A Randomized, Multi-center, Evaluator-blinded, No-treatment Controlled Study to Evaluate the Effectiveness and Safety of Sculptra for Correction of Midface Volume Deficit and/or Midface Contour Deficiency
Phase: NA
Conditions: Midface Volume Deficit
Sponsor: Galderma R&D

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A randomized, multi-center, evaluator-blinded, no-treatment controlled study to evaluate 
the effectiveness and safety of Sculptra for correction of Midface Volume Deficit and/or 
Midface Contour Deficiency
Study product:
Sculptra
Clinical Trial Number (CTN):
43CHSA1803
Sponsor:
Q-Med AB
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. Except as may 
be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold 
such information in confidence and neither disclose it to any third parties (except where 
required by applicable law) nor use it for any other purpose than in relation to the clinical 
study described herein.
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Summary of Changes in Clinical Study Protocol 43CHSA1803 from Version 1.0 to Version 
2.0
Added text is written in bold and deleted text is written as strikethrough.
Section in 
protocol
Rational for changes
Description of changes
Study 
Administrative 
Structure
Medical Expert 
changed.
Sponsor 
Signatures
The name of 
company was added.
, Q-Med 
AB 
Sponsor 
Signatures
Medical Expert 
changed.
Sponsor’s 
, Q-Med AB
Synopsis:
Study Design
Clarify.
Before start of enrolment into Group B, the injection 
technique will be evaluated by the Sponsor or designee of 
Sponsor and performed after the subjects in Group A for 
each investigator have received their first treatment, and 
second treatment. 
4.1 General 
Outline
Clarify.
Before start of enrolment into Group B, the injection 
technique will be evaluated by the Sponsor or designee of 
Sponsor and performed after the subjects in Group A for 
each investigator have received their first treatment, and 
second treatment. 
8.3.8 
Anticipated 
Adverse 
Events
According to the 
suggestion of the 
leading site EC, AEs 
description and 
precautions were 
added.
Information regarding anticipated AEs below is also
included in the Sculptra Investigators Brochure. 
Subcutaneous papules/, invisible but palpable or visible 
nodules including periorbital nodules, or areas of 
induration have been noted in the injection area. 
Nodules are occasionally associated with inflammation 
or discolouration. The early occurrence of subcutaneous 
nodules at the injection site (within 3–6 weeks after 
treatment) may be minimised by adhering to proper 
dilution and injection techniques. Delayed occurrences of 
subcutaneous nodules at the injection site (within 1–14 
months post injection) have been reported with 
sometimes a prolonged duration of up to 2 years. 
Improper injection techniques such as superficial 
placement, excessive amount of product or incorrect 
reconstitution may lead to appearance of papules or 
nodules at the injection site. Massaging the treatment 
area to ensure proper distribution of the product may 
minimise the appearance of such papules or nodules. 
For nodular areas or late granuloma formation, in some 
cases, they resolved spontaneously or following 
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treatment with multiple intralesional injections of 
corticosteroids and/or antineoplastic agents (e.g. 5-
fluorouracil). Surgical excision of the nodules was 
sometimes required when they were larger in size, 
occurring in difficult anatomical regions (e.g. lower 
eyelid) or persisting after other treatments.
This product must not be injected intramuscularly or 
intravascularly. 
Localised 
superficial 
necrosis 
and 
scarring may occur after injection in or near vessels. It is 
thought to result from the injury, obstruction, or 
compromise of blood vessels. Special caution should be 
taken if the patient has undergone a prior surgical 
procedure in the planned treatment area. Areas with 
limited collateral blood flow has an increased risk of 
ischaemia. Aspiration prior to injection is recommended. 
Unintentional introduction of soft tissue fillers into the 
vasculature in the face may lead to embolisation, 
occlusion of the vessels, ischaemia, necrosis or infarction 
at the implant site or in the area supplied by the blood 
vessels affected. Rare but serious adverse events include 
temporary or permanent vision impairment, blindness, 
cerebral ischaemia or cerebral haemorrhage leading to 
stroke, skin necrosis, and damage to underlying facial 
structures. Immediately stop the injection if any of the 
following symptoms occurs, including changes in vision, 
signs of a stroke, blanching of the skin, or unusual pain 
during or shortly after the procedure. Patients should 
receive 
prompt 
medical 
attention 
and 
possibly 
evaluation by an appropriate health care practitioner 
specialist, should an intravascular injection occur.
Subject 
information 
and informed 
consent form
Updates required: 
Yes  
   No  
Electronic case 
report form 
(eCRF)
Updates required:
Yes  
No  
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Study Administrative Structure
Sponsor
Q-Med AB
Seminariegatan 21
SE-752 28  Uppsala, Sweden
Telephone:
+46 18 474 90 00
Facsimile:
+46 18 474 90 01
 
Clinical Project Manager
Study Statistician
Further details on all participating Investigators and the complete administrative structure of the study 
are found in the study files. Note that administrative changes are to be documented in the study files 
without requiring a clinical study protocol (CSP) amendment.
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Sponsor Signatures
The CSP is electronically signed in the document management system within the Q-
Med AB quality management system by the representatives listed below.
Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Sponsor’s 
, Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Clinical Project Manager, Q-Med AB
Electronically signed in the document 
management system within Q-Med 
quality management system
Study Statistician, Q-Med AB
Electronically signed in the document 
management system within Q-Med quality 
management system 
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Signed Agreement of the Clinical Study Protocol
CTN:                                                      43CHSA1803
Title of the CSP:
A 
randomized, 
multi-center, 
evaluator-blinded, 
no-
treatment controlled study to evaluate the effectiveness 
and safety of Sculptra for correction of Midface Volume 
Deficit and/or Midface Contour Deficiency
I, the undersigned, have read and understand the protocol specified above, and agree on the 
contents. The study protocol, the Clinical Trial Agreement and the additional information 
given in the Investigator Brochure for Sculptra 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, multi-center, evaluator-blinded, no-treatment controlled study to 
evaluate the effectiveness and safety of Sculptra for correction of Midface Volume 
Deficit and/or Midface Contour Deficiency 
Clinical Trial Number:  
43CHSA1803
Countries involved, 
number of 
sites/country, number 
of subjects:
The study will be conducted at approximately 8 sites in China. 
Group A:
Each Treating Investigator will enroll 1 or 2 subjects as group A. These subjects will 
all receive treatment with Sculptra.
Group B:
Evaluator treatment-blind group with approximately 189 subjects will be 
randomized in a 2:1 ratio to treatment group or no-treatment control group, i.e.,
126 Subjects assigned to the Treatment Group and 63 subjects assigned to the 
Control Group.
Objectives:
To evaluate the effectiveness of Sculptra in the treatment of Midface 
Volume Deficit and/or Midface Contour Deficiency
To evaluate the safety of Sculptra in the treatment of Midface Volume 
Deficit and/or Midface Contour Deficiency
Endpoints:
Primary effectiveness endpoint: 
Percentage of responders, defined by at least 1 point improvement from baseline 
on the Medicis Midfacial Volume Scale (MMVS) on both sides of the face 
concurrently, as measured by the blinded evaluator at 12 months in both 
Treatment Group and Control group.
Secondary effectiveness endpoints:
Percentage of responders, defined by at least 1 point improvement from 
baseline on the MMVS on both sides of the face concurrently, as measured by 
the blinded evaluator at 6, 9, 18 and 24 months in Treatment Group, and at 6 
and 9 months in Control Group.
Percentage of responders, defined by at least 1 point improvement from 
baseline on the MMVS on both sides of the face concurrently, as measured by 
the treating investigator at 6, 9, 12, 18 and 24 months in Treatment Group, 
and at 6, 9 and 12 months in Control Group.
Volume change from baseline over time of the right and left midface areas 
combined, as measured by digital 3D photography at 6, 9, 12, 18 and 24
months in Treatment Group, and at 6, 9 and 12 months in Control Group.
Percentage of responders, defined by having “Improved”, “Much improved” 
or “Very much improved” according to the Global Aesthetic Improvement 
Scale (GAIS) on both sides of the face combined, as assessed by the subject 
and the treating investigator at 6, 9, 12, 18 and 24 months in Treatment 
Group, and at 6, 9 and 12 months in Control Group.
Percentage of subjects in each response category of each question in the
subject satisfaction questionnaire in Treatment Group at 6, 9, 12, 18 and 24
months.
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* Time of the Follow up visits at 6, 9, 12, 18 and 24 months is calculated from 
baseline/randomization.
Safety endpoints:
Incidence, intensity, duration, and onset of adverse events (AEs) collected 
throughout the study.
Incidence, intensity, and number of days of anticipated injection related 
reactions, collected using 4-week subject diaries after each treatment session 
for the Treatment Group.
Study Design:
For Group A, after screening, eligible subjects will be treated from day 1 and 
followed up for 24 months. 
For Group B, the study includes two phases as follows: 
Main study phase: It is randomized, evaluator-blinded and no-treatment 
controlled. After screening, all eligible subjects will be randomized either to the 
Treatment Group or the Control Group in a 2:1 ratio. All the subjects will be 
followed up for 12 months.  
Extension study phase: After the main study phase, the Treatment Group will be 
followed up for additional 12 months. 
Each Treating Investigator will enroll 1 or 2 subjects as Group A. Before start of 
enrolment into Group B, the injection technique will be evaluated by the Sponsor
or designee of Sponsor and performed after the subjects in Group A for each 
investigator have received their first treatment, and second treatment. If 
treatments are found to be correctly performed, no further training is needed, 
there are no outstanding questions regarding the injection technique and no other 
corrective actions are identified, the enrolment in Group B can start for that 
investigator. 
Summaries of the results for Group A and B will be done separately in the study 
report.
Treatment 
Each subject assigned to Group A and Treatment Group will receive up to 4 
injection sessions with 5(±1) weeks (at least 4 weeks) intervals. Initial treatment 
will be on Day 1. Study treatments should be stopped if optimal midface 
augmentation has been obtained or a maximum of 4 injection sessions completed.
Subjects assigned to the Control Group will not receive treatment during the study.
Evaluation of effectiveness
Midface fullness will be assessed using a separate Four-Point MMVS with photo 
guides for the right and left side by the treating investigator at each visit; and by 
the blinded evaluator at screening, baseline, 6, 9, 12, 18 and 24 months in Group 
A and Treatment Group, and at screening, baseline, 6, 9 and 12 months in Control 
Group.
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The measurement of volume change in the midface (right and left combined) from 
baseline will be calculated by 3D digital image analysis at 6, 9, 12, 18 and 24 months 
in Group A and Treatment Group, and at 6, 9 and 12 months in Control Group.
Aesthetic improvement of the Midface fullness will be assessed by the subject and 
the treating investigator, independent of each other, at each follow-up visit using
the 5-graded GAIS. Photographs of baseline condition will be used as reference.
Subjects will be asked about their satisfaction with the treatment outcome using a 
questionnaire at 6, 9, 12, 18 and 24 months in Group A and Treatment Group.
Evaluation of safety
Information regarding AEs will be collected continuously during the study. 
4-week subject diaries will also be used after each treatment session for Group A 
and Treatment Group to collect information about anticipated injection related 
reactions (i.e. pain, tenderness, localized redness, bruising, hematoma, edema, 
and “other”).
Interim Analysis
An interim analysis will be performed when the month 12 visit completed for all 
the subjects.
Inclusion criteria: 
The subject must meet the following criteria to be eligible for the study:
1.
Signed and dated informed consent to participate in the study.
2.
Men or women aged 18 years of age or older of Chinese origin.
3.
Subjects seeking augmentation therapy for the midface.
4.
MMVS score of 2, 3 or 4 on each side of the face as assessed by the blinded 
evaluator.
Exclusion criteria:
The presence of any of the following exclusion criteria will exclude a subject from 
enrolment in the study:
1.
Known/previous allergy or hypersensitivity to any of the constituents of 
the product.
2.
Known/previous allergy or hypersensitivity to local anaesthetics, e.g. 
lidocaine or other amide-type anaesthetics.
3.
History of severe or multiple allergies, such as anaphylaxis. 
4.
Previous tissue revitalization treatment with laser or light, mesotherapy, 
radiofrequency, 
ultrasound, 
cryotherapy, 
chemical 
peeling 
or 
dermabrasion in the area to be treated within 6 months before treatment.
5.
Previous surgery (including aesthetic facial surgical therapy or 
liposuction), piercing or tattoo in the area to be treated. 
6.
Previous tissue augmentation therapy or contouring with any permanent 
(non-biodegradable) or semi-permanent filler, autologous fat, lifting 
threads or permanent implant in the area to be treated. 
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7.
Previous use of any hyaluronic acid based or collagen based biodegradable 
facial tissue augmentation therapy in the area to be treated within 12 
months before treatment.
8.
Previous use of any neurotoxin below the level of the lower orbital rim on 
the face within 9 months before treatment.
9.
Presence of any disease or lesions near or at the area to be treated, e.g.
- Inflammation, active or chronic infection (e.g., in mouth, head and 
neck region);
- Facial psoriasis, eczema, acne, rosacea, perioral dermatitis, herpes 
simplex or herpes zoster;
- Scars or deformities;
- Cancer or pre cancer (e.g. actinic keratosis).
10. History of cancer or radiation in the area to be treated.
11. Subjects with a 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 6 
months prior to treatment or planned surgery, including dental implants, 
during the study period.
12. History of or active collagen diseases such as systemic lupus 
erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis or 
localized or systemic scleroderma.
13. Tendency to form keloids, hypertrophic scars, or any other healing 
disorder.
14. History of bleeding disorders or treatment with thrombolytics, 
anticoagulants or inhibitors of platelet aggregation (e.g. aspirin or other 
non-steroid anti-inflammatory drugs (NSAIDs), Omega-3, or vitamin E 
within a relevant period before treatment, per the investigator’s 
judgment.
15. Treatment 
with 
chemotherapy, 
immunosuppressive 
agents, 
immunomodulatory therapy (e.g. monoclonal antibodies), systemic 
corticosteroids within 3 months before treatment (inhaled corticoids are 
allowed).
16. Treatment with topical (facial below the level of the lower orbital rim) 
retinoids or corticosteroids within 1 month, or systemic retinoids within 6 
months before treatment.
17. Any medical condition that in the opinion of the Investigator would make 
the subject unsuitable for inclusion.
18. Other condition preventing the subject from entering the study in the 
Investigator’s opinion, e.g. subjects not likely to avoid other facial 
cosmetic treatments, subjects anticipated to be unreliable, unavailable or 
incapable of understanding the study assessments or having unrealistic 
expectations of the treatment result.
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19. Women who are pregnant or breast feeding, or Woman of childbearing 
potential who are not practicing adequate contraception or planning to 
become pregnant during the study period. 
20. Subjects planning to accept any other facial plastic surgical or cosmetic 
procedures below the level of the lower orbital rim during the study (e.g., 
laser or chemical resurfacing, needling, facelift, radiofrequency etc.).
21. The presence of moderate or severe abnormal rating for midface 
symmetry, i.e. more than 1 point difference in MMVS score between each 
side of the face.
22. Intention to change a significant amount of weight (≥2 BMI) during the 
study period.
23. 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. 
24. Participation in any other clinical study within 30 days before treatment. 
Investigational 
product, 
dose and mode of 
administration:
Sculptra is a poly-L-lactic acid implant in the form of a sterile non-pyrogenic 
suspension, which is reconstituted from a sterile dry powder by the addition of 
sterile water for injection. This suspension contains microparticles of poly-L-lactic 
acid, a crystalline form of polylactic acid.
Sculptra dry powder is supplied after aseptic filtration sterilisation in a sterile 
elongated clear glass vial. Each vial of dry powder contains: 150mg microparticles 
of poly-L-lactic acid (PLLA), 90mg sodium carboxymethylcellulose, 127.5mg non-
pyrogenic mannitol.
Sculptra powder should be reconstituted extemporaneously with 8 mL of sterile 
water for injection. Prior to injection, optionally add another 1 mL of local 
anaestethic lidocaine (20 mg/mL) to the vial. 
Scuptra should be injected into the deep dermis, subcutaneous layer or 
supraperiosteal layer with a 25-26 G needle. 
Scuptra will be administered inferior to the maxillary prominence, superior to the 
plane of nasal alae, including the area from the lateral canthus to the medial 
canthus and lateral to the nose on the subject’s right and left sides. When 
appropriate, the study product could be injected into the lateral and inferior
adjacent areas to ensure a smooth transition of midface contour.
Each subject will receive up to 4 injection sessions with 5(±1) weeks intervals. 
Study treatment injections should be stopped if optimal midface augmentation has
been obtained or a maximum of 4 injection sessions completed.
1 vial is generally recommended at each treatment session, i.e., initial treatment 
or each optional treatment respectively. Maximum 2 vials can be used for each 
treatment session at the discretion of the investigator.
Reference therapy, 
dose and mode of 
administration:
Not applicable.
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Much improved
Marked improvement in appearance from the 
original condition, but not completely optimal for this 
subject.
Improved
Obvious improvement in appearance from the 
original condition.
No change
The appearance is essentially the same as original 
condition.
Worse
The appearance is worse than the original condition.
Subject satisfaction questionnaire
Subjects in Group A and Treatment Group will be asked about their satisfaction 
with the treatment outcome using a subject satisfaction questionnaire.
Safety Assessment:
AE will begin to be collected after ICF signed. Each subject will be questioned about 
AEs at each clinical visit following the screening visit. The question asked will be 
“Since your last clinical visit have you had any health problems Information on AEs 
can also be obtained from laboratory test report, signs and symptoms detected 
during each examination, observations by the study personnel, subject diaries or 
spontaneous reports from the subjects.
Anticipated injection related reactions will be collected using 4-week subject 
diaries after each treatment session for Group A and Treatment Group. The subject 
will record the presence and maximum intensity of anticipated injection related 
reactions, i.e. pain, tenderness, localized redness, bruising, hematoma, edema, 
and “other”). 
The Investigator will assess the presence of any papules (˂ 5mm in diameter) or 
nodules (≥5mm in diameter). If present, the papules/nodules will be recorded as 
AE and should be further assessed as visible/non-visible and inflammatory/non-
inflammatory.
Statistical Methods: 
All summaries will be done separately for Group A and B. For statistical inference, 
only Group B will be used.
Primary analysis
The percentage of responders (a responder will be defined as a subject with at 
least 1 point improvement from baseline MMVS on both sides of the face 
concurrently) will be calculated at 12 months based on the blinded evaluator's 
assessment. The percentage of responders in the Sculptra treated subjects will 
then be compared with the percentage of responders in the no-treatment control 
group using a Fisher's exact test at a significance level of 5%. In addition, for each 
group the two-sided 95% confidence intervals around the estimates of the 
percentage of responders will also be calculated. The treatment will be deemed a 
success if the p-value for the treatment difference on the primary endpoint is less 
than 0.05.
Secondary analysis
The percentage of responders based on the MMVS on both sides of the face 
concurrently will also be derived at all applicable follow-up visits for both the 
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blinded evaluator’s assessment and the treating investigator’s assessment 
respectively. The response rates and their 95% confidence interval will be 
presented by visit and group. 
Fisher’s exact test will be used to compare the response rates at Month 6 and 9 
based on the blinded evaluator’s assessment. For response rates based on the 
treating investigator’s assessment, response rates will be compared at Month 6, 9 
and 12 using Fisher’s exact test.
The volume change in the midface area as compared with baseline (right and left 
sides combined) obtained by 3D imaging will be presented by treatment for all 
applicable follow-up visits. 
GAIS (by treating investigator and subject) and satisfaction with the treatment 
outcome will be analyzed descriptively.
Safety
Anticipated injection related reactions, as collected in Treatment Group, as 
collected in 4-week diaries after each treatment session, will be summarized using 
frequency tables. Adverse event incidences will be summarized by MedDRA 
system organ class (SOC) and preferred term (PT).
Sample size
There are no available clinical data for Sculptra studied under conditions similar to 
the current study. However, based on what is seen in clinical studies of injectable 
fillers in the facial areas, it is reasonable to assume a response rate of at least 60% 
in the Sculptra Treatment Group at Month 12. For the no treatment Control Group, 
response rate of 25.8% has been observed in an ongoing clinical trial in China. 
Based on this, it was assumed that the response rate will be maximum 30% in the 
no-treatment Control Group at Month 12.
With a sample size of 100 subjects treated with Sculptra and 50 subjects in the no-
treatment control group, Fisher’s Exact test will have approximately 90% power to 
detect difference between the anticipated percentage of responders at a 5%
significance level (two-sided). To account for 20% drop-outs, approximately 126
will be randomized to the Sculptra group and approximately 63 to the control
group.
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Abbreviations and definitions of terms 
AE
Adverse Event 
Blinded Evaluator
An evaluator responsible for independent evaluation of treatment 
result(s). The evaluator must not be involved in the treatment of the 
subject.
Co-ordinating 
Investigator
An Investigator assigned the responsibility for the coordination of 
Investigators at different centers participating in a multicenter study
CSP
Clinical Study Protocol
CTA
Clinical Trial Agreement
CTN
Clinical trial number
CV
Curriculum vitae
Device deficiency
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance (includes malfunctions, use 
errors, and inadequate labelling)
DMP
Data management plan
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
G
Gauge
GAIS
Global Aesthetic Improvement Scale
GCP
Good Clinical Practice
HA
Hyaluronic acid
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IFU
Instructions for Use
Investigational 
product
Medical device being assessed for safety or performance in a study. 
“Investigational product” is the same as “study device”, “investigational 
device”, or “investigational medical device”.
Institution
Any public or private entity or agency or medical or dental facility where 
clinical studies are conducted.
Investigator
The Principal Investigator or other qualified person, i.e. sub-Investigator, 
designated and supervised by the Principal Investigator at a study site to 
perform critical study-related procedures and/or make important study-
related decisions as specified on the delegation log. 
Investigator File
Essential documents relating to a clinical study as defined in GCP 
guidance document and maintained by the Investigator.
MedDRA
MMVS
NMPA
Medical Dictionary for Regulatory Activities
Medicis Midface Volume Scale
National Medical Products Administration
NSAIDs
non-steroid anti-inflammatory drugs
PI 
Principal Investigator
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PP
Per protocol
QA
Quality assurance
RA
Regulatory authority
PT
Preferred term
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDV
Source data verification
SOC
System organ class 
Sponsor file
Essential documents relating to a clinical study as defined in applicable 
GCP guidance document and maintained by the Sponsor.
U-HCG
Urinary human chorionic gonadotropin
WHO
World Health Organization
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Table of Contents
SUMMARY OF CHANGES IN CLINICAL STUDY PROTOCOL 43CHSA1803 FROM VERSION 1.0 TO 
VERSION 2.0
2
STUDY ADMINISTRATIVE STRUCTURE
4
SPONSOR SIGNATURES
5
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL
6
SYNOPSIS
7
ABBREVIATIONS AND DEFINITIONS OF TERMS
15
TABLE OF CONTENTS
17
1
ETHICAL CONSIDERATIONS
20
2
BACKGROUND INFORMATION
20
2.1
Indication and population description
20
2.2
Investigational product description
20
2.3
Reference product description
21
2.4
Previous experience
21
2.4.1
Non-Clinical Documentation
21
2.4.2
Clinical Documentation
21
2.5
Study rationale and Justification for design
22
2.6
Risk and benefits
22
3
OBJECTIVES AND ENDPOINTS
23
3.1
Objectives of the study
23
3.2
Endpoints of the study
24
3.2.1
Primary effectiveness endpoint:
24
3.2.2
Secondary effectiveness endpoints:
24
3.2.3
Safety endpoints:
24
4
DESIGN OF THE STUDY
24
4.1
General Outline
24
4.2
Number of Subjects
26
4.3
Duration of Subject Participation
26
4.4
Randomization and blinding
26
4.4.1
Randomization
26
4.4.2
Blinding
27
4.4.3
Emergency unblinding
27
4.5
Medical history
27
4.6
Concomitant Medication, Treatment, and Procedure
27
4.7
Schedule of events
29
4.8
Visits
32
4.8.1
Visits for Group A and Treatment Group
32
4.8.2
Visits for Control Group
34
5
SUBJECTS
35
5.1
Subject information and informed consent
35
5.2
Inclusion Criteria
35
5.3
Exclusion Criteria
36
5.4
Screening and Subject Numbers
37
5.5
Withdrawal of Subjects
38
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6
STUDY PRODUCTS
39
6.1
Investigational Product
39
6.2
Reference Product
39
6.3
Additional Products and Materials
39
6.4
Reconstitution instructions
39
6.5
Packaging, Labelling and Storage
40
6.6
Product accountability
40
6.7
Treatment
41
6.7.1
Treatment Procedure
41
6.7.2
Treatment regimen (dose)
42
6.7.3
Post-treatment Care
43
6.7.4
Post-trial provisions
43
6.7.5
Electronic case report form recordings
43
6.7.6
Treatment compliance
43
7
EFFECTIVENESS ASSESSMENTS
43
7.1
General information
43
7.2
Photography
44
7.3
Medicis Midface Volume Scale (MMVS)
44
7.4
3D Digital Imaging analysis
45
7.5
Global Aesthetic Improvement Scale (GAIS)
45
7.6
Subject satisfaction questionnaire
45
8
SAFETY ASSESSMENTS
47
8.1
Anticipated injection related reactions
47
8.2
Laboratory assessment
47
8.3
Adverse Events
48
8.3.1
Definition of Adverse Events
48
8.3.2
Definition of Serious Adverse Event
48
8.3.3
Recording Instructions
48
8.3.4
Reporting of Adverse Events
50
8.3.5
Reporting of Serious Adverse Events
50
8.3.6
Follow-up of Unresolved Events after study termination and new Events after study termination.
52
8.3.7
Pregnancy
52
8.3.8
Anticipated Adverse Events
52
8.4
Device Deficiencies
53
8.4.1
Definition of Device Deficiency
53
8.4.2
Recording Instructions
53
8.4.3
Reporting Device Deficiency
54
9
DATA HANDLING AND MANAGEMENT
54
9.1
Data management
54
9.2
Electronic case report forms
55
9.2.1
Data entry
55
9.2.2
The query process
55
9.2.3
User identification
56
9.2.4
Audit trail
56
9.3
Source documents
56
9.4
Record keeping and access to source data
56
9.5
Document and data retention
57
10
STATISTICAL METHODS
57
10.1
General
57
10.2
Analysis Populations
57
10.3
Demographics, baseline assessments, and subject characteristics
58
10.4
Effectiveness Analysis
58
10.5
Safety Analysis
59
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10.6
Handling of Missing Data
59
10.7
Interim Analysis
59
10.8
Data monitoring committee
60
10.9
Withdrawals and deviations
60
10.10
Sample Size
60
11
PROTECTION OF PERSONAL DATA
60
12
QUALITY CONTROL AND QUALITY ASSURANCE
61
12.1
Quality control
61
12.2
Quality assurance
61
12.3
Changes to the clinical study protocol
61
13
FINANCING, INDEMNIFICATION, AND INSURANCE
62
14
PUBLICATION POLICY
62
15
SUSPENSION OR PREMATURE TERMINATION
62
16
REFERENCES
63
17
APPENDICES
65
List of Tables
Table 1. Schedule of Events for Group A and Treatment Group............................................29
Table 2. Schedule of Events for Control Group ......................................................................31
Table 3. Medicis Midface Volume Scale .................................................................................44
Table 4.  Global Aesthetic Improvement Scale.......................................................................45
Table 5.  Grading for pain, tenderness, localized redness, bruising, hematoma and edema,  in 
the subject diary ......................................................................................................................47
List of Figures
Figure 1.  Flow chart……………………………………………………………………………………………………………….……….26
Figure 2. Treatment Area...……………………………………………………………….……….…………….………….…………42
List of Appendices
Appendix 1
Declaration of Helsinki 
Appendix 2
Photo guide for Medicis Midface Volume Scale
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1
Ethical Considerations
1.1 Statement of ethical compliance
The study shall be conducted in compliance with the Clinical Trial Agreement (CTA), the 
Clinical Study Protocol (CSP), applicable Good Clinical Practice (GCP), and applicable regional 
or national regulations. The international standard for clinical study of medical devices for 
human subjects, ISO14155:2011 shall be followed. The International Conference on 
Harmonisation (ICH) guideline for GCP (E6) shall be followed as applicable for medical device. 
The study shall be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki (Appendix 1).
1.2 Application to independent ethics committee and/or regulatory authorities
It is the responsibility of the Principal Investigator (PI) to obtain approval of the 
CSP/CSP amendment(s) from the independent ethics committee (IEC). The study shall not 
begin until the required favourable opinion from the IEC has been obtained. The PI shall file 
all correspondence with the IEC in the Investigator file and copies of IEC approvals shall be 
forwarded to the Sponsor. Any additional requirements imposed by the IEC or regulatory 
authorities (RA) shall be followed. 
The collection, access to, processing, and transfer of protected health information or sensitive 
personal data shall be carried out in accordance with applicable rules and regulations.
2
Background Information
2.1
Indication and population description
In Europe, Sculptra is indicated as a medical device for increasing the volume of depressed 
areas, particularly to correct skin depressions, such as in skin creases, wrinkles, folds, scars, 
and for skin aging. Sculptra is also suitable for large volume corrections of the signs of facial 
fat loss (lipoatrophy). 
In this study, Chinese subjects of at least 18 years old will be studied to evaluate the 
effectiveness and safety of Sculptra in the treatment of Midface Volume Deficit and/or 
Midface Contour Deficiency. Subjects with grade 2, 3 or 4 of MMVS on each side of the face 
as assessed by the blinded evaluator will be included.
2.2
Investigational product description 
Sculptra is a poly-L-lactic acid implant in the form of a sterile non-pyrogenic suspension, which 
is reconstituted from a sterile dry powder by the addition of sterile water for injection. This 
suspension contains microparticles of poly-L-lactic acid, a crystalline form of polylactic acid. 
Poly-L-lactic acid is a biocompatible, biodegradable, synthetic polymer from the alpha-
hydroxy-acid family.
Sculptra dry powder is supplied after aseptic filtration sterilisation in a sterile elongated clear 
glass vial with an aluminium ring at one end, which is hermetically sealed by a rubber bung, 
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covered by a flip-off cap. Each vial of dry powder contains: 150mg microparticles of poly-L-
lactic acid (PLLA), 90mg sodium carboxymethylcellulose, 127.5mg non-pyrogenic mannitol.
Sculptra dry powder is reconstituted with 8 mL of sterile water for injection to form a sterile 
nonpyrogenic suspension. As an optional means to provide pain relief during the injection 
procedure, an additional 1 mL of sterile 2% (20 mg/mL) lidocaine solution may be added to 
the vial of reconstituted product prior to injection for a final volume of 9 mL 
(Section“Treatment procedure”).
Sculptra consists of a suspension of solid poly-L-lactic particles with a defined narrow particle 
size distribution and slow degradation kinetics due to high molecular weight and high degree 
of crystallinity. The particle size and narrow particle size distribution enables the injection of 
the poly-L-lactic particles into the deep dermis or subcutaneous layer, where they provide 
soft tissue augmentation that will improve over the course of a few weeks, as the 
microparticles are gradually surrounded by host connective tissue.
For further description of Sculptra, refer to the Investigator Brochure.
2.3
Reference product description
Not applicable as no filler intended for midface volume deficit and/or midface contour 
deficiency is available in China at the time of this protocol.
2.4
Previous experience
2.4.1
Non-Clinical Documentation
A biological evaluation of Sculptra has been performed according to ISO 10993-1 (Biological 
evaluation of medical devices – Part 1: Evaluation and testing within a risk management 
process.) and data from the biological testing of Sculptra have shown that the product is safe 
and does not cause irritation, toxicity or any unwanted local effects after implantation. On a 
microscopic level, the product has been judged to be a moderate irritant. Furthermore, a 
pyrogenicity study was performed and the product is non-pyrogenic. 
The biological evaluation for Sculptra concludes that the nonclinical testing is relevant when 
assessing the biocompatibility profile. It is concluded that the biocompatibility testing 
performed on Sculptra is sufficient and supports the intended clinical use.
2.4.2
Clinical Documentation
2.4.2.1
Manufacturer-sponsored or acquired clinical studies
The safety and effectiveness of Sculptra as a treatment to correct the signs of facial fat loss in 
patients with HIV-associated lipoatrophy has been demonstrated in 6 clinical studies with 
extended follow-up periods (up to 5 years) and more than 650 subjects 1-5. All 6 studies were 
open label and non-comparative with regards to the product. Sculptra was proved to be a 
long term, well-tolerated and effective treatment for facial lipoatrophy in subjects 
seropositive for HIV. The clinical efficacy of Sculptra was maintained during the follow-up 
periods; all measures of efficacy in the studies showed improvement with Sculptra.
The use of Sculptra in the correction of facial wrinkles and folds was evaluated in four clinical 
studies, including a randomized evaluator blinded study comparing PLLA against a collagen 
implant for treatment of nasolabial folds6-8, the study results demonstrated wrinkle severity 
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improvement and global aesthetic improvement compared to the pre-treatment condition, 
as well as subject satisfaction with the results. 
Sculptra demonstrated an acceptable safety profile in the HIV-positive patients and treatment 
related AEs were generally limited to transient events associated with the immediate 
injection procedure. Long-term AEs, even with a follow-up period of up to 5 years, were 
limited to small, asymptomatic subcutaneous nodules and papules in the treatment area. The 
results were similar in the immune competent subjects.
Post market surveillance data for Sculptra also support that the AE profile is acceptable.
2.4.2.2
Clinical data in the published literature 
Sculptra has been also documented in scientific publications. Articles reporting results from 
sponsored studies associated with the manufacturer were omitted from the analysis because 
the data is covered in Section 2.4.2.1 above.
The results from treatment of HIV and non-HIV-associated facial lipoatrophy demonstrated, 
the aesthetic improvement remained at least 18 months after last treatment with some 
variation between subjects and studies9-22. Results from correction of wrinkles, folds, volume 
loss, skin depressions, in immune-competent subjects have also demonstrated aesthetic 
improvement remained for up to 36 months and 24 months (facial volume and nasolabial 
folds) with some variation between subjects and studies23-28. All the treatments have been 
well tolerated. 
Among all the studies, there are 4 studies 23-26 focused on midface/cheek in immune-
competent subjects, and all of them showed long-lasting volume increase and good safety 
profiles.
2.5
Study rationale and Justification for design
Based on pre-clinical testing/previous clinical experience as described in Section 2.4, it is
considered justified to conduct a study to investigate superiority of Sculptra relative to no-
treatment in the treatment of Midface volume Deficit and/or Midface Contour Deficiency by 
measuring the percentage of responders, defined by at least 1 point improvement from 
baseline on the MMVS on both sides of the face, at 12 months. The study will be used as 
clinical documentation for registration of the product in China. No treatment control is chosen 
as no filler intended for midface volume deficit and/or midface contour deficiency is available 
in China at the time of this protocol.
Evaluation with standardised evaluation tools will be used in the study. The MMVS is a 
validated scale29 and was used in the Restylane Lyft registration clinical trial 30 for midface 
augmentation in US and accepted by FDA.
2.6
Risk and benefits
As all other injectable medical devices, Sculptra has the potential to cause complications. 
After the injection of Sculptra, some common injection-related reactions might occur. These 
reactions include pain, tenderness, localized redness, bruising, hematoma and edema, which 
generally resolve within 2–6 days.
Subcutaneous papules, invisible but palpable or visible nodules including periorbital nodules, 
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or areas of induration have been noted in the injection area. Nodules are occasionally 
associated with inflammation or discolouration. The early occurrence of subcutaneous 
nodules at the injection site (within 3–6 weeks after treatment) may be minimised by 
adhering to proper dilution and injection techniques. Delayed occurrences of subcutaneous 
nodules at the injection site (within 1–14 months post injection) have been reported with 
sometimes a prolonged duration of up to 2 years. 
For nodular areas or late granuloma formation, in some cases, they resolved spontaneously 
or following treatment with multiple intralesional injections of corticosteroids and/or 
antineoplastic agents (e.g. 5-fluorouracil). Surgical excision of the nodules was sometimes 
required when they were larger in size, occurring in difficult anatomical regions (e.g. lower 
eyelid) or persisting after other treatments.
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, discolouration, 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. Rare but serious cases of ischemic events associated with temporary or 
permanent vision impairment, blindness, cerebral ischaemia or stroke have been reported 
following facial aesthetic treatments.
By April 2018, Sculptra had marketing approval in 18 countries/regions worldwide, including 
US, EU, Canada, Australia, Hong Kong, Taiwan, South Korea, etc. Sculptra has been proven 
safe and well tolerated with sustained aesthetic improvement for facial lipoatrophy or volume 
loss. The primary potential benefit of the study is a perceived improvement in the treated 
areas. However, there is a risk that the subject will not gain the full aesthetic correction of 
Midface volume Deficit and/or Midface Contour Deficiency. There is also a risk of device 
dislocation.
Given the anticipated low level of acceptable adverse events (AE) in connection with the 
injection, the risk-benefit assessment of the use of Sculptra for treatment of Midface volume 
Deficit and/or Midface Contour Deficiency appears to offer a clinical benefit at reasonable 
risk.
In addition, only study investigators qualified by education and experience, and who are 
skilled in the use of soft tissue fillers from their clinical practice and participation in clinical 
research, will be chosen in order to assure proper device implantation and management of 
study risk.
3
Objectives and Endpoints
3.1
Objectives of the study
To evaluate the effectiveness of Sculptra in the treatment of Midface Volume Deficit 
and/or Midface Contour Deficiency.
To evaluate the safety of Sculptra in the treatment of Midface Volume Deficit and/or 
Midface Contour Deficiency.
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3.2
Endpoints of the study
3.2.1 Primary effectiveness endpoint: 
Percentage of responders, defined by at least 1 point improvement from baseline on the 
MMVS on both sides of the face concurrently, as measured by the blinded evaluator at 
12 months in both Treatment Group and Control group .
3.2.2 Secondary effectiveness endpoints:
Percentage of responders, defined by at least 1 point improvement from baseline on the 
MMVS on both sides of the face concurrently, as measured by the blinded evaluator at 6, 
9, 18 and 24 months in Treatment Group, and at 6 and 9 months in Control Group.
Percentage of responders, defined by at least 1 point improvement from baseline on the 
MMVS on both sides of the face concurrently, as measured by the treating investigator 
at 6, 9, 12, 18 and 24 months in Treatment Group, and at 6, 9 and 12 months in Control 
Group.
Volume change from baseline over time of the right and left midface areas combined, as 
measured by digital 3D photography at 6, 9, 12, 18 and 24 months in Treatment Group, 
and at 6, 9 and 12 months in Control Group.
Percentage of responders, defined by having “Improved”, “Much improved” or “Very 
much improved” according to the Global Aesthetic Improvement Scale (GAIS) on both 
sides of the face combined, as assessed by the subject and the treating investigator at 6, 
9, 12, 18 and 24 months in Treatment Group, and at 6, 9 and 12 months in Control Group.
Percentage of subjects in each response category of each question in the subject 
satisfaction questionnaire in Treatment Group at 6, 9, 12, 18 and 24 months.
*Time of the Follow up visits at 6, 9, 12, 18 and 24 months is calculated from baseline/randomization.
3.2.3 Safety endpoints:
Incidence, intensity, duration, and onset of adverse events (AEs) collected throughout 
the study.
Incidence, intensity, and number of days of expected post-treatment events collected 
using 4-week subject diaries after each treatment session for the Treatment Group.
4
Design of the Study
4.1
General Outline
For Group A, after screening, eligible subjects will be treated from day 1 and followed up for 
24 months. 
For Group B, the study includes two phases as follows: 
Main study phase:  It is randomized, evaluator-blinded and no-treatment controlled. After 
screening, all eligible subjects will be randomized either to the Treatment Group or the 
Control Group in a 2:1 ratio. All the subjects will be followed up for 12 months.  
Extension study phase: After the main study phase, the Treatment Group will be followed up 
for additional 12 months. 
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Each Treating Investigator will enroll 1 or 2 subjects as Group A. Before start of enrolment 
into Group B, the injection technique will be evaluated by the Sponsor or designee of Sponsor
and performed after the subjects in Group A for each investigator have received their first 
treatment, and second treatment. If treatments are found to be correctly performed, no 
further training is needed, there are no outstanding questions regarding the injection 
technique and no other corrective actions are identified, the enrolment in Group B can start 
for that investigator. 
Summaries of the results for Group A and B will be done separately in the study report.
Treatment 
Each subject assigned to Group A and Treatment Group will receive up to 4 injection sessions 
with 5(±1) weeks (at least 4 weeks) intervals. Initial treatment will be on Day 1. Study 
treatments should be stopped if optimal midface augmentation has been obtained or a 
maximum of 4 injection sessions completed. Optimal midface augmentation is defined as the 
best possible aesthetic result that can be obtained for an individual study participant, as 
agreed upon by the treating investigator and subject.
Subjects assigned to the Control Group will not receive treatment during the study.
Evaluation of effectiveness
Midface fullness will be assessed using a separate Four-Point MMVS with photo guides for 
the right and left side by the treating investigator at each visit; and by the blinded evaluator 
at screening, baseline, 6, 9, 12, 18 and 24 months in Group A and Treatment Group, and at 
screening, baseline, 6, 9 and 12 months in Control Group.
The measurement of volume change in the midface (right and left combined) from baseline 
will be calculated by 3D digital image analysis at 6, 9, 12, 18 and 24 months in Group A and 
Treatment Group, and at 6, 9 and 12 months in Control Group.
Aesthetic improvement of the Midface fullness will be assessed by the subject and the 
treating investigator, independent of each other, at each follow-up visit using the 5-graded 
GAIS. Photographs of baseline condition will be used as reference.
Subjects will be asked about their satisfaction with the treatment outcome using a 
questionnaire at 6, 9, 12, 18 and 24 months in Group A and Treatment Group.
Evaluation of safety
Information regarding AEs will be collected continuously during the study. 
4-week subject diaries after each treatment session will also be used for Group A and 
Treatment Group to collect information about anticipated injection related reactions (i.e. pain,
tenderness, localized redness, bruising, hematoma, edema, and “other”) at the treated area.
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Figure 1. Flow chart
* Time of the Follow up visits at 6, 9, 12, 18 and 24 months is calculated from baseline/randomization.
4.2
Number of Subjects
The study will be performed at approximately 8 sites in China and approximately 32 subjects 
in Group A and 189 subjects in group B will be enrolled. 
4.3
Duration of Subject Participation
Screening period for each subject will be 0~ 21 days. 
Subjects assigned to Group A and Treatment Group will receive up to 4 treatments with 5 (+1) 
weeks intervals, and then be followed up for 24 months after baseline. So the total duration 
for Group A and the Treatment Group is up to 25 months. 
Subjects assigned to the Control Group will not receive any treatment and be followed up for 
12 months after baseline, so the total duration for the Control Group is about 13 months.
4.4
Randomization and blinding
4.4.1 Randomization
Approximately 189 subjects in group B will be randomized in a 2:1 ratio to treatment with 
Sculptra or to no treatment. Before starting the study, a computer generated randomization
list will be prepared under the supervision of a designated statistician. The randomization list 
will be stratified by site.
Each eligible subject will be assigned a subject number as they arrive for the baseline visit. For 
group B, randomization will be performed via the eCRF system.  The treatment information 
will be kept by the Treating Investigator during the study not to be disclosed to the Blinded
Evaluator.
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4.4.2 Blinding
Only the evaluator will be blinded, both treating investigator and subjects will be open-
labelled.
The Blinded Evaluator shall not be allowed to retrieve study supplies or to be present during 
opening of the study supplies or injections. The Treating Investigator is not allowed to discuss 
treatments with the blinded evaluator or the subjects. All documents with information on 
study products shall be kept in a separate binder not available to the blinded evaluator.
4.4.3 Emergency unblinding
Not applicable as the Treating Investigator is unblinded.
4.5
Medical history
History of surgical events and medical conditions that are judged as relevant by the 
Investigator shall be documented in the eCRF using medical terminology.
Any concomitant medications and any relevant medical history (including prior facial 
dermatological procedures performed, and fillers or implants used) or concurrent diseases 
will be asked for.
4.6
Concomitant Medication, Treatment, and Procedure
Except as noted below, concomitant medications or other treatments or procedures may be
utilized when the PI or his/her authorized designee considers it medically necessary.
Information regarding any use of concomitant medications, including over-the-counter
medications administered during the study is to be recorded in the eCRF. The generic name
or the trade name of all concomitant medication or a description of the procedure and the
reason for its use shall be documented in the eCRF.
The following medications, treatments, and procedures are restricted or prohibited during 
the study:

Thrombolytics, anticoagulants or inhibitors of platelet aggregation (e.g. aspirin or 
other non-steroidal anti-inflammatory drugs [NSAIDs]), Omega-3, or Vitamin E should 
not be used within two weeks before treatment to avoid increased bruising or 
bleeding at injection sites.

At the treatment days, lidocaine should be used with caution in patients receiving 
other local anesthetics or agents structurally related to amide-type local anesthetics 
e.g., certain antiarrhythmics, since the systemic toxic effects can be additive.

Concomitant 
treatment 
with 
chemotherapy, 
immunosuppressive 
agents,
immunomodulatory therapy (e.g., monoclonal antibodies) is prohibited.

Long term concomitant treatment with systemic or topical (facial) corticosteroids is
prohibited (inhaled corticoids are allowed). Corticosteroids should be used with
caution and should be adjudged as necessary by the Investigator.

Use of systemic or topical (facial) retinoic acid is prohibited.

Facial tissue augmenting therapy, contouring or revitalization treatment with fillers, 
lifting threads, permanent implant, mesotherapy, radiofrequency, ultrasound, 
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cryotherapy, fat-injection, neurotoxin, laser or light treatment, chemical peeling or
dermabrasion below the level of the lower orbital rim are prohibited.

Planned surgery including aesthetic facial surgical therapy or facial liposuction, sinus
surgery or dental root surgery, or tattoo in the area to be treated is prohibited.

Participation in any other clinical study is prohibited
If a subject has used any of the above prohibited medications or performed any of the above 
prohibited procedures, a protocol deviation will be documented. The subject should continue 
in the study for the scheduled follow-up visits.
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4.8
Visits
4.8.1 Visits for Group A and Treatment Group
4.8.1.1
Screening (D-21 to D1)

Informed consent

Demography (Initials, Date of birth, Gender and Ethnic origin)

Screening laboratory tests (haematology and serum chemistry)

Inclusion and exclusion criteria

Pregnancy test for childbearing potential women

MMVS (by Blinded Evaluator and treating investigator)

Medical history/concurrentdiseases including prior facial dermatological procedures 
performed, and fillers or implants used

Concomitant medications/procedures

AE during the visit
4.8.1.2
Baseline (D1)

Height and Weight

Medical history/concurrentdiseases

Vital signs (before treatment, pulse rate, blood pressure, respiratory rate, body 
temperature)

Inclusion and exclusion criteria

Randomization 

Pregnancy test for childbearing potential women (before treatment)

Photography (before treatment)

MMVS (before treatment, by Blinded Evaluator and treating investigator)

Treatment

Dispense subject diary

Concomitant medications /procedures

Device deficiencies

AE since last visit
If screening and baseline visit occur on the same day, the following procedures for baseline 
will not be repeated.

Medical history/concurrentdiseases

Inclusion and exclusion criteria

MMVS (before treatment, by Blinded Evaluator and treating investigator)

Concomitant medications /procedures

Pregnancy test for childbearing potential women(before treatment)

AE since last visit
4.8.1.3
Optional treatment 2, 3, and 4 (only for subjects who receive the treatment)

Photography (before treatment)
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
MMVS (before treatment, by treating investigator)

GAIS (before treatment, by treating investigator and subject)

Pregnancy test for childbearing potential women (before treatment)

Treatment 

Collect and review subject diary

Dispense subject diary

Concomitant medications/procedures

Device deficiencies

AE since last visit
4.8.1.4
5W(±1w) after last treatment

Photography

MMVS (by treating investigator)

GAIS (by treating investigator and subject)

Collect and review subject diary

Concomitant medications /procedures

AE since last visit
4.8.1.5
6M (±2w), 9M (±2w), 12M (±2w), and 18M (±3w)  Follow-up

Weight

Photography

MMVS (by Blinded Evaluator and treating investigator)

GAIS (by treating investigator and subject)

Subject satisfaction questionnaire

Concomitant medications /procedures

AE since last visit

Laboratory tests (Only performed at 12M)
4.8.1.6
24M (±4w) Final visit or Early termination

Weight

Photography 

MMVS (by Blinded Evaluator and treating investigator)

GAIS (by treating investigator and subject)

Subject satisfaction questionnaire

Pregnancy test for childbearing potential women

Concomitant medications/procedures

AE since last visit

Laboratory tests (Only performed at early termination if termination occurs before 12
months visit)

Study termination
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4.8.2 Visits for Control Group
4.8.2.1
Screening (D-21 to D1)

Informed consent

Demography (Initials, Date of birth, Gender and Ethnic origin)

Screening laboratory tests (haematology and serum chemistry)

Inclusion and exclusion criteria

Pregnancy test for childbearing potential women

MMVS (by Blinded Evaluator and treating investigator)

Medical history/concurrentdiseases including prior facial dermatological procedures 
performed, and fillers or implants used

Concomitant medications/procedures

AE during the visit
4.8.2.2
Baseline (D1)

Height and Weight

Medical history/concurrentdiseases

Vital signs (pulse rate, blood pressure, respiratory rate, body temperature)

Inclusion and exclusion criteria

Randomization 

Photography 

MMVS (by Blinded Evaluator and treating investigator)

Concomitant medications /procedures

AE since last visit
If screening and baseline visit occur on the same day, the following procedures for baseline 
will not be repeated.

Medical history/concurrentdiseases

Inclusion and exclusion criteria

MMVS (by Blinded Evaluator and treating investigator)

Concomitant medications /procedures

AE since last visit
4.8.2.3
6M (±2w), 9M (±2w) Follow-up

Weight

Photography

MMVS (by Blinded Evaluator and treating investigator)

GAIS (by treating investigator and subject)

Concomitant medications /procedures

AE since last visit
4.8.2.4
12M (±2w) Follow-up / Final visit or early termination

Weight

Photography 
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
MMVS (by Blinded Evaluator and treating investigator)

GAIS (by treating investigator and subject)

Concomitant medications /procedures

AE since last visit

Study termination
5
Subjects
5.1
Subject information and informed consent
The PI or his/her authorised designee must always use the IEC-approved subject information 
and Informed Consent Form and it must not be changed without prior discussion with the 
Sponsor and approval from the applicable IEC.
It is the responsibility of the PI or his/her authorised designee to give each subject prior to 
inclusion in the study, full and adequate verbal and written information regarding all aspects 
of the clinical study that are relevant to the subject’s decision to participate throughout the 
study, e.g. explain the purpose and procedures of the study, the duration and number of 
expected participants, possible risks involved, and the opinion of the IEC. The subject shall be 
informed that the participation is confidential and voluntary and that the subject has the right 
to withdraw from the study at any time, without any effect on his/her future medical care, 
treatment or benefits to which the subject is otherwise entitled. The information shall be
provided in a language clearly and fully understandable to the subject. The subject shall be
given sufficient time to read and understand the Informed Consent Form and to consider 
participation in the study. Before any study-related activities are performed, the Informed 
Consent Form shall be personally signed and dated by the subject and the PI or his/her 
authorised designee responsible for conducting the informed consent process. The consent 
includes information that data will be collected, recorded, processed, and transferred to 
countries outside China. The data will not contain any information that can be used to identify 
any subject.
All signed Informed Consent Forms shall be filed in the Investigator file. The subject shall be 
provided with a copy of the signed and dated Informed Consent Form and any other written 
information.
The Investigator shall ensure that important new information is provided to new and existing 
subjects throughout the study
5.2
Inclusion Criteria
The subject must meet the following criteria to be eligible for the study:
1. Signed and dated informed consent to participate in the study.
2. Men or women aged 18 years of age or older of Chinese origin.
3. Subjects seeking augmentation therapy for the midface.
4. MMVS score of 2, 3 or 4 on each side of the face as assessed by the blinded evaluator.
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5.3
Exclusion Criteria
The presence of any of the following exclusion criteria will exclude a subject from enrolment 
in the study:
1. Known/previous allergy or hypersensitivity to any of the constituents of the product.
2. Known/previous allergy or hypersensitivity to local anaesthetics, e.g. lidocaine or 
other amide-type anaesthetics.
3. History of severe or multiple allergies, such as anaphylaxis. 
4. Previous tissue revitalization treatment with laser or light, mesotherapy, 
radiofrequency, ultrasound, cryotherapy, chemical peeling or dermabrasion in the 
area to be treated within 6 months before treatment.
5. Previous surgery (including aesthetic facial surgical therapy or liposuction), piercing 
or tattoo in the area to be treated. 
6. Previous tissue augmentation therapy or contouring with any permanent (non-
biodegradable) or semi-permanent filler, autologous fat, lifting threads or permanent 
implant in the area to be treated. 
7. Previous use of any hyaluronic acid based or collagen based biodegradable facial 
tissue augmentation therapy in the area to be treated within 12 months before 
treatment.
8. Previous use of any neurotoxin below the level of the lower orbital rim on the face 
within 9 months before treatment.
9. Presence of any disease or lesions near or at the area to be treated, e.g.
- Inflammation, active or chronic infection (e.g., in mouth, head and neck region);
- Facial psoriasis, eczema, acne, rosacea, perioral dermatitis, herpes simplex or 
herpes zoster;
- Scars or deformities;
- Cancer or pre cancer (e.g. actinic keratosis).
10. History of cancer or radiation in the area to be treated.
11. Subjects with a 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 6 months prior to the treatment visit or planned 
surgery, including dental implants, during the study period.
12. History of or active collagen diseases such as systemic lupus erythematosus, 
rheumatoid arthritis, polymyositis, dermatomyositis or localized or systemic 
scleroderma.
13. Tendency to form keloids, hypertrophic scars, or any other healing disorder.
14. History of bleeding disorders or treatment with thrombolytics, anticoagulants or 
inhibitors of platelet aggregation (e.g. aspirin or other non-steroid anti-inflammatory 
drugs (NSAIDs), Omega-3, or vitamin E within a relevant period before treatment, per 
the investigator’s judgment. 
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15. Treatment with chemotherapy, immunosuppressive agents, immunomodulatory 
therapy (e.g. monoclonal antibodies), systemic corticosteroids within 3 months 
before treatment (inhaled corticoids are allowed).
16. Treatment with topical (facial below the level of the lower orbital rim) retinoids or 
corticosteroids within 1 month, or systemic retinoids within 6 months before 
treatment.
17. Any medical condition that in the opinion of the Investigator would make the subject 
unsuitable for inclusion.
18. Other condition preventing the subject from entering the study in the Investigator’s 
opinion, e.g. subjects not likely to avoid other facial cosmetic treatments, subjects 
anticipated to be unreliable, unavailable or incapable of understanding the study 
assessments or having unrealistic expectations of the treatment result.
19. Women who are pregnant or breast feeding, or Woman of childbearing potential who 
are not practicing adequate contraception or planning to become pregnant during 
the study period. 
20. Subjects planning to accept any other facial plastic surgical or cosmetic procedures 
below the level of the lower orbital rim during the study (e.g., laser or chemical 
resurfacing, needling, facelift, radiofrequency etc.).
21. The presence of moderate or severe abnormal rating for midface symmetry, i.e. more 
than 1 point difference in MMVS score between each side of the face.
22. Intention to change a significant amount of weight (≥2 BMI) during the study period.
23. 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. 
24. Participation in any other clinical study within 30 days before treatment.
5.4
Screening and Subject Numbers
Each screened subject will be assigned a screening number consisting of “S” and the site 
number followed by a consecutive number starting with 01 at each site, e.g. S101, S102.The
screening number shall be listed on a subject screening and inclusion log. 
A “screening failure” is defined as a subject who does not fulfil the eligibility criteria. For 
screening failures, the eCRF screening visit shall be completed to an extent that makes it clear 
which assessments have been made and the reason why the subject did not fulfil the eligibility 
criteria. The reason for excluding a subject from entering the study shall also be specified in 
the subject screening and inclusion log. 
When the Investigator has confirmed that all inclusion criteria and no exclusion criteria are 
met, each enrolled subject will be assigned a subject number by the eCRF. For group A, 
consisting of a capital letter A, the site number, then followed by a consecutive number 
starting with 001 at each site, e.g. A1001, A1002; for group B, consisting of the site number 
followed by a consecutive number starting with 001 at each site, e.g. 1001, 1002.
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The subject number, subject name, and other information sufficient to link the eCRF to the 
medical records (e.g. national identification number, chart number, etc.) shall be recorded on 
a subject identification list. The subject identification list shall only be available at the site, 
both throughout and after the study.
5.5
Withdrawal of Subjects
Each subject shall be advised in the Informed Consent Form that the subject has the right to 
withdraw from the study at any time, for any reason, without prejudice. Subjects may also be 
discontinued from this study if the Investigator determines that it is in the subject’s best 
interest to do so, and may be withdrawn at the Investigator's discretion at any time.
The withdrawal criteria are:

Medical reasons: If the subject suffers from a medical condition that in the judgement 
of the Investigator makes it medically necessary to withdraw the subject. The specific 
rationale for Investigator-initiated withdrawal of a subject for medical reasons shall 
document the specific condition for withdrawing the subject.

Withdrawal of informed consent: 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 authorised 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, e.g. call three times at different hours and leave 
messages if applicable before declaring the subject lost to follow-up.

Other: Examples of other reasons for withdrawal may be failure to comply with protocol 
requirements or to complete the protocol-specified evaluations.
The reason and date for withdrawal shall be documented in the eCRF. When possible, an 
explanatory comment shall be added in the study termination module/pages to further 
explain the reason for withdrawal. If withdrawal of a subject occurs during a regular study 
visit, the eCRF for that specific visit shall be completed as far as possible together with the 
study termination eCRF module. 
If withdrawal of a subject occurs between regular study visits the subject should when 
possible (irrespective of the reason for withdrawal) be scheduled for a termination visit. In 
these cases the eCRF for the early termination visit should be completed. The subject will 
need to follow the same requirements for the final visit.
If a subject is withdrawn from the study, all data collected until the time of withdrawal will be 
used in the analyses.
A withdrawn or discontinued subject must not be replaced or re-entered into the study.
If an AE which, according to the Investigator’s assessment, is related to the use of the study 
product and is still ongoing at the time of the withdrawal, such events shall be followed-up 
after the last study visit until resolved, assessed as chronic or stable, or for at least three 
months.
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6
Study Products 
6.1
Investigational Product 
Sculptra is a poly-L-lactic acid implant in the form of a sterile non-pyrogenic suspension, which 
is reconstituted from a sterile dry powder by the addition of sterile water for injection. This 
suspension contains microparticles of poly-L-lactic acid, a crystalline form of polylactic acid.
Sculptra dry powder is supplied after aseptic filtration sterilisation in a sterile elongated clear 
glass vial. Each vial of dry powder contains: 150mg microparticles of poly-L-lactic acid (PLLA), 
90mg sodium carboxymethylcellulose, 127.5mg non-pyrogenic mannitol.
6.2
Reference Product
Not applicable.
6.3
Additional Products and Materials

Sterile water for injection

18G needles for reconstitution

5ml Plastic syringes for reconstitution

25G or 26G needles for injection

1ml or 2ml Plastic syringes for injection

2% Lidocaine HCI 
6.4
Reconstitution instructions
Sculptra is reconstituted extemporaneously in the following way:
1). Remove the flip-off cap from the vial and clean the penetrable stopper of the vial with an 
antiseptic.
Please note that the following steps 2–5 should be performed to ascertain air pressure relief 
in the vial and to allow for sufficient head-space when shaking the vial to dissolve the content.
2). Attach an 18G sterile needle to a sterile single-use 5 mL syringe.
3). Draw 5 mL of sterile water for injection into the 5 mL syringe.
4). Introduce the 18G sterile needle into the stopper of the vial, find the open slit in the 
stopper and slowly add all sterile water for injection into the vial letting the water flow on to 
the inner wall of the vial. Remove the syringe and needle.
5). Shake the vial vigorously for about 1 minute to dissolve the excipients. Inspect the vial for 
any lumps, and if needed shake more. A translucent suspension with some foam on the top 
will be obtained. 
6). Add 3 mL of additional sterile water for injection using the syringe and a new 18G needle. 
Remove the syringe and needle. Shake again in order to get a homogenous suspension. 
Following reconstitution, Sculptra can be used immediately or may be stored for up to 
72 hours prior to injection. 
7). Product should be gently agitated immediately prior to use. Agitate the vial until a 
homogenous translucent suspension is obtained. A single vial swirling agitator may be used. 
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As it is a single use vial, discard any material remaining after use or after 72 hours following 
reconstitution.
8). Clean the penetrable stopper of the vial with an antiseptic, and use a new 18G sterile 
needle to withdraw an appropriate amount of the suspension into a single-use 1-2 mL sterile 
syringe. Tilt the vial horizontally and withdraw suspension from the lower lateral of the vial 
to avoid withdrawing foam. Do not store the reconstituted product in the syringe.
9). Replace the 18G needle with a 25G or 26G sterile needle before injecting the product into 
the deep dermis, subcutaneous layer or supraperiosteal layer. Do not inject Sculptra using 
needles of an internal diameter smaller than 26G.
10). To withdraw remaining contents of the vial, repeat steps 8 through 9. Do not inject the 
foam.
If desired for the purpose of providing pain relief during the injection procedure, after 
completion of step 6 of the Reconstitution instructions described above, add another 1 mL of 
2% (20 mg/mL) lidocaine solution to the vial immediately prior to injection. Clean the 
penetrable stopper of the vial with an antiseptic, add the lidocaine solution and an 18G sterile 
needle and shake the suspension. Go to step 7 of the Reconstitution instructions described 
above and complete the procedure. It should be noted that the addition of lidocaine 
according to these instructions will lead to a final vial volume of 9 mL with a lidocaine 
concentration of 2.2 mg/mL.
6.5
Packaging, Labelling and Storage
Sculptra is supplied as a sterile freeze-dried preparation for injection in a clear glass vial, which 
is sealed by a penetrable stopper, covered by an aluminum seal with a flip-off cap. 
The vials are labelled with name of the product, name of the manufacturer (Q-Med AB) and 
are packed in cartons. Each carton of Sculptra contains only one vial. The carton will be 
labelled in local language, specifying the protocol number, lot number, expiry date and that 
the product is to be used for clinical studies exclusively.
Sculptra powder should be stored at room temperature away from heat (maximum 30°C). 
Upon reconstitution, Sculptra can be stored up to 72 hours at refrigeration (2–8°C) or room 
temperature up to 30°C.
Do not freeze.
After use, treatment syringes and needles may be potential biohazards. Handle accordingly 
and dispose of in accordance with accepted medical practice and applicable local 
requirements.
6.6
Product accountability
The study product will be released to the PI or his/her authorised designee after study 
approvals have been received from the IEC and the CTA has been signed by all parties.
The PI must ensure that the study product is kept in a secure location, with access limited to 
those authorised by the PI.
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The study product must be traceable from the manufacturer to its use in subjects until return 
or disposal. It is therefore important that the PI maintains accurate product accountability 
records, i.e. documentation of the physical location of all study product, deliveries, and return 
of study product between the Sponsor or a third-party vendor and the PI, and documentation 
of administration of product to the subject. A shipping record shall be kept of all study 
products received from the Sponsor; including the product name, date received, batch 
number, expiration date, and amount received. In addition, dispensing logs shall be 
maintained including the product name, dispense date, the number of syringes used, the 
number of syringes left in stock, and the subject receiving study product. A log for 
accountability procedure is provided by the Sponsor. 
When the study is completed, all unused or expired study product at each study site shall be 
returned to the Sponsor or a third-party vendor for destruction. Any malfunctioning study 
products shall be reported as described in Section 8.5.3.
Product deliberately or accidentally destroyed during shipment or at a study site shall be 
accounted for and documented. Used syringes, disposable needle, and any opened unused 
material must be discarded immediately after the treatment session and must not be reused 
due to risk for contamination of the unused material and the associated risks including 
infections according to standard procedures at the site. Disposal of hazardous material, i.e. 
syringes and needles must conform to applicable laws and regulations. The study product 
must not be used outside the study.
6.7
Treatment 
6.7.1
Treatment Procedure
Before treatment with Sculptra, the patient should be informed completely of the indications, 
contraindications, warnings, and precautions for use, possible side effects and mode of 
administration of Sculptra. 
Make sure to work under aseptic and hygienic conditions. Clean the injection site with an 
antiseptic. Local anesthetics (topical, infiltrative, or regional blocks) before the treatment will 
be used at the discretion of the treating Investigator.
The subject should not wear make-up on the day of treatment, if make-up was already applied 
this must be completely removed prior to any injection. 
Sculptra dry powder will be reconstituted with 8 mL of sterile water for injection to form a 
sterile nonpyrogenic suspension. As an optional means to provide pain relief during the 
injection procedure, an additional 1 mL of sterile 2% (20 mg/mL) lidocaine solution may be 
added to the vial of reconstituted product prior to injection for a final volume of 9 mL.
Scuptra should be injected into the deep dermis, subcutaneous layer or supraperiosteal layer 
with a 25G or 26 G needle. To avoid breakage of the needle, do not attempt to bend it before 
or during treatment. If the needle gets bent, discard it and complete the procedure with a 
replacement needle.
Sculptra will be administered inferior to the maxillary prominence, superior to the plane of 
nasal alae, including the area from the lateral canthus to the medial canthus and lateral to 
the nose on the subject’s right and left sides (Figure 2). When appropriate, the study product 
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is injected into the lateral and inferior adjacent area to ensure a smooth transition of midface 
contour. 
To maintain a homogeneous suspension throughout the procedure, intermittently, agitate 
the product in the syringe. Before initial injection, expel a few drops of the product through 
the attached needle to eliminate air and to check for needle blockage. If the needle becomes 
occluded or dull during an injection session, replacement may be necessary. If clogging occurs, 
remove the needle, expel a small amount of product, attach a new sterile needle, then expel 
a few drops of Sculptra to eliminate the air and re-check for needle blockage.
Figure 2. Treatment Area
6.7.2
Treatment regimen (dose)
Each subject will receive up to 4 injection sessions with 5(±1) weeks intervals. Study treatment 
injections should be stopped if optimal midface augmentation has been obtained or a 
maximum of 4 injection sessions completed. Optimal midface augmentation is defined as the 
best possible aesthetic result that can be obtained for an individual study participant, as 
agreed upon by the treating investigator and subject.
1 vial is generally recommended at each treatment session, i.e., initial treatment or each 
optional treatment respectively. Maximum 2 vials can be used for each treatment session at 
the discretion of the investigator.
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6.7.3
Post-treatment Care 
After the injection session, ice (in a suitable cloth, avoiding any direct contact with the skin) 
should be applied to the treatment area in order to reduce swelling and/or bruising.
It is important to thoroughly massage the treated area(s) to evenly distribute the product (use 
of an appropriate cream may help to reduce the friction on the skin surface during 
massaging).
The patient must avoid exposing the treated area to heat (sun bathing, sauna, steam baths, 
etc.), ultraviolet or extreme cold least until any initial swelling and erythema has resolved. 
6.7.4
Post-trial provisions 
After the study is finalised Q-Med AB will not supply any more treatments to the subjects, 
even if the result does not persist.
6.7.5
Electronic case report form recordings
The following details of each injection are to be recorded in the eCRF: 

Date for administration

Lot number 

Whether 2% Lidocaine added. 

Local anaesthetic used (product name, volume injected/amount applied, and 
concentration)

Administered volume per side

Injection technique per side

Depth of injection per side

Post-treatment care (massage, ice pack, etc)
In addition, any technical problems (device deficiencies) or clinical complications (AEs) 
associated with the injection will be recorded in the eCRF.
6.7.6
Treatment compliance
The treatment is an implant administered by the Treating Investigator and the details of the 
administration are recorded in the eCRF. No other measurements of treatment compliance 
will be made.
7
Effectiveness Assessments
7.1
General information
The methods for collecting effectiveness data include assessment of MMVS 9(Section 7.3), 3D 
digital imaging analysis (section 7.4), GAIS (Section 7.5), and Subject satisfaction 
questionnaire (Section 7.6). 
Assessments will be performed by the subjects, the treating Investigator, and the blinded
evaluator, as described in the respective section. To avoid inter-observer variability, every 
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 Do not meet your expectations
 You did not have any specific expectations before the injections
4). Do you think that the treatment brings you more?
(tick all boxes that apply)
 Youth
 Beauty
 Harmony
 Symmetrical appearance
 Pep/Liveliness/Freshened look
 Self esteem /confidence
5). Would you say that you feel more attractive?
 Yes
 No
6). How do you feel about yourself since the treatment was performed?
 Very much better
 Much better
 Somewhat better
 The Same
 Worse; if worse, please explain why:
7). Overall, how satisfied are you with the treatment result?
 Very satisfied
 Satisfied
 Somewhat satisfied
 Not satisfied
8). Did you get any feedback about your look from your family, friends, colleagues?
 Positive feedback
 Negative feedback
 No feedback
9). Would you recommend this treatment to friends?
 Yes
 No
10). Would you do like to receive the same treatment again?
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 Yes, exactly the same
 No ; if no, please explain why                                                                                            .
8
Safety Assessments
8.1
Anticipated injection related reactions
The subjects of for Group A and Treatment Group will evaluate anticipated injection related 
reactions, i.e. pain, tenderness, localized redness, bruising, hematoma and edema, which 
generally resolve within 2-6 days. The subject will be instructed by the Investigator to record 
pain, tenderness, localized redness, bruising, hematoma, edema and other daily for 
evaluation of these events in 4-week diaries after each treatment session. The presence and 
maximum intensity of the symptoms will be recorded for the treated area (table 5). The 
treating Investigator will review the diary at the next visit after each treatment and if 
necessary, appropriate intervention (treatment or procedure) will be carried out at the 
discretion of the Investigator. If required, the Investigator can also decide that the subject’s 
participation in the study should be terminated.
Table 5. Grading for pain, tenderness, localized redness, bruising, hematoma, edema and other, in
the subject diary
None
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)
8.2
Laboratory assessment
Laboratory samples for Haematology and Serum chemistry assessment will be taken at the 
screening visit (day -21 to day 1) for all subjects. In Group A and Treatment Group, it will also 
be taken at 12 months visit or at early termination if termination occurs before 12 months 
visit. 
The following laboratory assessments will be performed:

Haematology: haemoglobin, red blood cells, white blood cells, differential count and 
platelet count.

Serum chemistry: renal function tests (creatinine and BUN); and liver function tests 
(aspartate amino transferase (ASAT), alanine amino transferase (ALAT) total bilirubin, 
direct bilirubin and indirect bilirubin).
Pregnancy test (Urine HCG) will be performed at screening, all injection visits (prior to 
treatment and the study completion/early termination for Group A and Treatment Group,
and at screening for Control group, in all women of childbearing potential, including those 
currently using contraception. The test result must be negative for the subject to receive any 
treatment with study product.
Other laboratory test might be performed at the discretion of the investigator. All laboratory 
assays will be performed at a local laboratory. Reference ranges will be supplied by the 
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laboratory and used by the Investigator to assess the laboratory data for clinical significance 
and out of range pathological changes. 
The results of the hematology and serum chemistry will only be used for safety assessment 
by investigator and will not be collected in the eCRF. The pregnancy test for women of 
childbearing potential will be recorded in the eCRF.
8.3
Adverse Events
8.3.1
Definition of Adverse Events
An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons*, 
whether or not related to the study product. 
This definition includes:

events related to the investigational product or the reference product

events related to the procedures involved
. *For users or other persons, this definition is restricted to events related to the investigational product
8.3.2
Definition of 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-threatening** illness or injury, or
2. a permanent impairment of a body structure or body function, or
3. in-patient or prolonged hospitalisation***, or
4. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) led to foetal distress, foetal death, or a congenital abnormality or birth defect
In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such (see section 8.4.4).
**The term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. (Source: ICH-E2A clinical safety data management: definitions and standards for expedited 
reporting).
*** Planned hospitalisation for a pre-existing condition, or a procedure required by the CSP, without serious 
deterioration in health, is not considered a SAE. (Source: ISO14155:2011).
8.3.3
Recording Instructions
AE will begin to be collected after ICF signed. Each subject will be questioned about AEs at 
each clinical visit following the screening visit. The question asked will be "Since your last 
clinical visit have you had any health problems?" Information on AEs can also be obtained 
from signs and symptoms detected during each examination or from a laboratory test, 
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observations by the study personnel, subject diaries or spontaneous reports from the 
subjects. 
The Investigator will assess the presence of any papules (˂5mm in diameter) or nodules 
(≥5mm in diameter). If present, the papules/nodules will be recorded as AE and should be 
further assessed as visible/non-visible and inflammatory/non-inflammatory.
When an AE is related to a device deficiency (refer to section 8.4), including technical device 
malfunction, the AE shall be recorded on the AE module in the eCRF and the technical 
complaint shall be reported separately on the clinical study complaint form.
Investigators, or other study personnel, will record all AEs in the eCRF, including:

Event term (recorded in standard medical terminology and avoiding abbreviations),

Description of event and affected area (if applicable),

Start date (First day with symptoms)

Stop date (Last day with symptoms)

Intensity (mild, moderate or severe according to definition in section 8.3.3.1)

Seriousness (serious or not serious, according to definition in section 8.3.2)

Causal relationship to study product and study product injection procedure (yes or 
no)

Action taken (none, medication treatment, non-pharmacological treatment or other 
procedures/ tests, subject withdrawn)

Outcome of the AE (ongoing, recovered, recovered with sequelae, death, chronic/ 
stable, not recovered at study end)
The AE module in the eCRF must be signed and dated by the Investigator.
8.3.3.1
Intensity
For each reported AE, the intensity will be recorded. The following definitions of intensity 
are to be used:
Mild:
A mild AE means awareness of symptoms or signs, but easily tolerated 
(acceptable).
Moderate:
A moderate AE means enough discomfort to interfere with usual activity 
(disturbing).
Severe:
A severe AE means incapacity to work or to do usual activity 
(unacceptable).
If the intensity changes over time the maximum intensity of the AE should be recorded.
8.3.3.2
Causal Relationship and Seriousness
Each AE, serious as well as non-serious, will 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. 
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A two-point scale (Yes or No) will be used for causality assessments. The Investigators shall 
be asked to indicate a response to each of the following questions in the eCRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?” and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product injection procedure?”
If any of these questions is answered Yes, the AE is considered related. 
Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in order 
to fulfil regulatory requirements. 
8.3.4
Reporting of Adverse Events
AE reporting on each subject will start after the ICF has been signed. The reporting will 
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.
8.3.5
Reporting of Serious Adverse Events
After becoming aware of any SAE, the Investigator shall report it to his/her administrative 
department of medical device clinical trials under the clinical trial institution, which in turn 
shall notify the Sponsor Representative in writing. This initial report can be made via fax or 
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:

CTN
Subject identification (age, gender, subject number)
AE description
date when AE occurred
date when AE became serious
Name of PI and original reporter (if other than Investigator)
Name of study product
Treatment specification
The Investigator will assure completeness of the SAE information and the supporting 
documentation.
Follow-up information and data missing in the initial SAE reporting shall be gathered as soon 
as possible and reported to the Sponsor via Sponsor’s representative immediately but not 
later than 24 hours of awareness of the new data. Complete and adequate information on 
each SAE is required. All attempts to obtain this information, including dates for follow-up 
activities, must be documented by the Investigator.
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Supporting documentation to be provided with the SAE report:

Concomitant Medication Form/list

Concomitant Procedure/Treatment Form/list

AE Form/list

Medical History Form/list

Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
_______________________________________________________________________
Fax number for SAE reporting:               +46 18 474 91 01
E-mail for SAE reporting:
safety.q-med@galderma.com
Surface mail for providing
              
complementary information:                     Q-Med AB
                                                                     Attn. Corporate Medical Affairs & Vigilance
                                                                       Seminariegatan 21
                                                                       SE-752 28 UPPSALA, Sweden   
E-mail for Device deficiency, 
Clinical Study Complaint Form:_            Complaints.q-med@galderma.com
______________________________________________________________________
E-mail address will be pre-programmed in the eCRF system.
For non-urgent complementary information not possible to send by e-mail or fax, please use 
surface mail.
The SAE form (NMPA template in Chinese) 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 (contact details refer to 24-hour contact person list in ISF). A copy of the fully 
completed SAE form shall be kept at the site.
In addition, according to national regulations, the investigator will report a SAE Form (NMPA
SAE template) to the administrative department of medical device clinical trials in his/her 
hospital, and they should, within 24 hours, deliver a written report to the corresponding 
Ethics Committee and the local food and drug administrative department of province, 
autonomous region and municipality at the place where the clinical trial institution locates. 
In case of a death incident, the clinical trial institutions and investigators should furnish the 
Ethics Committee and the Sponsor Representative with all required materials.
The Sponsor Representative is responsible for, within five (5) business days upon being 
informed, reporting any SAE or device defect with the likelihood of SAE to Shanghai Municipal 
FDA and Shanghai Municipal Health Commission by fax or mail. The relevant correspondence 
will be documented in TMF; meanwhile, the Sponsor Representative should notify other 
clinical trial institutions and investigators participating in the study, and promptly report it to 
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the Ethics Committee of the involved clinical trial institutions via the administrative 
department of medical device clinical trials according to national regulations. 
8.3.6
Follow-up of Unresolved Events after study termination and new Events after study 
termination. 
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure and ongoing at study end, shall be followed up after the subject's 
participation in the study is over. Such events shall be followed-up after the last study visit
until resolved, assessed as chronic or stable, or for at least three months. Final outcome after 
study end should be reported on a paper AE form.
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure with onset after subject participation in the study has ended shall be 
collected and reported to Sponsor on a paper AE form or in the post marketing AE form or 
SAE paper form if applicable. The events shall thereafter be followed up until resolved or 
considered chronic or stable, or for at least three months. Final outcome shall be reported on 
the AE follow up form or in the post marketing AE form. The Investigator shall report any such 
AE or SAE including all previous Adverse events reported during the study and medical history 
of the patient to the Sponsor immediately but not later than 24 hours of awareness of the 
event. This report can be made via fax or e-mail according to contact details specified in 
section 8.3.5.
8.3.7
Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy during the study period the subject must continue to be followed 
within the study and the outcome of pregnancy must be reported even if the expected date 
of 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 8.3.5. The report can be prospective or 
retrospective. Follow-up shall be conducted to obtain outcome information on all prospective 
reports. 
Cases that led to foetal distress, foetal death or a congenital abnormality or birth defect are 
to be regarded as SAEs and shall be reported on the exposure in utero report form to the 
Sponsor immediately but no later than 24 hours after the Investigators awareness. These 
events shall be handled as SAEs during data processing. Other complications during the 
pregnancy that are related to the pregnant woman and fulfils any serious criteria, such as pre-
eclampsia requiring hospitalisation, shall be reported and handled as SAEs. Elective abortions 
without complications will not be reported as AEs.
8.3.8
Anticipated Adverse Events
Information regarding anticipated AEs below is also included in the Sculptra Investigators 
Brochure. 
Subcutaneous papules/, invisible but palpable or visible nodules including periorbital nodules, 
or areas of induration have been noted in the injection area. Nodules are occasionally 
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associated with inflammation or discolouration. The early occurrence of subcutaneous 
nodules at the injection site (within 3–6 weeks after treatment) may be minimised by 
adhering to proper dilution and injection techniques. Delayed occurrences of subcutaneous 
nodules at the injection site (within 1–14 months post injection) have been reported with 
sometimes a prolonged duration of up to 2 years. Improper injection techniques such as 
superficial placement, excessive amount of product or incorrect reconstitution may lead to 
appearance of papules or nodules at the injection site. Massaging the treatment area to 
ensure proper distribution of the product may minimise the appearance of such papules or 
nodules. 
For nodular areas or late granuloma formation, in some cases, they resolved spontaneously 
or following treatment with multiple intralesional injections of corticosteroids and/or 
antineoplastic agents (e.g. 5-fluorouracil). Surgical excision of the nodules was sometimes 
required when they were larger in size, occurring in difficult anatomical regions (e.g. lower 
eyelid) or persisting after other treatments.
This product must not be injected intramuscularly or intravascularly. Localised superficial 
necrosis and scarring may occur after injection in or near vessels. It is thought to result from 
the injury, obstruction, or compromise of blood vessels. Special caution should be taken if the 
patient has undergone a prior surgical procedure in the planned treatment area. Areas with 
limited collateral blood flow has an increased risk of ischaemia. Aspiration prior to injection 
is recommended. 
Unintentional introduction of soft tissue fillers into the vasculature in the face may lead to 
embolisation, occlusion of the vessels, ischaemia, necrosis or infarction at the implant site or 
in the area supplied by the blood vessels affected. Rare but serious adverse events include 
temporary or permanent vision impairment, blindness, cerebral ischaemia or cerebral 
haemorrhage leading to stroke, skin necrosis, and damage to underlying facial structures. 
Immediately stop the injection if any of the following symptoms occurs, including changes in 
vision, signs of a stroke, blanching of the skin, or unusual pain during or shortly after the 
procedure. Patients should receive prompt medical attention and possibly evaluation by an 
appropriate health care practitioner specialist, should an intravascular injection occur.
8.4
Device Deficiencies
8.4.1
Definition of Device Deficiency
A device deficiency is defined as an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety* or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
*Inadequacy of device safety refers to properties of the device which could have or have led to an AE. 
8.4.2
Recording Instructions
When a device deficiency is discovered the Clinical Study Complaint Form in the eCRF will be 
completed by the Investigator. The type of complaint shall be described and injury to the 
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subject or user or unintended exposure to study product shall be reported as applicable. If an 
injury has occurred, an AE module or a SAE Form should be completed following instructions 
in section 8.3. If no SAE was experienced as a result of the device deficiency the Investigator
shall assess whether or not the device deficiency could have led to an SAE if:

Suitable action had not been taken,

Intervention had not been made or,

Circumstances had been less fortunate
The Sponsor will also make the same assessment in the Clinical Study Complaint Form. 
8.4.3
Reporting Device Deficiency
The Investigator will complete the Clinical Study Complaint Form to the Sponsor using the 
contact details specified in section 8.3.5. A device deficiency that led to a SAE and any device 
deficiency that could have led to a SAE shall be reported within 24 hours after the 
Investigator’s awareness in accordance to section 8.3.5.
In order to fulfil regulatory reporting requirements, all deficiencies with the study product 
must be assessed by both the Investigator and the Sponsor to determine if it could have led 
to a SAE.
If an SAE has resulted from a device deficiency or if either the Investigator or the Sponsor 
assesses that the device deficiency could have led to an SAE the event will be reported in 
accordance with Regulatory requirements, as applicable.
The deficient study product shall be kept, if applicable, by the study site until the QA 
complaints group has confirmed whether the product shall be returned to Sponsor for further 
study or if it can be destroyed at the study site.
9
Data Handling and Management 
9.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter clinical data information into a database, efficiently and avoiding errors. The data 
management routine includes procedures for handling eCRFs, database set-up and 
management, data entry and verification, data validation, and documentation of the 
performed activities including information of discrepancies in the process. The data 
management process will be described in detail in the data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the 
CSP. Data validation will be performed by computerised logical checks and manual review. 
Drugs and events will be coded in accordance with World Health Organization (WHO) Drug 
and medical dictionary for regulatory activities (MedDRA) dictionaries as specified in the 
DMP. Safety data (SAE) 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. 
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Study data will be transferred to SAS datasets which thereafter will be write-protected. 
Statistical analyses will be generated in SAS using data from the locked datasets.
9.2
Electronic case report forms 
An eCRF is required and shall be completed electronically for each screened subject 
(screening visit) and included subjects (subsequent visits). 
The eCRF includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Study data will 
be transcribed directly from the source documents, which are to be defined at each site 
before inclusion of the first subject.
Authorised study site personnel designated by the PI shall complete data collection. 
Appropriate training and security measures shall be completed with all authorised study site 
personnel prior to the study being initiated and any data being entered into the system for 
any subject.
The study data is the sole property of the Sponsor and shall not be made available in any form 
to third parties without written permission from the Sponsor. At the end of the study, 
electronic data are kept at the Sponsor and a copy (provided by the vendor) at the study site 
as part of the Investigator file.
Any delegation of collection of data shall be specified in a signature and delegation log.
9.2.1
Data entry
All data shall be entered in English. The eCRFs should always reflect the latest observations 
on the subjects participating in the study. Therefore, the eCRFs shall be completed within 5 
working days after the subject’s visit. The subject’s identity must always remain confidential, 
i.e. the name and address of the subjects must not be registered in the eCRFs or in the 
database. The Investigator must verify that all data entries in the eCRFs are accurate and 
correct. If some assessments are not done, or if certain information is not available, not 
applicable or unknown, the Investigator shall indicate this in the eCRF. The Investigator shall 
electronically sign off the study data. By signing, the Investigator takes responsibility for the 
accuracy, completeness, and legibility of the data reported to the Sponsor in the eCRF.
9.2.2
The query process
The monitor shall review the eCRFs and evaluate them for completeness and consistency by 
100%. Each eCRF shall be compared with the respective source documents to ensure that 
there are no discrepancies between critical data. All entries, corrections, and alterations shall 
be made by the PI or his/her authorised designee. The monitor cannot enter data in the 
eCRFs. Once study data have been submitted to the central server via the eCRF, corrections 
to the data fields will be audit trailed, meaning that the reason for change, the name of the 
person who made the change, together with time and date will be logged. Roles and rights of 
the site personnel responsible for entering study data into the eCRF shall be determined in 
advance. If discrepant data is detected during review of the data, either by the Sponsor or its 
representatives, the responsible data manager or monitor shall raise a query in the electronic 
data capture application. The query shall state the question or data to be changed and shall 
be resolved in the system by the PI or his/her authorised designee. The appropriate study site 
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personnel shall answer the queries in the eCRF. This will be audit trailed by the electronic data 
capture application meaning that the name of study site personnel, time, and date is logged.
9.2.3
User identification
Electronic CRF records will be automatically appended with the identification of the creator, 
by means of their unique User ID. 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 User ID and password; 
date and time stamps will be added automatically at time of electronic signature. If an entry 
in an eCRF requires change, the correction shall be made in accordance with the relevant 
software procedures. 
9.2.4
Audit trail
All changes will be fully recorded in a protected audit trail and a reason for the change shall 
be stated. Once all data have been entered, verified, and validated, the database will be 
locked.
9.3
Source documents
The eCRF is essentially considered a data entry form and does not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents 
used by the Investigator or hospital that relate to the subject’s medical history, that verifies 
the existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study. They include photographs, memoranda, material 
dispensing records, subject files, etc.
The PI is responsible for maintaining source documents. These shall be made available for 
inspection by the monitor at each monitoring visit. The Investigator must submit a completed 
eCRF for each subject for whom signed informed consent has been collected. All supportive 
documentation submitted with the eCRF, such as photographs, should be clearly identified 
with the subject number. Any personal information, including name, shall be removed or 
rendered illegible to preserve individual confidentiality.
9.4
Record keeping and access to source data
The PI/institution shall permit study-related monitoring, audits and IEC review and shall 
provide direct access to the source data/medical record including the identity of all 
participating subjects (sufficient information to link records, i.e. eCRF, medical records, 
original signed Informed Consent Forms and detailed records of study product 
accountability). The records should be retained by the PI as required by local legislation and 
international guidelines. Any transfer of responsibility for storage of the records shall be 
documented and the Sponsor should be informed in writing.
The Sponsor shall verify that each subject has consented in writing to direct access to the 
original medical record/source data (by the use of written subject information and signed 
informed consent). The data recorded in the eCRFs shall 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. 
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The source data location log specifies what data that should be available in the medical 
record. The source data location log should also specify the data for which the eCRF serves as 
the source. Such data only need to be recorded in the eCRF and are typically associated with 
study-specific procedures and not with normal clinical care practice. For this type of study 
data the Investigator would not be expected to duplicate the information into the medical 
record.
9.5
Document and data retention
All records pertaining to the conduct of the study, including signed eCRFs, Informed Consent 
Forms, study product accountability records, source documents, and other study 
documentation must be retained after study completion according to national legislation and 
the CTA. Sponsor will inform the sites as to when these documents no longer needs to be 
retained. Measures should be taken to prevent accidental or premature destruction of these 
documents (e.g. protection against damage and unauthorised access, preferably by storage 
in a fire-proof cabinet). Refer to the CTA.
After study completion and database lock, a security sealed CD with electronic study data 
shall be provided by the eCRF vendor for archiving.
It is the PI’s responsibility to inform Q-Med AB in writing if the Investigator file is moved or if 
the responsibility for the documents is transferred to someone else
10 Statistical Methods
10.1 General
A comprehensive Statistical Analysis Plan (SAP) with detailed description of all statistical 
analyses will be written and finalized prior to database lock (DBL). All summaries for Group A 
and B will be done separately. For Group A, only descriptive statistics will be used. All 
statistical analyses, including summary tables and data listings, will be performed using the 
SAS® system (version 9.4 or later). 
Continuous variables will be summarised using standard statistical measures, such as mean, 
median, standard deviation, minimum and maximum values. Categorical variables will be 
presented in frequency tables with number and percent of observations for each level.
All confidence intervals will be two-sided and use the 95% confidence level. All statistical 
testing will be two-sided and performed at a significance level of 5%.
10.2 Analysis Populations
The following populations will be defined:

Safety
Includes all subjects in Group B who were treated with 
Sculptra or randomized to no-treatment group. Subjects 
are analyzed based on the as treated principle.

Full Analysis Set (FAS)
Includes all subjects in Group B who were treated with 
Sculptra or randomized to no-treatment group. Subjects 
are analyzed according to the randomisation assignment.
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
Per Protocol (PP) 
Includes all subjects in FAS that comply to the protocol 
procedures with no deviations that can affect the 
evaluation of the primary variable.
The FAS population is the primary population for all effectiveness analyses. All safety analyses 
will be based on the Safety population.
For Group A, all analyses will be performed based on all subjects.
10.3 Demographics, baseline assessments, and subject characteristics
Demographic endpoints and subject characteristics will be presented by study product using 
descriptive statistics.
10.4 Effectiveness Analysis
Primary analysis
The percentage of responders (a responder will be defined as a subject with at least 1 point 
improvement from baseline MMVS on both sides of the face concurrently) will be calculated 
at 12 months both in Treatment Group (denoted as π12M Sculptra) and Control Group (denoted 
as 
π12M 
Control)
based 
on 
the 
blinded 
evaluator's 
assessment. 
The null hypothesis H0: π12M Sculptra= π12M Control will be tested against the alternative hypothesis 
H1: π12M Sculptra ≠ π12M Control by using a Fisher's exact test at a significance level of 5%. In 
addition, for each group the two-sided 95% confidence intervals around the estimates of the 
percentage of responders will also be calculated. The treatment will be deemed a success if 
the p-value for the treatment difference on the primary endpoint is less than 0.05 (i.e. the 
proportion of responders is statistically significantly larger in the Treatment Group compared 
to the Control Group).
Secondary analysis
The percentage of responders based on the MMVS on both sides of the face concurrently will 
also be derived at all applicable follow-up visits for both the blinded evaluator’s assessment 
and the treating investigator’s assessment respectively. The response rates and their 95% 
confidence interval will be presented by visit and group. 
Fisher’s exact test will be used to compare the response rates in the Treatment group versus
the Control group based on the blinded evaluator’s assessment and the treating investigator’s 
assessment 
respectively.
In 
other 
words, 
the 
null 
hypothesis 
H0: π
t,Sculptra = πt, 
Control
will be tested against the alternative hypothesis 
H1: π t,Sculptra ≠ πt, Control for each of the timepoints t = Month 6 and Month 9 for the blinded 
evaluator’s assessment, and t = Month 6, Month 9 and Month 12 for the treating 
investigator’s assessment.
The volume change in the midface area as compared with baseline (right and left sides 
combined) obtained by 3D imaging will be presented descriptively by treatment for all 
applicable follow-up visits. 
GAIS (by treating investigator and subject) and satisfaction with the treatment outcome will 
be analyzed descriptively.
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10.5 Safety Analysis
Number and percentage of subjects reporting anticipated injection related reactions, as 
collected in diaries will be presented in total and by maximum intensity. A graph will be 
generated to illustrate the incidence over time. Number of days with the event will be 
summarized using mean, SD, min, max and median.
All AEs will be coded according to MedDRA. 
A summary of all AEs, by treatment, 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 unrelated AE and number of events (in total as 
well as serious AEs)

Number of subjects who did not have an AE.
Related AEs as well as number of subjects with related AEs will be summarised by SOC, PT and 
intensity and by treatment. In addition, for related AEs the number of days to onset and the 
duration of event will be summarised by SOC and PT and treatment using mean, SD, min, max 
and median. Action taken for related AEs will also be summarized.
Serious AEs will be listed. 
Non- related AEs will be summarised by SOC, PT, and intensity and by treatment. 
10.6 Handling of Missing Data
Number of missing values will be summarized and reported as appropriate. 
Different assumptions regarding the missing data will be used. For the primary effectiveness 
analysis, missing values in the FAS will be assumed to be missing due to lack of effect. 
Therefore missing data up to the Month 12 visit will be imputed using the baseline 
observation carried forward (BOCF) method. As an alternative approach, missing data will be 
assumed to be unrelated to treatment effect. To impute data under this assumption, missing 
data up to the Month 12 visit will be imputed using the hot deck method. More details will be 
given in the SAP. Both of these alternatives will estimate the effectiveness of the treatment 
policy (irrespective of use of unallowed treatments, procedures, or medications) rather than 
the true, clinical treatment effect.
To obtain an estimate of the true, clinical treatment effect, the primary effectiveness analysis 
will be performed using the PP population.
All other endpoints will be analysed on available data, i.e. no imputations will be done.
10.7 Interim Analysis
An interim analysis will be performed when the month 12 visit completed for all the subjects.
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10.8 Data monitoring committee
Not applicable for this study.
10.9 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 DBL.
Deviations from the statistical plan will be documented in protocol Deviation log.
10.10 Sample Size
There are no available clinical data for Sculptra studied under conditions similar to the current 
study. However, based on what is seen in clinical studies of injectable fillers in the facial areas, 
it is reasonable to assume a response rate of at least 60% in the Sculptra Treatment Group at 
Month 12. For the no treatment Control Group, response rate of 25.8% has been observed in 
an ongoing clinical trial in China. Based on this, it was assumed that the response rate will be 
maximum 30% in the no-treatment Control Group at Month 12.
With a sample size of 100 subjects treated with Sculptra and 50 subjects in the no-treatment 
control group, Fisher’s Exact test will have approximately 90% power to detect difference 
between the anticipated percentage of responders at a 5% significance level (two-sided). To 
account for 20% drop-outs, approximately 126 will be randomized to the Sculptra group and 
approximately 63 to the control group.
11 Protection 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.
All processing of personal data must be carried out in accordance with national legislation 
concerning the protection of personal data. The Institution and the PI are responsible for 
complying with all requirements pursuant to national legislation in the country in which the 
Institution and the PI are located. The Sponsor will ensure that all requirements are complied 
with for data processing, which is carried out in Sweden by the Sponsor.
The Informed Consent Form shall contain information about what personal data to be 
collected in the study and that this will be kept confidential. The provided information shall 
be sufficient to enable all subjects to give their consent not only to the participation in the 
study, but also to the processing of personal data. Such information includes information 
regarding the purposes of the collecting, processing, data transfer to countries outside China, 
and the length of time during which personal data will be stored. The subject shall have the 
right of access to stored personal data, and the right to correction of incorrect information. If 
a subject decides to terminate the study prematurely, data collected before withdraw of 
consent will be used in the evaluation of the study, however no new data may be collected. 
Authorised representatives from the Sponsor or a RA may visit the study site to perform 
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audits/inspections, including source data verification, i.e. comparing data in the subjects’ 
medical records and the eCRF. Data and information shall be handled strictly confidential.
12 Quality Control and Quality Assurance
12.1 Quality control
On-site monitoring of the study will be arranged by the Sponsor according to GCP guidelines 
to verify that the rights and well-being of the subjects are protected, the reported data are 
accurate, complete, verifiable from source documents, and that the conduct of the study 
complies with the approved CSP, subsequent amendment(s), GCP and the applicable 
regulatory requirements. 
Any CSP deviation shall be reported in the eCRF, which shall be verified, discussed, and 
collected, by the monitor and appropriate corrective and preventive actions shall be taken. 
The PI is responsible for promptly reporting any deviations from the CSP that affects the 
rights, safety or well-being of the subject or the scientific integrity of the study, including 
those which occur under emergency circumstances, to the Sponsor as well as the IEC if 
required by national regulations. Deviations shall be reviewed to determine the need to 
amend the CSP or to terminate the study. Handling of CSP deviations shall be performed as 
described in the monitoring manual.
12.2 Quality assurance
The study site may be subject to quality assurance audit by the Sponsor as well as inspection 
by appropriate RA. It is important that the PI and other relevant study site personnel are 
available during the monitoring visits, possible audits, and inspections, and that sufficient 
time is devoted to the monitoring process.
Each participating member of the study site team shall provide a curriculum vitae (CV) or 
equivalent that demonstrates their qualifications to conduct the study. The CV shall give 
name, date and place of birth, address and place of work, and shall show the training, 
appointments and, for the PI, any other information that confirms the suitability of the PI to 
be responsible for the study. 
It is the responsibility of the PI to ensure that all personnel involved in the study are fully 
informed of all relevant aspects of the study, including detailed knowledge of and training in 
all procedures to be followed. All Investigators and other responsible persons shall be listed 
together with their function in the study on the signature and delegation log.
12.3 Changes to the clinical study protocol
The PI and other site personnel involved in the study must not implement any deviation from 
or changes to the CSP without agreement with the Sponsor and prior review and documented 
approval from the IEC, except where necessary to eliminate an immediate hazard to the 
subjects. All changes to the final CSP must be documented in a written protocol amendment. 
However, administrative changes are to be documented in the Sponsor file without requiring 
a protocol amendment.
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13 Financing, Indemnification, and Insurance
The CTA outlines the compensation and payment terms of the study. The CTA must be signed 
before the first subject is screened in the study. If there are differences between the CTA and 
the CSP regarding certain rights and obligations, the CTA is the prevailing document. 
Q-Med AB’s obligations in this clinical study are covered by Galderma’s global general liability 
program. An insurance certificate will be provided upon request. The institution/PI is 
obligated to maintain insurance coverage for their obligations in the clinical study according 
to the CTA.
14 Publication Policy
The PI’s, institutions, 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 multicentre study shall have made a 
substantial, direct, intellectual contribution to the work. Authorship will be based on (1) 
substantial contributions to the conception or design of the work; or the acquisition, analysis, 
or interpretation of data for the work; and (2) drafting the work or revising it critically for 
important intellectual content; and (3) final approval of the version to be published; and (4) 
agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved*.
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 should 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.
*Defining the role of authors and contributors, compiled by the International Committee of 
Medical Journal Editors (ICMJE) (http://www.icmje.org). 
15 Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IEC or if it is judged 
that the subjects are subjected to unreasonable risks, or for valid scientific or administrative 
reasons. 
The Sponsor may also decide to close a single study site due to unsatisfactory subject 
enrolment or non-compliance with the CSP, GCP, or applicable regulatory requirements.
In the event of premature termination, Q-Med AB will provide information on the handling of 
currently enrolled subjects who have not completed the study
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16 References
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T., Hanke, C.W., Humble, G., et al. (2012). Injectable poly-L-lactic acid for human 
immunodeficiency virus-associated facial lipoatrophy: cumulative year 2 interim analysis of an 
open-label study (FACES). Dermatol Surg 38, 1193-1205.
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Mest, D.R., and Humble, G. (2006). Safety and efficacy of poly-L-lactic acid injections inpersons 
with HIV-associated lipoatrophy: the US experience. Dermatol Surg 32, 1336-1345.
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Mest, D.R., and Humble, G.M. (2009). Retreatment with injectable poly-l-lactic acid for 
HIVassociated facial lipoatrophy: 24-month extension of the Blue Pacific study. Dermatol Surg 
35 Suppl 1, 350-359.
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Moyle, G.J., Lysakova, L., Brown, S., Sibtain, N., Healy, J., Priest, C., Mandalia, S., and Barton, 
S.E. (2004). A randomized open-label study of immediate versus delayed polylactic acid 
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Valantin, M.A., Aubron-Olivier, C., Ghosn, J., Laglenne, E., Pauchard, M., Schoen, H., Bousquet, 
R., Katz, P., Costagliola, D., and Katlama, C. (2003). Polylactic acid implants (New-Fill) to correct 
facial lipoatrophy in HIV-infected patients: results of the open-label study VEGA. AIDS 17, 
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Brandt, F.S., Cazzaniga, A., Baumann, L., Fagien, S., Glazer, S., Kenkel, J.M., Lowe, N.J., 
Monheit, G.D., Narins, R.S., Rendon, M.I., et al. (2011). Investigator global evaluations of 
efficacy of injectable poly-L-lactic acid versus human collagen in the correction of nasolabial 
fold wrinkles. Aesthet Surg J 31, 521-528.
7.
Brown, S.A., Rohrich, R.J., Baumann, L., Brandt, F.S., Fagien, S., Glazer, S., Kenkel, J.M., Lowe, 
N.J., Monheit, G.D., Narins, R.S., et al. (2011). Subject global evaluation and subject 
satisfaction using injectable poly-L-lactic acid versus human collagen for the correction of 
nasolabial fold wrinkles. Plast Reconstr Surg 127, 1684-1692.
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Narins, R.S., Baumann, L., Brandt, F.S., Fagien, S., Glazer, S., Lowe, N.J., Monheit, G.D., Rendon, 
M.I., Rohrich, R.J., and Werschler, W.P. (2010). A randomized study of the efficacy and safety 
of injectable poly-L-lactic acid versus human-based collagen implant in the treatment of 
nasolabial fold wrinkles. J Am Acad Dermatol 62, 448-462.
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Burgess, C.M., and Quiroga, R.M. (2005). Assessment of the safety and efficacy of poly-Llactic 
acid for the treatment of HIV-associated facial lipoatrophy. J Am Acad Dermatol 52, 233-239.
10. Carey, D., Baker, D., Petoumenos, K., Chuah, J., Rogers, G.D., Watson, J., Cooper, D.A., Emery, 
S., Carr, A., and Investigators, F. (2009). Poly-l-lactic acid for HIV-1 facial lipoatrophy: 48-week 
follow-up. HIV Med 10, 163-172.
11. Carey, D.L., Baker, D., Rogers, G.D., Petoumenos, K., Chuah, J., Easey, N., Machon, K., Cooper, 
D.A., Emery, S., Carr, A., et al. (2007). A randomized, multicenter, open-label study of poly-L-
lactic acid for HIV-1 facial lipoatrophy. J Acquir Immune Defic Syndr 46, 581-589.
12. Cattelan, A.M., Bauer, U., Trevenzoli, M., Sasset, L., Campostrini, S., Facchin, C., Pagiaro, E., 
Gerzeli, S., Cadrobbi, P., and Chiarelli, A. (2006). Use of polylactic acid implants to correct facial 
lipoatrophy in human immunodeficiency virus 1-positive individuals receiving combination 
antiretroviral therapy. Arch Dermatol 142, 329-334.
13. Guaraldi, G., Orlando, G., De, F.D., De, L., I, Rottino, A., De, S.G., Pedone, A., Spaggiari, A., 
Baccarani, A., Borghi, V., et al. (2005). Comparison of three different interventions for the 
correction of HIV-associated facial lipoatrophy: a prospective study. Antivir Ther 10, 753-759.
14. Hanke, C.W., and Redbord, K.P. (2007). Safety and efficacy of poly-L-lactic acid in HIV 
lipoatrophy and lipoatrophy of aging. J Drugs Dermatol 6, 123-128.
15. Lafaurie, M., Dolivo, M., Girard, P.M., May, T., Bouchaud, O., Carbonnel, E., Madelaine, I., Loze, 
B., Porcher, R., and Molina, J.M. (2013). Polylactic acid vs. polyacrylamide hydrogel for 
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treatment of facial lipoatrophy: a randomized controlled trial [Agence Nationale de 
Recherches sur le SIDA et les Hepatites Virales (ANRS) 132 SMILE]. HIV Med 14, 410-420.
16. Lafaurie, M., Dolivo, M., Porcher, R., Rudant, J., Madelaine, I., and Molina, J.M. (2005). 
Treatment of facial lipoatrophy with intradermal injections of polylactic acid in HIV infected 
patients. J Acquir Immune Defic Syndr 38, 393-398.
17. Levy, R.M., Redbord, K.P., and Hanke, C.W. (2008). Treatment of HIV lipoatrophy and 
lipoatrophy of aging with poly-L-lactic acid: a prospective 3-year follow-up study. J Am Acad 
Dermatol 59, 923-933.
18. Narciso, P., Bucciardini, R., Tozzi, V., Bellagamba, R., Ivanovic, J., Giulianelli, M., Scevola, S., 
Palummieri, A., Fragola, V., Massella, M., et al. (2009). Immediate versus delayed surgical 
intervention for reconstructive therapy of HIV-associated facial lipoatrophy: a randomized 
open-label study. AIDS Res Hum Retroviruses 25, 979-987.
19. Ong, J., Clarke, A., White, P., Johnson, M., Withey, S., and Butler, P.E. (2007). Does severity 
predict distress? The relationship between subjective and objective measures of appearance 
and psychological adjustment, during treatment for facial lipoatrophy. Body Image 4, 239-248.
20. Duracinsky, M., Leclercq, P., Armstrong, A.R., Dolivo, M., Mouly, F., and Chassany, O. (2013). 
A longitudinal evaluation of the impact of a polylactic acid injection therapy on health related 
quality of life amongst HIV patients treated with anti-retroviral agents under real conditions 
of use. BMC Infect Dis 13, 92.
21. Duracinsky, M., Leclercq, P., Herrmann, S., Christen, M.O., Dolivo, M., Goujard, C., and 
Chassany, O. (2014). Safety of poly-L-lactic acid (New-Fill(R)) in the treatment of facial 
lipoatrophy: a large observational study among HIV-positive patients. BMC Infect Dis 14, 474.
22. Orlando, G., Guaraldi, G., De, F.D., Rottino, A., Grisotti, A., Blini, M., De, S.G., Pedone, A., 
Spaggiari, A., Baccarani, A., et al. (2007). Long-term psychometric outcomes of facial 
lipoatrophy therapy: forty-eight-week observational, nonrandomized study. AIDS Patient Care 
STDS 21, 833-842.
23. Byun, S.Y., Seo, K.I., Shin, J.W., Kwon, S.H., Park, M.S., Lee, J., Park, K.C., Na, J.I., and Huh, C.H. 
(2015). Objective analysis of poly-l-lactic acid injection efficacy in different settings. Dermatol 
Surg 41, S314-S320.
24. Chen, H.H., Javadi, P., Daines, S.M., and Williams, E.F., III (2015). Quantitative assessment of 
the longevity of poly-L-lactic acid as a volumizing filler using 3-dimensional photography. 
JAMA Facial Plast Surg 17, 39-43.
25. Lowe, P., Lowe, N.J., and Patnaik, R. (2011). Three-dimensional digital surface imaging 
measurement of the volumizing effect of injectable poly-L-lactic acid for nasolabial folds. J 
Cosmet Laser Ther 13, 87-94.
26. Suh, D.H., Lee, S.J., Kim, S.M., Lee, J.D., and Kim, H.S. (2014). The safety and efficacy of poly-
L-lactic acid on sunken cheeks in Asians. J Cosmet Laser Ther 16, 180-184.
27. Salles, A.G., Lotierzo, P.H., Gimenez, R., Camargo, C.P., and Ferreira, M.C. (2008). Evaluation 
of the poly-L-lactic acid implant for treatment of the nasolabial fold: 3-year follow-up 
evaluation. Aesthetic Plast Surg 32, 753-756.
28. Schierle, C.F., and Casas, L.A. (2011). Nonsurgical rejuvenation of the aging face with injectable 
poly-L-lactic acid for restoration of soft tissue volume. Aesthet Surg J 31, 95-109.
29. Lorenc ZP, Bank D, Kane M, Lin X, Smith S. Validation of a Four Point Photographic Scale for 
the Assessment of Midface Volume Loss and/or Contour Deficiency. Plast Reconstr Surg 2012 
Dec; 130(6):1330-6.
30. Weiss RA et al. Effectiveness and Safety of Large Gel Particle Hyaluronic Acid with Lidocaine 
for Correction of Midface Volume Deficit or Contour Deficiency. Dermatol Surg. 2016 Jun; 
42(6):699-709.
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17 Appendices
Appendix 1
Declaration of Helsinki 
Appendix 2
Photo guide for MMVS
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Appendix 1
Declaration of Helsinki
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WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving
Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be
applied with consideration of all other relevant paragraphs.
2.
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.
General Principles
3.
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient
will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.”
4.
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients,
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty.
5.
Medical progress is based on research that ultimately must include studies involving human subjects.
6.
The primary purpose of medical research involving human subjects is to understand the causes,
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality.
7.
Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights.
8.
While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects.
9.
It is the duty of physicians who are involved in medical research to protect the life, health, dignity,
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
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Appendix 1
Declaration of Helsinki
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or other health care professionals and never with the research subjects, even though they have given 
consent.
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of 
the protections for research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that minimises possible harm to the environment.
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional.
13. Groups that are underrepresented in medical research should be provided appropriate access to
participation in research.
14. Physicians who combine medical research with medical care should involve their patients in research
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in
research must be ensured.
Risks, Burdens and Benefits
16. In medical practice and in medical research, most interventions involve risks and burdens. Medical 
research involving human subjects may only be conducted if the importance of the objective
outweighs the risks and burdens to the research subjects.
17. All medical research involving human subjects must be preceded by careful assessment of predictable
risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation.
Measures to minimise the risks must be implemented. The risks must be continuously monitored,
assessed and documented by the researcher.
18. Physicians may not be involved in a research study involving human subjects unless they are confident
that the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof of
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.
Vulnerable Groups and Individuals
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
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Declaration of Helsinki
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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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Declaration of Helsinki
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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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Appendix 1
Declaration of Helsinki
5(5)
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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2019-06-19 10:58
Justification
Approved by Technical Expert
2019-06-19 11:50
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Approved by Owner
2019-06-20 00:56
Justification
Approved by Project Manager
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