A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of a New Dilution and Injection Volume of AbobotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines
Phase: PHASE3
Conditions: Glabellar Frown Lines
Sponsor: Galderma R&D

 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of a New Dilution and 
Injection Volume of AbobotulinumtoxinA for the Treatment of 
Moderate to Severe Glabellar Lines 
 
 
NCT Number: NCT03960957 
 
 
Protocol Document date: 24Jan2019 
 
 
 

Page 1 of 79
CLINICAL STUDY PROTOCOL
PROTOCOL NUMBER: 43USD1805
CONFIDENTIAL
This document contains confidential, proprietary information
All the information provided to the Investigator and his/her staff and all data obtained through this 
Q-Med AB clinical study protocol are confidential.  The Sponsor reserves all proprietary rights. 
No information may be disclosed to any third party without prior written consent from 
Q-Med AB.
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TABLE OF CONTENTS
TITLE PAGE..................................................................................................................................................2
TABLE OF CONTENTS...............................................................................................................................3
SYNOPSIS ......................................................................................................................................................9
CLINCIAL STUDY SCHEMATIC AND FLOW CHART......................................................................15
SCHEDULE OF ASSESSMENTS..............................................................................................................17
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................................19
1
BACKGROUND AND RATIONALE..............................................................................................21
1.1
Medical Background and Short Rationale for the Clinical Study............................................21
1.2
Drug Profile...................................................................................................................................22
1.3
Target Indication ..........................................................................................................................22
1.4
Risk/Benefit Assessment...............................................................................................................22
2
CLINICAL STUDY OBJECTIVES, ENDPOINTS, AND CLINICAL HYPOTHESIS .............23
2.1
Clinical Study Objectives .............................................................................................................23
2.1.1
Primary Efficacy Objectives and Endpoints .........................................................................23
2.1.2
Secondary Efficacy Objectives and Endpoints......................................................................24
2.1.3
Exploratory Efficacy Objectives and Endpoints...................................................................24
2.1.4
Safety Objectives and Endpoints............................................................................................25
2.2
Clinical Hypothesis .......................................................................................................................26
3
OVERALL CLINICAL STUDY DESCRIPTION..........................................................................26
4
CLINICAL STUDY DURATION AND TERMINATION ............................................................27
5
SELECTION AND DISPOSITION OF CLINICAL STUDY POPULATION............................27
5.1
Number of Subjects.......................................................................................................................27
5.2
Clinical Study Population Characteristics..................................................................................27
5.2.1
Inclusion Criteria.....................................................................................................................27
5.2.2
Exclusion Criteria....................................................................................................................28
5.3
Medical History.............................................................................................................................29
5.4
Previous and Concomitant Therapies.........................................................................................30
5.4.1
Definition ..................................................................................................................................30
5.4.2
Categories .................................................................................................................................30
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5.4.3
Recording..................................................................................................................................30
5.4.4
Authorized Concomitant Therapies.......................................................................................30
5.4.5
Prohibited Concomitant Therapies........................................................................................31
5.5
Procedures/Reasons for Subject Discontinuation ......................................................................31
6
CLINICAL SUPPLIES......................................................................................................................33
6.1
Clinical Supply Identification and Use........................................................................................33
6.1.1
AbobotulinumtoxinA...............................................................................................................33
6.1.2
Placebo......................................................................................................................................33
6.1.3
Study Products(s) Description ................................................................................................34
6.1.4
Subject Identification Number (SIN).....................................................................................34
6.1.5
Method of Treatment Assignment..........................................................................................34
6.1.6
Kit Number/Randomization Number ....................................................................................35
6.1.7
Instructions for Use and Administration...............................................................................35
6.1.7.1
Study Products....................................................................................................................35
6.1.7.1.1
.....................................................................................35
6.1.7.1.2
............................................................................................................................35
6.1.7.2
Treatment Preparation ......................................................................................................35
6.1.7.3
Injection Technique............................................................................................................36
6.1.7.4
Treatment Procedure .........................................................................................................37
6.1.7.5
Post-treatment Care ...........................................................................................................37
6.1.7.6
Treatment Regimen............................................................................................................37
6.1.7.7
38
6.2
Study Products(s) Packaging and Labeling................................................................................38
6.3
Supplies Management...................................................................................................................38
6.3.1
Accountability ..........................................................................................................................38
6.3.2
Storage of Study Products(s)...................................................................................................38
6.3.3
Dispensing and Return ............................................................................................................38
6.3.4
Treatment Compliance Management and Record................................................................39
6.3.5
Dose Modification ....................................................................................................................39
6.3.6
Product Quality Complaints...................................................................................................39
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6.4
Blinding..........................................................................................................................................39
6.4.1
Verification of Blinding...........................................................................................................39
6.4.2
Unblinding During the Clinical Study ...................................................................................40
7
CLINICAL STUDY ASSESSMENT................................................................................................40
7.1
Efficacy Assessments.....................................................................................................................40
.....42
7.2
Safety Assessment .........................................................................................................................42
7.2.1
Focused Physical Examination ...............................................................................................42
7.2.2
Adverse Events.........................................................................................................................43
7.2.2.1
Definitions............................................................................................................................43
7.2.2.1.1
Adverse Events (AE)........................................................................................................43
7.2.2.1.2
Treatment Emergent Adverse Event (TEAE)...................................................................44
7.2.2.1.3
Serious Adverse Events (SAE) .........................................................................................44
7.2.2.1.4
Unexpected Adverse Drug Reaction................................................................................44
7.2.2.1.5
Adverse Event Reporting Period .....................................................................................45
7.2.2.1.6
Severity ............................................................................................................................45
7.2.2.1.7
Relationship to the Study Product and/or Clinical Study Procedure..............................45
7.2.2.2
Reporting Procedures.........................................................................................................46
7.2.2.2.1
Procedures for Reporting Adverse Events.......................................................................46
7.2.2.2.2
Procedure for Reporting a Serious Adverse Event..........................................................47
7.2.2.2.3
Procedures for Reporting Pregnancies ...........................................................................48
7.3
Other Assessments ........................................................................................................................49
7.3.1
Photography .............................................................................................................................49
7.3.2
Pregnancy Test.........................................................................................................................49
7.4
Appropriateness of Measurements..............................................................................................49
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8
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES ........................................50
......................................................................................................55
8.2
Subject Instructions......................................................................................................................56
9
STATISTICAL METHODS PLANNED .........................................................................................56
9.1
Statistical and Analytical Plans ...................................................................................................56
9.1.1
Data Transformations .............................................................................................................56
9.1.2
Populations Analyzed and Evaluability.................................................................................56
9.1.2.1
Intent-to-treat (ITT) Efficacy Population.........................................................................56
9.1.2.2
Per-protocol (PP) Efficacy Population..............................................................................56
9.1.2.3
Safety Population................................................................................................................56
9.1.2.4
Imputation of Missing Data ...............................................................................................57
9.1.3
Data Presentation and Graphics.............................................................................................57
9.1.3.1
Safety Analysis ....................................................................................................................57
9.1.4
Withdrawals and Deviations...................................................................................................58
9.1.5
Inferential Statistical Analyses ...............................................................................................58
9.2
Sample Size Determination ..........................................................................................................59
9.2.1
Historical Data .........................................................................................................................59
9.2.2
Assumptions .............................................................................................................................59
9.2.3
Sample Size Calculation ..........................................................................................................59
9.2.4
Interim Analysis.......................................................................................................................59
10
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ..............60
10.1
Personnel Training........................................................................................................................60
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10.2
Clinical Monitoring.......................................................................................................................60
10.3
Data Management.........................................................................................................................60
10.4
Quality Assurance/Audit/Inspection ...........................................................................................60
10.5
Changes in Clinical Study Conduct/Amendments.....................................................................61
10.5.1
Clinical Study Conduct............................................................................................................61
10.5.2
Amendments.............................................................................................................................61
11
ETHICS AND GENERAL CLINICAL STUDY CONDUCT CONSIDERATIONS ..................61
11.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ..........................61
11.2
Ethical Conduct of the Clinical Study.........................................................................................62
11.3
Subject Information and Consent ...............................................................................................62
11.4
Protection of Personal Data .........................................................................................................62
11.5
Contractual Requirements...........................................................................................................63
11.6
Data Collection and Archiving.....................................................................................................63
11.6.1
Data Collection.........................................................................................................................63
11.6.2
Source Documentation.............................................................................................................63
11.6.3
Archives ....................................................................................................................................63
11.7
Insurance .......................................................................................................................................64
11.8
Publication Policy..........................................................................................................................64
11.9
Investigator and Administrative Structure ................................................................................65
12
LITERATURE REFERENCE LIST................................................................................................67
13
APPENDICES ....................................................................................................................................68
78
14
SIGNED AGREEMENT OF THE CLINICAL STUDY PROTOCOL........................................79
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CLINCIAL STUDY SCHEMATIC AND FLOW CHART
Table 1
Clinical Study Schematic
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
C
Degrees Celsius
AE 
Adverse Event
ADR
Adverse Reaction
BOCF 
Baseline Observation Carried Forward
BoNT
Botulinum Toxin
BoNT-A
Botulinum Toxin Type A
BoNT-A-HAC
Botulinum Toxin Type A-Haemagglutinin Complex
CDMS
Clinical Data Management System
CM
Concomitant Medication
CMH
Cochran-Mantel-Haenszel
CPM
Clinical Project Manager
CRF/eCRF
Case Report Forms/electronic Case Report Forms
CRO
Contract Research Organization
CSP
Clinical Study Protocol
DC
Discontinuation
DMP
Data Management Plan
EDC
Electronic Data Capture
e.g. 
For Example (Latin: exempli gratia)
ET
Early Termination
etc
Et cetera
FDA
Food and Drug Administration
FSFV
First Subject First Visit (date of first subject included i.e., informed 
consent signature)
GAIS
Global Aesthetic Improvement Scale
GCP 
Good Clinical Practice 
GL
Glabellar Lines
HIPAA
Health Insurance Portability and Accountability Act of 1996
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
i.e. 
That is (Latin: id est)
IEC
Independent Ethics Committee 
ILA
Investigator Live Assessment
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IUD
Intrauterine Device
KM
Kaplan-Meier
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Abbreviation
Term
LSFV
Last Subject First Visit (date of last subject included i.e., informed 
consent signature)
LSLV
Last Subject Last Visit (date of last subject’s last study visit)
MD
Medical Doctor
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
mL
Milliliter
N or n
Number
N/A
Not Applicable
NaCI
Sodium Chloride
OC
Observed Cases
OTC
Over-the-Counter
PE
Physical Examination
PP
Per-Protocol
PQC
Product Quality Complaint
SAE
Serious Adverse Event
SIN
Subject Identification Number
SOC
System Organ Class
SOP
Standard Operating Procedure
SSA
Subject Self-Assessment
SUSAR
Suspected Unexpected Serious Adverse Reaction
TOC
Table of Contents
TEAE
Treatment Emergent Adverse Event
U
Units
UPT
Urine Pregnancy Test
US
United States
USP
United States Pharmacopeia
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1
BACKGROUND AND RATIONALE
1.1
Medical Background and Short Rationale for the Clinical Study
Botulinum toxin (BoNT) is a potent neurotoxic protein produced by the Gram-positive 
anaerobic bacterium, Clostridium botulinum. The molecule is produced naturally by these 
bacteria together with a series of accessory proteins, forming what is termed the “toxin 
complex”. The neurotoxin is the cause of the severe and potentially fatal disease of botulism. In 
addition, the protein is used in very small quantities as a treatment modality for aesthetic and 
medical indications, many of which are characterized by increased muscle activity. Botulinum 
toxins occur in seven known serotypes (A-G) that are produced by different strains of 
Clostridium botulinum. Clinically important biologic activity is limited primarily to the A and B 
serotypes, of which the type A serotype (BoNT-A) is used widely throughout the world for the 
treatment of a range of clinical conditions. BoNT-A blocks the release of acetylcholine into the 
neuromuscular junction (synapse) cleft, thereby prohibiting the activation of acetylcholine 
receptors. Paresis by chemical denervation thus occurs in the target muscle, leading to inhibition 
of muscular contraction.
In the early 1990s, patients treated with BoNT-A for blepharospasm were observed to lose their 
frown lines,1,2 and since publishing these observations, the use of BoNT-A in the aesthetic setting 
has accelerated. Injectable BoNT-A products have been investigated for multiple aesthetic 
indications in attempts to reverse the appearance of aging, especially in the facial region.1 In the 
treatment of facial lines, the effect of BoNT-A injections usually persists for approximately 
4-6 months. Facial muscle activity and severity of the facial wrinkles then returns to baseline. 
Full functionality of facial muscles is usually restored by approximately 6 months post-
treatment.3
AbobotulinumtoxinA (Dysport) was approved by the United States Food and Drug 
Administration (FDA) in 2009. AbobotulinumtoxinA is indicated for the temporary 
improvement in the appearance of moderate to severe GL associated with procerus and 
corrugator muscle activity in adult patients less than 65 years of age. To achieve a clinical 
effect, a total of 50 U is given intramuscularly in five equal aliquots of 10 U each into each of 
five sites, two in each corrugator muscle and one in the procerus muscle. Re-treatments should 
be administered no more frequently than every three months. 
The rationale of the study is to evaluate the currently approved abobotulinumtoxinA dose of 
50 U using a larger injection volume of 0.1 mL per injection site for the treatment of moderate 
to severe glabellar lines. This injection volume provides better control of the injection, 
minimized the margin of error, and is comparable to other BoNT-A preparations, (i.e., 
onabotulinumtoxinA [Botox®] and incobotutinumtoxinA [Xeomin®]). Based on anecdotal 
experience, it is also reflective of current clinical practice among some physicians and other 
qualified medical professionals.
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5.4
Previous and Concomitant Therapies
5.4.1
Definition
Previous therapies are defined as therapies that have been stopped within the 4 weeks preceding 
the screening visit or within timeframes specified in the inclusion/exclusion criteria.
Concomitant therapies are defined as follows:

any existing therapies ongoing at the time of the screening visit,

any changes to existing therapies (such as changes in dose or formulation) during the 
course of the clinical study, or

any new therapies received by the subject since the screening visit.  
5.4.2
Categories
The following two categories are to be considered for previous and concomitant therapies: 

Drugs including but not limited to, prescription, over-the-counter (OTC), birth control 
pills/patches/hormonal devices, vitamins, herbal medicines/supplements, and homeopathic 
preparations.

Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers (area of treatment should be indicated), X-rays, surgeries, tooth extractions.
5.4.3
Recording
Previous and concomitant therapies are to be recorded in the subject’s source documents and
eCRFs.
Concomitant therapies are to be reviewed at each visit and updated in the source documents and 
eCRFs as needed. 
Any new concomitant therapy or modification of an existing therapy may be linked to an AE.  A 
corresponding AE form should be completed to account for the change in therapy, except in some 
cases such as therapy used for prophylaxis, dose modification for a chronic condition, etc.
5.4.4
Authorized Concomitant Therapies
Unless listed in prohibited concomitant therapies (see Section 5.4.5), all are authorized.
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5.4.5
Prohibited Concomitant Therapies
The following therapies are prohibited because they may interfere with the efficacy and/or safety 
assessment of the study products(s):

Botulinum toxin of any serotype.

Any other investigational new drug or device.

Any absorbable (temporary) or non-absorbable (permanent) material above the lower 
orbital rim. 

Facial aesthetic procedures (e.g ablative skin resurfacing, chemical peel, photorejuvenation 
or skin/vascular laser intervention) above the lower orbital rim.

Planned facial surgery or eye surgery (including LASIK procedure).

Medications that affect neuromuscular transmission such as curare-like depolarizing agents, 
lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics.
If a prohibited therapy becomes a necessary treatment for best clinical interest of the subject or 
due to safety reason, the Medical Monitor (Section 11.9) should be notified, if time permits, to 
discuss possible alternatives prior to administration of a prohibited therapy.
If a subject receives a prohibited therapy during the clinical study, the Medical Monitor (Section 
11.9) should be notified to discuss the subject’s continuation in the clinical study..
5.5
Procedures/Reasons for Subject Discontinuation
An Investigator may decide to discontinue a subject from the clinical study for safety reasons.
Although the importance of completing the entire clinical study should be explained to the 
subject by the clinical study personnel, any subject is free to discontinue participation in this 
clinical study at any time and for whatever reason, specified or unspecified, and without any 
prejudice.  No constraints are to be imposed on the subject, and when appropriate, a subject may 
be treated with other conventional therapy when clinically indicated. 
When a subject does not complete the clinical study, he/she will be fully assessed, if such 
assessment is possible.  The procedures designated for the Month 6/ ET visit should be completed 
for all subjects discontinuing the clinical study and the appropriate eCRF should be completed.
All discontinuations and the reason for discontinuation are to be documented by the Investigator 
on the exit form. For discontinuation due to an AE, the AE form is to be completed. The 
Investigator should also ensure that the subject receives suitable therapy for the AE.
Potential reasons for discontinuation, as listed on the exit form, are defined below:
Adverse Event:
Complete an AE form.
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Withdrawal by 
Subject:
Includes consent withdrawal, subject relocation, schedule conflicts, 
etc.  Explain the reason for withdrawal in the comment section of the 
eCRF exit form.
Lost to Follow-up:
Confirmed with two documented phone calls and a certified letter 
(delivery receipt requested) without answer.  Explain in the comment 
section of the eCRF exit form.
Other:
This category is to be used for a subject who discontinues due to a 
reason other than as specified in the predefined categories above. 
Explain the reason for discontinuation in the comment section of the 
eCRF exit form.
A subject who has been randomized and assigned a kit number/randomization number cannot be 
replaced by another subject if he/she discontinues the clinical study for any reason. Additional 
subjects could be enrolled (randomized/assigned to treatment) in order to attain the number of 
evaluable subjects.
Pregnancies occurring during the screening period are considered screen failures; they should be 
recorded as such in the eCRF and no pregnancy form is to be completed. In case of a pregnancy 
occurring after the baseline visit, follow the procedures described in Section 7.2.2.2.3. The 
subject may remain in the study, but no invasive procedure should be conducted (e.g. no sample 
taken for lab test).
The Sponsor may also decide to prematurely terminate or suspend a subject’s participation in the 
clinical study.
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In the event of early termination/suspension of the clinical study, a rapid recall of study 
products(s) will be initiated.  
6.3.4
Treatment Compliance Management and Record
The treatment is an injection administered by the Investigator. It will be recorded in the eCRF 
that the injection has been administered. No other measurements of treatment compliance will be 
made.
6.3.5
Dose Modification 
Dose modifications are not permitted.
6.3.6
Product Quality Complaints
Product Quality complaints (PQCs) should be reported to the Sponsor Contact or designee 
(Section 11.9). A PQC is an external judgement presuming a quality defect of a product; quality 
issue for a product relating to its presentation or use, identified by a subject, a practitioner or 
investigator site personnel, a distributor, or anyone else involved in clinical supplies handling. 
Examples may include but are not limited to appearance issues, odor, damaged stoppers, low fills, 
and foreign matter in the product. These complaints may or may not represent a potential risk to 
the subject. A PQC form must be completed by the study center personnel and forwarded to the 
Sponsor or designee within 24 hours of awareness. Affected study product should be quarantined, 
and not used, until further notice by the Sponsor.
Additional contact details are provided in the Investigator’s site file.
6.4
Blinding
This is a double-blind, placebo-controlled study in which neither the Investigator, sub-
Investigator, study staff, nor the subject will know the subject's study product assignment. 
Preparation and administration of the study products, abobotulinumtoxinA or placebo, will be 
completed in exactly the same way.
An un-blinded statistician will generate the randomization schedule; however, they will not be 
involved in any other aspect of the study prior to database lock.
6.4.1
Verification of Blinding
The Sponsor’s staff or designees will assess and verify maintenance of the study blind during the 
study through routine monitoring visits. 
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7.2.2
Adverse Events
AEs are to be monitored throughout the course of the clinical study from the time the informed 
consent form has been signed. All AEs are to be reported on the AE form of the eCRF with 
complete information as required. 
If AEs occur, the main concern shall be the safety of the subjects. At the time of the ICF 
signature, each subject must be provided with the name and phone number of clinical study 
center personnel for reporting AEs and medical emergencies.
7.2.2.1
Definitions
7.2.2.1.1
Adverse Events (AE)
According to ICH E2A, an AE is any untoward medical occurrence in a patient or a clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
Thus any new sign, symptom or disease, or any clinically significant worsening of an existing 
sign, symptom or disease (including new episodes of a chronic disease [e.g., hay fever, allergy]) 
compared to the condition at the first visit, should be considered as an AE. Lack of efficacy is not 
considered as an AE.
Notes:

There should be an attempt to report a diagnosis rather than the signs, symptoms or 
abnormal laboratory values associated with the report of an AE. However, a diagnosis 
should be reported only if, in the investigator’s judgment, it is relatively certain. Otherwise, 
symptoms, signs, or laboratory values should be used to describe the AE.

Pregnancy is not to be considered as an AE; however, is an important medical event that 
must be monitored as described in Section 7.2.2.2.3.

The effects of Dysport and all BoNT products may spread from the area of injection to 
produce symptoms consistent with BoNT effects. These symptoms have been reported 
hours to weeks after injection. Remote spread of toxin that affects swallowing and 
breathing can be life threatening, and there have been reports of death. The risk of 
symptoms is increased in subjects who have underlying conditions (e.g. disorders of the 
neuromuscular junction) that would predispose them to these symptoms. Dysport is 
contraindicated in individuals with known hypersensitivity to any BoNT preparation or to 
any of the components in the formulation. 
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7.2.2.1.2
Treatment Emergent Adverse Event (TEAE)
A TEAE is an event that emerges during treatment, having been absent pre-treatment, or worsens 
relative to the pretreatment state.
Investigators are responsible for monitoring, recording, and reporting all AEs that occur during 
the study as described. TEAEs will be delineated from AEs following database lock.
7.2.2.1.3
Serious Adverse Events (SAE)
A SAE is any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening,

Requires inpatient hospitalization or prolongation of existing hospitalization,

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the safety of the subject, and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasia, or 
convulsions that do not result in hospitalization.
Note: The term “life-threatening” refers to an event in which the subject 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.
Inpatient hospitalization is considered to have occurred if the subject has had to stay for a night at 
the hospital.  The criterion for prolongation of hospitalization is also defined as an extra night at 
the hospital.  Hospitalization may not constitute sufficient grounds to be considered as an SAE if 
it is solely for the purpose of a diagnostic test(s) (even if related to an AE), elective 
hospitalization for an intervention that was already planned before subject enrolment in the 
clinical study, admission to a day-care facility, social admission (e.g., if the subject has no place 
to sleep), or administrative admission (e.g., for a yearly examination).
7.2.2.1.4
Unexpected Adverse Drug Reaction
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable study product information (e.g., Investigator’s 
Brochure for an unapproved investigational product or the medicinal package insert/summary of 
product characteristics for an approved investigational product).
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7.2.2.1.5
Adverse Event Reporting Period
The clinical study period during which AEs must be reported is the period from when the subject 
signed the ICF to the end of the subject’s participation.
The Sponsor should be informed if the Investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who has 
participated in a clinical study, even after a subject has completed the clinical study.  
7.2.2.1.6
Severity
Severity is a clinical determination of the intensity of an AE and not the severity of a disease.
The Investigator is to classify the intensity of AEs using the following definitions as a guideline.  
For this classification, the Investigator will take into account the possible range of the intensity of 
the event and report the grade of intensity which is the most appropriate according to his/her
medical judgment.
Mild
Awareness of signs or symptom, but easily tolerated.
Moderate
Discomfort, enough to cause interference with usual activity.
Severe
Incapacitating with inability to work or perform usual activity.
7.2.2.1.7
Relationship to the Study Product and/or Clinical Study Procedure
The Investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study product and/or clinical study procedure.
Medical judgment should be used to determine the relationship, considering all relevant factors 
including the pattern of reaction, temporal relationships, relevant medical history, and 
confounding factors such as co-medication or concurrent diseases.
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1).
The relationship assessment for an AE is to be completed using the following definitions as a 
guideline:
Reasonable Possibility:
According to the reporting Investigator, there is a reasonable possibility (i.e., suggestive evidence 
or arguments) that there is a causal relationship irrespective of the dose administered between:

The study product (active or placebo) and the AE.

The clinical study protocol procedure (e.g., bruising or marks from blood draws, injection 
related trauma, etc.) and the AE.
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A two-point scale (Yes or No response) shall be used for the causality assessment. The 
Investigator 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. 
No Reasonable Possibility:
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the study product or the clinical study protocol procedure and the AE.
7.2.2.2
Reporting Procedures
7.2.2.2.1
Procedures for Reporting Adverse Events
The collection of AEs is from the time that a subject signs the ICF to their final visit.
At each post-enrollment visit, the Investigator (or sub-Investigator) will question the subject 
about AEs using an open non-persuasive question to elicit reporting of AEs, for example “Have 
you noticed any change in your health since the last visit?”  Directed questioning and 
examination will then be performed as appropriate. 
Any AE occurring during the AE reporting period, whether it is related to the study product or 
not, will be recorded immediately in the source document, and described on the AE form of the 
eCRF along with the date of onset, severity, relationship to the study product, and outcome, 
without omitting any requested and known information.  Additional information will be requested 
under certain circumstances.  
Adverse Events (AEs) assessed as related to the treatment or study procedure will be monitored 
until they have resolved or reached a stable condition.  Other AEs will be monitored until the last 
visit if they have not resolved or reached a stable condition. 
The Investigator will obtain and maintain in the subject’s files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and follow-up 
of the subject.  If necessary, the Investigator will contact the subject’s personal physician or 
hospital staff to obtain further details.
For SAEs (see Section 7.2.2.2.2) and pregnancies (see Section 7.2.2.2.3), the Sponsor is to be 
informed immediately by e-mail.  The event must be reported by e-mail to the Safety Mailbox 
within 24 hours of receipt of the information (contact details in Section 7.2.2.2.2).
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7.2.2.2.2
Procedure for Reporting a Serious Adverse Event
For a SAE occurring during the period of the clinical study, regardless of whether it is related to 
the treatment or not, and of whether it is expected or not, the Investigator must do the following:
1.
Take prompt and appropriate medical action, if necessary.  The safety of the subject is the 
first priority.
2.
Ensure that the event is classified as an SAE (Section 7.2.2.1.3).
3.
Complete the AE form provided in the eCRF as fully as possible.
Print and complete the SAE form.  E-mail the completed form, accompanied by any other 
relevant information or anonymized medical records (e.g., laboratory test results) within 
24 hours of receipt of the information to Safety Mailbox listed below. The demographics, 
medical history, drugs/therapies form, medical and surgical procedures form, and AE pages 
of the eCRF must be completed and available for review in the EDC system at the time of 
the report.
4.
Immediately send the completed SAE report form to the Safety Mailbox via e-mail and 
discuss further actions to be taken.
Additional contact details are provided in the Investigator’s site file.
5.
Monitor and record the progress of the event until it resolves or reaches a clinically stable 
outcome, with or without sequelae.  For all additional follow-up evaluations, send by e-mail 
all additional follow-up information on the SAE to the Safety Mailbox within 24 hours of 
receipt of the updated information.  SAEs will be monitored until the Investigator and 
Sponsor agree that the event is satisfactorily resolved.
6.
Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject.  If 
necessary, contact the subject’s personal physician or hospital staff to obtain further details.
7.
Inform the Sponsor of the final outcome of the event.  Send a revised or updated SAE form 
and AE form, if appropriate to the Safety Mailbox.
8.
Prompt notification of SAEs by the Investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. The Sponsor 
has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. The Sponsor will 
comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, Institutional Review Boards (IRBs), and Investigators. Investigator 
safety reports are prepared for Suspected Unexpected Serious Adverse Reactions 
(SUSARs) according to local regulatory requirements and the Sponsor policy and are 
forwarded to Investigators as necessary. An Investigator who receives an Investigator 
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9.1.2.4
Imputation of Missing Data
The Observed Cases (OC) will be used for all safety analyses as well as the exploratory analyses. 
The primary ITT analysis will be performed using baseline observation carried forward (BOCF), 
and repeated using multiple imputation (MI) for missing values. The secondary efficacy analyses 
will be performed using BOCF. If deemed necessary, any analyses may be repeated using OC, 
BOCF, or MI as appropriate.
9.1.3
Data Presentation and Graphics
All statistical analyses, including summary tables and data listings, will be performed using the 
SAS® system (version 9).
Subject disposition, completion and discontinuation by study visit, protocol deviations, 
demographics and baseline characteristics, medical history, medical and surgical procedures, 
prior and concomitant medications, will be summarized by treatment group.
All efficacy variables will be summarized by treatment at each visit.  The categorical variables 
will be summarized by number of subjects and percentage for each response category (N, %).  
The continuous variables will be summarized using n (number of observations), mean, median, 
minimum, maximum, and standard deviation for the data collected at each visit. 
For analysis of duration of effect and time to onset of treatment response, Kaplan-Meier plots and 
estimates of the median event times will be used. Responder rates over time will be presented in 
graphs.
All study data will also be listed in subject data listings. Graphs will be utilized as appropriate.
9.1.3.1
Safety Analysis
AEs will be summarized descriptively by treatment group, SOC and PT using number and 
percentage of subjects with at least one event and number of events. The results will be further 
broken down by other factors such as severity, causality, seriousness, and whether the event led 
to discontinuation. Duration and time to onset of related AEs will also be presented by treatment 
group, SOC and PT.
The numbers and percentages of subjects with abnormalities in physical examination will also be 
summarized. The results of the urine pregnancy tests will be listed.
All AEs will be monitored by the Sponsor to determine if they meet the criteria of remote spread 
of effect of the toxin or hypersensitivity. A list of preferred terms for these types of events will be 
provided in the SAP, and will be further analyzed to determine if there is a plausible possibility 
that they represent distant spread of toxin or hypersensitivity. In order to perform the analysis, 
variables including alternative etiology (medical history, concomitant medication, or diagnosis 
which could account for the symptoms), location of Dysport administration, and temporal 
relationship to Dysport administration will be considered by the Sponsor.
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10
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE
10.1
Personnel Training
Investigators and other responsible persons should be listed together with their function on the 
study on the signature and delegation log. Study staff shall provide a curriculum vitae or 
equivalent, as appropriate.
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 documented 
training in all procedures to be followed.
10.2
Clinical Monitoring
The conduct of the clinical study will be closely monitored by representatives of the Sponsor to 
verify adherence to the clinical study protocol, ICH-GCP guidelines, and applicable SOPs.  
The Investigator will allow the CRO/Sponsor’s representatives, to have direct access to all 
clinical study records, CRFs, corresponding subject medical records, study product(s) dispensing 
records, and any other documents considered source documentation.  Additionally, the 
CRO/Sponsor representative is to have access to the study product storage area and clinical study
facilities.
The Investigator also agrees to assist the representative if required.
10.3
Data Management
All data management procedures will be detailed in a Data Management Plan (DMP). 
The DMP will describe the Clinical Data Management System (CDMS) that will be used to 
collect data (either EDC or paper CRF), and whether the data management activities are 
performed internally or outsourced.  Computerized edit checks and review processes will be 
performed on an ongoing basis as outlined in the DMP until all data clarifications are resolved.  
The data will be exported to be stored in SAS datasets.  After all data clarifications are resolved, 
coding is approved, SAE/pregnancy reconciliation has been completed (if applicable) and 
subject’s evaluability is determined, the database will be locked.
10.4
Quality Assurance/Audit/Inspection
The clinical study is conducted under the sponsorship of the Sponsor in compliance with the 
applicable international and local regulatory requirements as well as applicable ICH guidelines 
and in accordance with the SOPs for clinical study conduct and monitoring from the Sponsor 
and/or the Contract Research Organization (CRO).
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Audits of clinical study centers may be conducted by the Sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IRBs/IECs before, during, 
or after the clinical study.  
The Investigator will allow and assist the CRO/Sponsor’s representatives, IRBs/IECs and any 
regulatory agency to have direct access to all requested clinical study-related records.
For the audits performed by, or on behalf of, the Sponsor auditors, audit certificate(s) will be 
provided by Quality Assurance.
10.5
Changes in Clinical Study Conduct/Amendments
10.5.1
Clinical Study Conduct
With the exception of eliminating an immediate hazard to a subject, the Investigator should not 
deviate from the clinical study protocol or implement any changes without written approval from 
the Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of a 
protocol amendment.
Changes that involve only logistical or administrative changes to the clinical study protocol are 
authorized.  The Investigator should document and explain any deviation from the clinical study
protocol.
10.5.2
Amendments
The Sponsor may modify the clinical study protocol at any time for ethical, medical, or scientific 
reasons. Any amendments will be handled according to applicable local regulations.
The Sponsor does not have to notify non-substantial amendments to the competent authorities or 
the Ethics Committees. However, non-substantial amendments should be recorded and detailed in 
subsequent submissions e.g., in the subsequent notification of a substantial amendment.
11
ETHICS AND GENERAL CLINICAL STUDY CONDUCT CONSIDERATIONS
11.1
Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
This clinical study protocol and all amendments will be reviewed and approved by the 
appropriate IECs/IRBs.
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11.2
Ethical Conduct of the Clinical Study
This clinical study will be conducted in accordance with the protocol, the HELSINKI declaration 
(1964) and subsequent amendments, and the ICH GCP, and in compliance with applicable 
regulatory requirements. 
11.3
Subject Information and Consent
All subjects who participate in this clinical study are required to be fully informed about the 
clinical study in accordance with GCPs guidelines, federal regulations, HIPAA, and guidelines 
and in accordance with local requirements.  
The ICF (inclusive of HIPPA and photo consent), approved by an IRB/IEC, will be fully 
explained to the subject.  The subject must agree to photo consent in order to participate in the 
clinical study. 
Prior to enrollment into the clinical study, the subject and the PI or designee must sign and date 
the consent form(s).  The Investigator is responsible for maintaining each subject’s consent 
form(s) in the Investigator’s site file and providing each subject with a copy of the signed and 
dated consent form(s).
11.4
Protection of Personal Data
The completion of the study involves the gathering and processing of Personal Data as specified 
in the Regulation (EU) 2016/679 on the protection of individuals with regard to the processing of 
personal data and on the free movement of such data. For the purposes of the study, Sponsor will 
be considered the Data Controller, and Principal Investigator and Institution 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 Principal Investigator are 
responsible for complying with all requirements pursuant to national legislation in the country in 
which the Institution and Principal Investigator are located.
The Principal Investigator understands that clinical studies conducted under an IND are exempt 
from the study subject identifier confidentiality provisions of the Health Insurance Portability and 
Access Act of 1996 (HIPAA), as provided at CFR § 512(b)(iii), and the study subject should be 
made aware of this exception in the informed consent. The Sponsor shall, to the extent feasible, 
protect study subject identifier information.
The Institution and Principal Investigator are jointly responsible for obtaining the appropriate 
informed consent of each subject for the processing of Personal Data required in order to 
complete the study. Such consent shall include the consent to the transfer of Personal Data to 
government authorities located in countries outside the US. 
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The Institution and Principal Investigator are jointly responsible for providing sufficient 
information to all subjects to enable them to give their informed consent not only to the 
participation in the study, but also to the processing of Personal Data. Such information includes 
information regarding the purposes of the processing, the length of time during which Personal 
Data will be stored, the right of access to stored Personal Data and the right to correction or 
purging of incorrect or obsolete Personal Data. A subject may also withdraw his or her consent at 
any time. A subject who withdraws his or her consent to the processing of Personal Data must be 
considered to have withdrawn from the study but the data collected until the consent was 
withdrawn may be used in the statistical analyses.
All collection, processing and analyses of protected health information, personal data or similar 
will be conducted in compliance with applicable local, national and international rules, 
regulations and guidelines.
11.5
Contractual Requirements
A 
contractual 
agreement 
will
be 
signed 
between 
the 
CRO/Sponsor 
and 
each 
Investigator/Institution.  This document will contain supplementary information, including 
financial terms, confidentiality, the clinical study schedule, third party responsibility, and 
publication rights.
11.6
Data Collection and Archiving
11.6.1
Data Collection
The Investigator must maintain all required records for all subjects.  Data for this clinical study
will be recorded in the subject’s source documents and in the eCRFs provided by the Sponsor.  
All data should be recorded in the eCRFs completely and promptly.
11.6.2
Source Documentation
The Investigator must keep accurate separate records (other than the eCRFs) of all subject visits, 
being sure to include all pertinent clinical study-related information.  A statement should be made 
indicating that the subjects have been included in this clinical study and have provided signed 
written Informed Consent.  All AEs must be thoroughly documented.
Results of any diagnostic tests conducted during the clinical study should also be included in the 
source documentation.  
11.6.3
Archives
All pertinent data, samples, photographs, correspondence, and reports, the original or amended 
clinical study protocol, and all other material relating to the clinical study will be maintained 
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12
LITERATURE REFERENCE LIST
1. Monheit, G. D. and A. Pickett (2017). "AbobotulinumtoxinA: A 25-Year History." Aesthet 
Surg J 37(suppl_1): S4-s11
2. Carruthers, J. and A. Carruthers (2007). "The evolution of botulinum neurotoxin type A for 
cosmetic applications." J Cosmet Laser Ther 9(3): 186-192.
3. Rzany, B., D. Dill-Muller, D. Grablowitz, M. Heckmann, D. Caird and G. German-Austrian 
Retrospective Study (2007). "Repeated botulinum toxin A injections for the treatment of lines 
in the upper face: a retrospective study of 4,103 treatments in 945 patients." Dermatol Surg 
33(1 Spec No.): S18-25.
4. Dysport (BTX-A-HAC Powder) Aesthetic Indications Investigator’s Brochure, version 6.0, 
28 Aug 2018: Ipsen Group.
5. DYSPORT® (abobotulinumtoxinA) for injection US Prescribing Information (2017).
6. Pusic, AL., AF. Lassen, AM. Scott, SJ. Cano (2013) “Development and psychometric 
evaluation of the FACE-Q satisfaction with appearance scale: a new patient-reported outcome 
instrument for facial aesthetics patients.” Clin Plast Surg. Apr;40(2):249-60.
7. Klassen, AF., SJ Cano, AM. Scott, AL. Pusic (2014) “Measuring outcomes that matter to 
face-lift patients: development and validation of FACE-Q appearance appraisal scales and 
adverse effects checklist for the lower face and neck.” Plast Reconstr Surg. Jan;133(1):21-30.
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Sign page:1 of 1
SIGNATURES PAGE
Date
Signed by
2019-01-24 00:57
Justification
Approved by Technical Expert
2019-01-24 07:58
Justification
Approved by Technical Expert
2019-01-24 08:49
Justification
Approved by Owner
2019-01-24 15:42
Justification
Compiled by
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