data validation, and documentation of the performed activities including information of 
discrepancies in the process. The data management process will be described in detail in the 
data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the CSP
and the CRF template. Data validation will be performed by computerized logical checks and 
manual review. Drugs and events will be coded in accordance with World Health Organization 
(WHO) Drug and medical dictionary for regulatory activities (MedDRA) dictionaries as 
specified in the DMP. Safety data (SAE and if applicable AE of special interest) in the clinical 
database will be reconciled against the data in the safety database.
When all efforts have been made to ensure that the data recorded in the eCRFs and entered in 
the database is as correct and complete as possible, the clinical database will be locked. Study
data will be transferred to SAS datasets, which thereafter will be write-protected. Statistical 
analyses will be generated in SAS using data from the locked datasets.
Electronic case report forms 
A 21 Code of Federal Regulations 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 should be completed electronically for each screen failure as well as enrolled 
subjects. 
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 should
be entered directly from the source documents, which are to be defined at each site before 
inclusion of the first subject.
Authorized study site personnel designated by the Investigator should complete data collection. 
Appropriate training and security measures should be completed with all authorized 
investigation site personnel prior to the study being initiated and any data being entered into 
the system for any subject.
The study data is the sole property of the Sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate RA, without written 
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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 should be specified in a signature and delegation log.
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.
The query process
The monitor shall review the eCRFs and evaluate them for completeness and consistency. Each 
eCRF shall be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations shall be made by 
the PI or his/her authorized designee. The monitor cannot enter data in the eCRFs. Once study
data have been submitted to the central server via the eCRF, corrections to the data fields will 
be audit trailed, meaning that the reason for change, the name of the person who made the 
change, together with time and date will be logged. Roles and rights of the site personnel 
responsible for entering study data into the eCRF shall be determined in advance. If discrepant 
data is detected during review of the data, either by the Sponsor or by its representatives, the 
responsible data manager or monitor shall raise a query in the electronic data capture 
application. The query shall state the question or data to be changed and shall be resolved in 
the system by the PI or his/her authorized designee. The appropriate study site personnel shall
answer the queries in the eCRF. This will be audit trailed by the electronic data capture 
application meaning that the name of study site personnel, time, and date is logged.
User identification
Electronic CRF records will be automatically appended with the identification of the creator, 
by means of their unique UserID. Specified records shall be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the Investigator’s unique UserID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry in 
an eCRF requires change, the correction shall be made in accordance with the relevant software 
procedures. 
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.
Source documents
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 
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criteria, and all records covering the subject’s participation in the study.  They include 
laboratory notes, memoranda, material dispensing records, subject files, etc.
The Investigator is responsible for maintaining source documents.  These should 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, 
should be clearly identified with the CTN and subject number. Any personal information, 
including name, should be removed or rendered illegible to preserve individual confidentiality.
Record keeping and access to source data
The Investigator/Institution should permit study-related monitoring, audits, IRB review, and 
RA inspections and should provide direct access to the source data/medical record including 
the identity of all participating subjects (sufficient information to link records, i.e. eCRF, 
medical records, original signed informed consent forms and detailed records of study product 
accountability).  The records should be retained by the Investigator as required by local 
legislation and international guidelines.  Any transfer of responsibility for storage of the records 
should be documented and the Sponsor should be informed in writing.
The Sponsor should 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. 
Document and data retention
All records pertaining to the conduct of the study, including signed eCRFs, informed consent 
forms, study product accountability records, source documents, and other study documentation 
must be retained for as long as is specified in the CTA.  Measures should be taken to prevent 
accidental or premature destruction of these documents (e.g. protection against damage and 
unauthorized access, preferably by storage in a fire-proof cabinet). 
It is the Investigator’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
General
A comprehensive Statistical Analysis Plan (SAP) with detailed description of all statistical 
analyses will be developed before database lock. 
All study data will be listed in subject data listings.
All statistical analyses, including summary tables and data listings, will be performed using 
SAS.  Confidence intervals (CIs) will be two-tailed and constructed at a confidence level of 
95%. Statistical tests will be performed at a significance level of 5%, and p-values will be two-
sided, unless otherwise specified.
Continuous endpoints will be summarised using descriptive statistics, e.g. number of subjects 
(n), mean, median, standard deviation, minimum and maximum values. Categorical endpoints 
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will be presented in frequency tables with number and percentage of observations for each 
level.
Analysis populations
The following populations will be defined:

Modified 
Intention-to-
treat (mITT)
Includes all subjects who are randomized and will be 
analyzed according to the randomization scheme; 
subjects with a GIHS month 3 assessment via a remote 
visit will be excluded from the mITT.

Intention-to-treat (ITT)
Includes all subjects who are randomized and will be 
analyzed according to the randomization scheme

Per protocol (PP)
Includes all subjects in ITT who complete 3 months after 
baseline visit without any deviations considered to have 
substantial impact on the primary effectiveness

Safety
Includes all subjects who were treated with Restylane-L
or randomized to the control group, and will be analyzed 
according to as-treated principle
The mITT will be used for the primary effectiveness analysis. All secondary effectiveness
endpoints will be analyzed based on the ITT population, 
 
 
 
Safety analysis is performed based on the safety population set.
The disposition of subjects will be presented in tables and/or figures as appropriate. The 
number of screened, treated, completed, and withdrawn subjects will be presented, as well as 
number of subjects in each analysis population set.
Demographics, baseline assessments, and subject characteristics
Demographic endpoints, baseline assessments, and subject characteristics will be presented 
based on the ITT analysis set using descriptive statistics by treatment, as appropriate.
Effectiveness analysis
Primary effectiveness analysis:
Responder rate based on the GIHS as assessed live by the Blinded Evaluator at month 3 after 
baseline will be the primary effectiveness endpoint. A responder will be defined as a subject 
with at least 1 point improvement from baseline on both sides of the face concurrently. For a 
significant result, the two-sided p-value of the comparison of responder rates between the 
treated and untreated subjects at month 3, using the Cochran-Mantel-Haenszel (CMH) test 
stratified by injection tool, needs to be smaller than 0.05. 
The null hypothesis will be that there is no relationship between responder rate and treatment 
group (i.e. the responder rate is the same in both groups). The alternative hypothesis will be 
that there is a relationship between responder rate and treatment group (i.e. the responder rate 
is different in the two groups).
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The estimates of the responder rate in each treatment group will be presented as well as the 
difference in responder rates. Corresponding confidence intervals for responder rates and the 
difference in responder rates along with the p-value for the difference will also be presented.
Secondary effectiveness analysis:
Responder rates (defined as at least 1 point improvement from baseline on both sides of the 
face concurrently) based on the GIHS as assessed by the Blinded Evaluator at month 6, 9, and 
12 after baseline and at 3 and 6 months after optional treatment will be analyzed in the same 
way as the primary effectiveness endpoint. No correction for multiplicity will be done; p-values 
obtained for any endpoint other than the primary will only be provided for ease of interpretation 
of the results.
All other secondary effectiveness analyses will be done descriptively as appropriate. 
Safety analysis
Number and percentage of subjects reporting each pre-defined, expected, post-treatment 
symptoms, as collected in the 28 days diary, will be presented in total and by maximum 
severity.  Number of days with the event will be presented by treatment group and category: 1, 
2-7, 8-13, and 14-28.
All AEs will be coded according to MedDRA and summarized by system organ class (SOC), 
preferred term (PT) and treatment.  
A summary of all AEs will be provided, which will include:

number of subjects with at least one AE and number of events (in total as well as serious 
AEs)

number of subjects with at least one related AE and number of events (in total as well 
as serious AEs)

number of subjects with at least one mild, moderate and severe AE and number of 
events (in total as well as serious AEs)

number of subjects with at least one unrelated AE and number of events (in total as well 
as serious AEs)

number of subjects who did not have an AE
The number of subjects with AEs related to study product or injection procedure as well as the 
number of events will be summarized by SOC, PT and maximum severity. In addition, for 
related AEs the number of days to onset and the duration of event will be summarized by SOC 
and PT using mean, SD, min, max and median.  Action taken for related AEs will also be 
summarized.  Serious AEs will be listed. AEs with onset >21 days after most recent treatment 
will be listed.
Non-related AEs will be summarized by SOC, PT and intensity.
To evaluate consistency of AEs across different subgroups, AEs will also be summarized by 
subgroups defined as described below.
Safety analysis will be descriptive only.
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Subgroup analyses
Effectiveness
The GIHS and GAIS endpoints will be analyzed in the needle group and the cannula group 
separately, using the same analysis method as for the primary analysis for GIHS, and 
descriptively for GAIS (control subjects will be pooled). 
 
 
 
 
 
CMH tests will be used for comparison of responder rates, as well as confidence intervals of 
the differences in responder rates. These will be displayed in graphs.
Safety
In order to evaluate the safety of treatment using needle and cannula respectively, AE data will 
be summarized by needle, cannula and no treatment separately.
Handling of drop-outs and missing data
Number of missing values will be summarized and reported as appropriate.
For mITT analysis of the Blinded Evaluator GIHS responder rate at month 3 after baseline 
(primary endpoint), 
. Impact of missing data on the primary endpoint will be evaluated by performing 
sensitivity analysis based on the baseline observation carried forward (BOCF) method, and the 
observed cases.
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All other effectiveness endpoints will be evaluated based on the observed cases in ITT.
Descriptive statistics of all safety data will be performed on observed cases in the Safety 
population.
Interim analysis
Not applicable.
Data monitoring committee
Not applicable.
Withdrawals and deviations
All withdrawn subjects will be listed individually, including at least subject number, date and 
reason for withdrawal, and last visit performed.
Subjects with CSP deviations will be listed individually, including subject number and 
observed deviation. Depending on the seriousness of the deviation, subject might be excluded 
from the PP population, which shall be documented prior to database lock.
Deviations from the statistical plan will be documented in the Clinical Study Report.
Sample size
Due to the public health emergency related to the COVID-19 pandemic during 2020, steps have 
been taken to ensure patient and practitioner safety in alignment with FDA Guidance dated 
May 11, 2020 (Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency). Most notably, in partnership with clinical sites and the IRB, 
optional remote assessment procedures for efficacy and safety endpoints has been implemented 
to ensure safety and respect localized and elective restrictions. Therefore, the sample size has 
been increased during the conduct of the study to ensure a sufficient number of subjects in the 
mITT population used in the assessment of the primary effectiveness endpoint.
The study was initially planned to enroll a total sample size of approximately 238 subjects; 
approximately 204 randomized to treatment with Restylane-L (~102 injected using needle, and 
~102 injected using cannula) and approximately 34 randomized to no treatment. 
Based on information on missing data and the number of remote visits performed at study sites
so far, the study is now planned to enroll approximately 329 subjects; approximately 282 will 
be randomized to treatment with Restylane-L (~146 will be injected using needle, and ~136
will be injected using cannula) and approximately 47 will be randomized to no treatment in 
order to achieve the required number of mITT subjects in each stratum.
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11. Protection of personal data
All processing of personal data must be carried out in accordance with national legislation 
concerning the protection of personal data. The Institution and the Investigator are responsible 
for complying with all requirements pursuant to national legislation in which the Institution 
and the Investigator are located. The Sponsor will ensure that all requirements for data 
processing are fulfilled.
The Investigator understands that clinical  studies  conducted  under an  IDE  are exempt from 
the  study subject identifier confidentiality provisions of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA), and the study subject should be made aware of this 
exception in the informed consent. The Institution and Investigator are jointly responsible for 
providing sufficient information to all subjects to enable them to give their informed consent 
not only to the participation in the investigation, but also to the processing of Personal Data. 
Such information includes information regarding the purposes of the processing, the length of 
time during which Personal Data will be stored, the right of access to stored Personal Data and 
the right to correction or purging of incorrect or obsolete Personal Data. A subject may also 
withdraw his or her consent at any time.
A subject who withdraws his or her consent to the processing of Personal Data must be 
considered to have withdrawn from the investigation, but the data collected until the consent 
was withdrawn may be used in the statistical analyses.
Authorized representatives from the Sponsor or a RA may visit the investigational site to 
perform audits/inspections, including source data verification, i.e., comparing data in the 
subjects’ medical records and the eCRF. Data and information will be handled with strict 
confidentiality.
The study shall include collection and processing of personal data as specified in the Regulation 
(EU) 2016/679 (General Data Protection Regulation, GDPR) on the protection of individuals
with regard to the processing of personal data. For the purposes of the study, Sponsor will be 
considered the data controller, and Institution and PI will both be considered data processors.
12. Quality Control and Quality Assurance
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. 
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Any CSP deviation shall be documented appropriately, verified, discussed, and collected by 
the monitor and appropriate actions will be taken. The PI is responsible for promptly reporting
any deviations from the CSP that affects the rights, safety or well-being of the subject or the 
scientific integrity of the study, including those that occur under emergency circumstances, to 
the Sponsor as well as the IRB if required by national regulations. Deviations will be reviewed 
to determine the need to amend the CSP or to terminate the study.
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.
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.
Changes to the clinical study protocol
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 
IRB 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. 
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 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 
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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 resolvedV. 
Conditions 1, 2, 3, and 4 must all be met in order to be designated as author. Those who do not
meet all four criteria will be acknowledged. Among the authors that fulfil the above mentioned 
criteria, one author will be appointed by Q-Med AB to take primary responsibility for the 
overall work as primary author.
15. Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IRB or RA, or if it 
is judged that the subjects are subjected to unreasonable risks, or for valid scientific or 
administrative reasons, or for business reasons.
The Sponsor may also decide to close a single study site due to unsatisfactory subject enrolment 
or non-compliance with the CSP, GCP, or applicable regulatory requirements.
In the event of premature termination, Q-Med AB will provide information on the handling of 
currently enrolled subjects who have not completed the study.
                                                
V 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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16. References
1.
Alam M, Gladstone H, Kramer EM, et al. ASDA guidelines of care: injectable fillers. Dermatol Surg. 2008; 
34 (suppl 1): S115-S148.
2.
Fitzpatrick T.B. (1988). The validity and practicality of sun-reactive skin types I through VI. Arch. 
Dermatol. 124, 869–871.
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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.
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9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, 
right to self-determination, privacy, and confidentiality of personal information of research subjects. The 
responsibility for the protection of research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given consent.
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that minimises possible harm to the environment.
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.
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20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs or 
priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this 
group should stand to benefit from the knowledge, practices or interventions that result from the research.
Scientific Requirements and Research Protocols
21. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research 
must be respected.
22. The design and performance of each research study involving human subjects must be clearly described and 
justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding 
funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.
Research Ethics Committees
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
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.
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After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed.
All medical research subjects should be given the option of being informed about the general outcome and 
results of the study.
27. When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent must be sought by an appropriately qualified individual who 
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the health of the 
group represented by the potential subject, the research cannot instead be performed with persons capable of 
providing informed consent, and the research entails only minimal risk and minimal burden.
29. When a potential research subject who is deemed incapable of giving informed consent is able to give assent 
to decisions about participation in research, the physician must seek that assent in addition to the consent of 
the legally authorised representative. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed consent have been 
stated in the research protocol and the study has been approved by a research ethics committee. Consent to 
remain in the research must be obtained as soon as possible from the subject or a legally authorised 
representative.
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
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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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Appendix 2
Galderma Infraorbital Hollows Scale (GIHS)
The following validated scale will be used to assess Infraorbital Hollows assessed by Blinded 
evaluator and Treating Investigator.
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Appendix 5
Summary of changes to the clinical study protocol
Summary of Changes in Clinical Study Protocol 43USTT1904 from Version 
9.0 to Version 10.0
Section in the 
clinical study 
protocol
Rational for changes
Description of changes
Synopsis, and section 
3.1.2
Synopsis, sections 
10.4.1, 10.4.2, and 
10.6.1
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Sign page:1 of 1
SIGNATURES PAGE
Date
Signed by
2021-12-15 07:46
Justification
Approved by Technical Expert
2021-12-15 10:57
Justification
Approved by Technical Expert
2021-12-15 14:56
Justification
Approved by Project Manager
2021-12-15 20:29
Justification
Approved by Owner
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PPD
PPD
PPD
PPD