A Multicenter, Open-Label, Interventional Study to Evaluate Subject Satisfaction of AbobutulinumtoxinA Treatments in Moderate to Severe Glabellar Lines
Phase: PHASE4
Conditions: Glabellar Frown Lines
Sponsor: Galderma R&D

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CLINICAL STUDY PROTOCOL
PROTOCOL NUMBER: 43USD1802
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.
Effective date: 
 
 2018-08-03 04:36
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TITLE PAGE
Dysport Efficacy and Measured Satisfaction (DREAM) Study: 
A Multicenter, Open-Label, Interventional Study to Evaluate Subject Satisfaction of 
AbobotulinumtoxinA Treatments in Moderate to Severe Glabellar Lines
CTN: 43USD1802
Protocol Amendment 1
SPONSOR:
Name:
Q-Med AB, a Nestlé Skin Health affiliate
Address:
Phone:
CONTRACT RESEARCH ORGANIZATION (CRO):
Name:
MedTrials, Inc.
Address:
Phone:
SAFETY:
For safety questions, please contact the Sponsor Contact using the contact details provided in 
Section 12.9. Serious adverse events (SAEs) and pregnancy report forms should be submitted as 
described in Sections 8.2.1.2.2 and 8.2.1.2.3.
MEDICAL MONITOR:
For any medical questions related to the clinical study protocol, please contact the Medical Monitor  
using the contact details provided in Section 12.9.
This clinical study shall be performed in compliance with the clinical trial agreement (CTA), the 
CSP, ICH-Good Clinical Practice (GCP), and applicable regional and national regulations. The 
study shall be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki  (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/).
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Table of Contents
TITLE PAGE..................................................................................................................................................2
SYNOPSIS ......................................................................................................................................................8
CLINICAL STUDY SCHEMATIC AND FLOW CHART......................................................................13
SCHEDULE OF ASSESSMENTS..............................................................................................................15
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................................17
1
BACKGROUND AND RATIONALE..............................................................................................19
1.1
Medical Background and Short Rationale for the Clinical Study............................................19
1.2
Drug Profile...................................................................................................................................19
1.3
Risk/Benefit Assessment...............................................................................................................20
2
CLINICAL STUDY OBJECTIVES AND CLINICAL HYPOTHESIS........................................20
2.1
Clinical Study Objectives .............................................................................................................20
2.1.1
Primary Efficacy Objectives and Endpoints .........................................................................21
2.1.3
Safety Objectives and Endpoints............................................................................................22
3
5.1
Number of Subjects.......................................................................................................................23
5.2
Clinical Study Population Characteristics..................................................................................23
5.2.1
Inclusion Criteria.....................................................................................................................23
5.2.2
Exclusion Criteria....................................................................................................................24
5.3
Medical History.............................................................................................................................25
5.4
Previous and Concomitant Therapies.........................................................................................25
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5.5
Procedures/Reasons for Subject Discontinuation ......................................................................27
6
CLINICAL SUPPLIES......................................................................................................................29
6.1
Clinical Supply Identification and Use........................................................................................29
6.1.2
Subject Identification Number (SIN).....................................................................................29
6.1.3
Method of Treatment Assignment..........................................................................................30
6.1.4
Kit Number/Randomization Number ....................................................................................30
6.3.3
Dispensing and Return ............................................................................................................33
6.3.4
Treatment Compliance Management and Record................................................................33
6.4
Dose Modification .........................................................................................................................33
6.5
Blinding..........................................................................................................................................33
7
EFFICACY ASSESSMENTS ...........................................................................................................34
7.1
Overall Subject Satisfaction by Direct Questioning ..................................................................34
8
SAFETY ASSESSMENTS ................................................................................................................36
8.1
Focused Physical Examination ....................................................................................................36
8.2
Adverse Events..............................................................................................................................36
  
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8.2.1.1
Definitions............................................................................................................................36
8.2.1.1.1
Adverse Events (AE)........................................................................................................36
8.2.1.1.2
Treatment Emergent Adverse Events (TEAE)..................................................................37
8.2.1.1.3
Serious Adverse Events (SAE) .........................................................................................37
8.2.1.1.4
Unexpected Adverse Drug Reaction................................................................................38
8.2.1.1.5
Adverse Event Reporting Period .....................................................................................38
8.2.1.1.6
Severity ............................................................................................................................38
8.2.1.1.7
Relationship to the Study Product and/or Clinical Study Procedure..............................38
8.2.1.2
Reporting Procedures.........................................................................................................39
8.2.1.2.1
Procedures for Reporting Adverse Events.......................................................................39
8.2.1.2.2
Procedure for Reporting a Serious Adverse Event..........................................................40
8.2.1.2.3
Procedures for Reporting Pregnancies ...........................................................................41
8.3
Other Assessments ........................................................................................................................42
8.3.2
Pregnancy Test.........................................................................................................................42
8.4
Appropriateness of Measurements..............................................................................................42
9
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES ........................................43
.......................48
10
STATISTICAL METHODS PLANNED .........................................................................................49
  
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10.1.2.4
Safety Population................................................................................................................49
10.1.2.5
Imputation of Missing Data ...............................................................................................50
10.1.3.1
Safety....................................................................................................................................50
10.1.4
Withdrawals and Deviations...................................................................................................51
10.1.5
11
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ..............52
11.1
Personnel Training........................................................................................................................52
11.2
Clinical Monitoring.......................................................................................................................52
11.3
Data Management.........................................................................................................................52
11.4
Quality Assurance / Audit / Inspection .......................................................................................52
12
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS ...................54
12.1
Institutional Review Board (IRB)................................................................................................54
12.2
Ethical Conduct of the Clinical Study.........................................................................................54
12.3
Subject Information and Consent ...............................................................................................54
12.4
Protection of Personal Data .........................................................................................................54
12.5
Contractual Requirements...........................................................................................................55
12.6
Data Collection and Archiving.....................................................................................................55
12.6.1
Data Collection.........................................................................................................................55
12.6.2
Source Documentation.............................................................................................................55
12.6.3
Archives ....................................................................................................................................56
12.7
Insurance .......................................................................................................................................56
  
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13
LITERATURE REFERENCE LIST................................................................................................58
14
APPENDICES ....................................................................................................................................59
List of Tables
List of Figures
  
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SYNOPSIS
Clinical Study Title: Dysport Efficacy and Measured Satisfaction (DREAM) Study: A Multicenter, Open-Label, 
Interventional Study to Evaluate Subject Satisfaction of AbobotulinumtoxinA Treatments in Moderate to Severe 
Glabellar Lines
Short Title: DREAM Study
Clinical Study Phase:
Phase 4
Clinical Study Population:
Male and female subjects, 18 to 65 years of age with moderate to severe glabellar 
lines at maximum frown.
Clinical Study Design:
This is a multicenter, open-label, interventional, phase 4 study to assess subject 
satisfaction with a twice-yearly abobotulinumtoxinA treatment regimen.
Number of Clinical Study 
Centers (Planned):
Approximately 6 centers.
Region(s) / Country(ies) 
Involved (Planned):
US
Clinical Study Duration:
The planned clinical study duration (from first subject first visit [FSFV] to last subject 
last visit [LSLV]) is approximately 15 months.
Duration of Subject 
Participation: 
Clinical study participation for each subject is up to 13 months.
Key Inclusion Criteria
1.
Male or female, 18 to 65 years of age.
f
4.
Female of non-childbearing potential (i.e., post-menopausal [absence of
menstrual bleeding for 1 year prior to screening, without any other medical
reason], or has undergone hysterectomy or bilateral oophorectomy).
  
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SYNOPSIS
Clinical Study Title: Dysport Efficacy and Measured Satisfaction (DREAM) Study: A Multicenter, Open-Label, 
Interventional Study to Evaluate Subject Satisfaction of AbobotulinumtoxinA Treatments in Moderate to Severe 
Glabellar Lines
or
Female of childbearing potential with a negative urine pregnancy test at
screening/baseline, and agrees to use an acceptable, reliable and approved 
contraceptive method for the duration of enrollment in the study. Male subjects 
do not require birth control measures.
5.
Time and ability to complete the study and comply with instructions.
6.
Understands the study requirements and signed the informed consent form
(ICF).
Key Exclusion Criteria
1.
Botulinum toxin treatment in the face within 9 months prior to the
screening/baseline visit.
2.
Known allergy or sensitivity to any component of the study product, or allergy to
cow’s milk protein.
  
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SYNOPSIS
Clinical Study Title: Dysport Efficacy and Measured Satisfaction (DREAM) Study: A Multicenter, Open-Label, 
Interventional Study to Evaluate Subject Satisfaction of AbobotulinumtoxinA Treatments in Moderate to Severe 
Glabellar Lines
e 
12. Receipt of any investigational drug or device within 30 days prior to study
treatment, from a previous clinical study.
Study Product:
AbobotulinumtoxinA / DYSPORT®
Strength/Concentration:
Reconstitution volume
Dosage (total dose per 
treatment):
Route:
I
Dose Regimen:
Location of Treated Area:
Glabellar region
Efficacy Assessment:
Efficacy assessments include:
Overall Satisfaction Question Elicited by Direct Questioning to Subject
(subject assessment)
Efficacy Objectives and 
Endpoints:
Primary objective and endpoint:
The primary objective of the study is to evaluate subject satisfaction after 
abobotulinumtoxinA treatment every six months (twice yearly). 
  
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SYNOPSIS
Clinical Study Title: Dysport Efficacy and Measured Satisfaction (DREAM) Study: A Multicenter, Open-Label, 
Interventional Study to Evaluate Subject Satisfaction of AbobotulinumtoxinA Treatments in Moderate to Severe 
Glabellar Lines
The primary endpoint will evaluate the proportion of subjects satisfied (“highly 
satisfied” or “satisfied”) with the treatment results assessed by the satisfaction 
question at the month 12 visit.
:
.
Safety Assessment:
Safety assessment include:

Treatment emergent adverse events (TEAEs)

Focused physical examination (PE)
Safety Objectives and 
Endpoints:
The safety objective of the study is to evaluate the safety of abobotulinumtoxinA in 
the treatment of glabellar lines.
The safety endpoint will include the incidence and severity of treatment emergent 
adverse events (TEAEs) throughout the study.
Other Assessments:
Other assessments include:

Pregnancy Test
Principal statistical method: The primary objective of the study will be evaluated by calculating the proportion of 
subjects that respond “Highly satisfied” or “Satisfied” 
  
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SYNOPSIS
Clinical Study Title: Dysport Efficacy and Measured Satisfaction (DREAM) Study: A Multicenter, Open-Label, 
Interventional Study to Evaluate Subject Satisfaction of AbobotulinumtoxinA Treatments in Moderate to Severe 
Glabellar Lines
 The aim is to show that the 
confidence interval is above 50%, i.e. the majority of subjects are satisfied.
Incidence and severity of TEAEs will be presented descriptively.
  
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 t
  
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Title 
Doc id  
43USD1802 Clinical Study Protocol Dysport  DREAM study
MA-38095
Version:
Effective date:
Effective
 2018-08-03 04:36
2.0
Print date:
 2019-06-05 11:55
  
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Title 
Doc id  
43USD1802 Clinical Study Protocol Dysport  DREAM study
MA-38095
Version:
Effective date:
Effective
 2018-08-03 04:36
2.0
Print date:
 2019-06-05 11:55
  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
C
Degrees Celsius
AbobotulinumtoxinA
Commercially available DYSPORT®
AE
Adverse Event
approx
Approximately (or use ‘about’, not C. or ca.)
CDMS
Clinical Data Management 
CPM
Clinical Project Manager
CRA
Clinical Research Associate
CRF/eCRF
Case Report Forms/electronic Case Report Forms
CRO
Contract Research Organization
DC
Discontinuation
DMP
Data Management Plan
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)
GL
Glabellar line
GCP 
Good Clinical Practice 
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICH
International Conference on Harmonisation 
ID
Identity
i.e.
That is (Latin: id est)
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine Device
LOCF
Last Observation Carried Forward
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
mL
Milliliter
N/A
Not Applicable
OTC
Over-the-Counter
  
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Abbreviation
Term
p
Page(s)
PE
Physical Examination
PP
Per-Protocol
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TOC
Table of Contents
TEAE
Treatment-emergent Adverse Event
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. 
 
 
 
 
 
 
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
 
 
 
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. 
 
 
 
 
The rationale for the current study is to evaluate subject satisfaction, efficacy, and safety of 
 
of abobotulinumtoxinA administered 
in the glabellar region. The aim is for the 
Sponsor to better understand the subject’s needs and expectations with respect to 
abobotulinumtoxinA treatment and the treatment regimen.
1.2
Drug Profile
AbobotuliniutoxinA contains a neurotoxin complex that is produced by fermentation of
Clostridium botulinum bacteria toxin type A, Hall strain. This haemagglutinin complex is 
  
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composed of a number of proteins naturally produced along with the toxin which is believed to 
stabilise it but which has no apparent therapeutic effect in its own right. 
 
 
 
 
 
1.3
Risk/Benefit Assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2
CLINICAL STUDY OBJECTIVES AND CLINICAL HYPOTHESIS
2.1
Clinical Study Objectives
The objectives of this study are to evaluate subject satisfaction, efficacy, and safety after 
abobotulinumtoxinA treatment every six months (twice yearly).
  
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2.1.1
Primary Efficacy Objectives and Endpoints
The primary objective of the study is to evaluate subject satisfaction after abobotulinumtoxinA 
treatment every six months (twice yearly). 
 
The primary endpoint will evaluate the proportion of subjects satisfied (“highly satisfied” or 
“satisfied”) with the treatment results assessed by the satisfaction question at the month 12 visit.
2.1.2
 
 
 
 
 
  
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2.1.3
Safety Objectives and Endpoints
The safety objective of the study is to evaluate the safety of abobotulinumtoxinA in the treatment 
of glabellar lines.
The safety endpoint will include the incidence and severity of treatment emergent adverse events 
(TEAEs) throughout the study.
2.2
Clinical Hypothesis
The clinical hypothesis of the study is that a majority of subjects will be highly satisfied or satisfied 
with the treatment results using abobotulinumtoxinA every 6 months.
3
OVERALL CLINICAL STUDY DESCRIPTION
This is a multicenter, open-label, interventional, phase 4 study to assess subject satisfaction with a 
twice-yearly abobotulinumtoxinA treatment regimen.
Following signature of informed consent and the screening process, eligible subjects will be treated 
at the baseline visit (Day 0) with 
 abobotulinumtoxinA in the glabellar region. Subjects 
will be re-treated at the month 6 visit, 
 
Subjects will be monitored for up to 13 months following the initial treatment at baseline.
 
  
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4
CLINICAL STUDY DURATION AND TERMINATION
The planned clinical study duration (from FSFV to LSLV) is approximately 15 months. The date 
of end of the clinical study is defined as the date of the last visit of the last subject.
 
 
 
 
5
SELECTION AND DISPOSITION OF CLINICAL STUDY POPULATION
5.1
. 
5.2
Clinical Study Population Characteristics
In order to be eligible for the clinical study, subjects must fulfill all of the following criteria. These 
criteria are applicable at screening/baseline unless specified. 
5.2.1
Inclusion Criteria
1.
Male or female, 18 to 65 years of age.
2.
Moderate to severe glabellar lines 
 
 
4.
Female of non-childbearing potential (i.e., post-menopausal [absence of menstrual bleeding 
for 1 year prior to screening, without any other medical reason], or has undergone 
hysterectomy or bilateral oophorectomy).
or
Female of childbearing potential with a negative urine pregnancy test at screening/ baseline, 
and agrees to use an acceptable, reliable and approved contraceptive method for the duration 
of enrollment in the study. Male subjects do not require birth control measures.
  
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5.2.2
Exclusion Criteria
1.
Botulinum toxin treatment in the face within 9 months prior to the screening/baseline visit.
2.
Known allergy or sensitivity to any component of the study product, or allergy to cow’s milk
protein.
  
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12.
Receipt of any investigational drug or device within 30 days prior to study treatment, from a 
previous clinical study.
 
 
 
 
 
 
5.3
Medical History
Relevant history of surgical events and medical conditions shall be documented in the electronic 
case report form (eCRF) using medical terminology.
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.  
  
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5.4.2
 
 
 
 
5.4.3
 
 
 
 
 
5.4.4
5.4.5
 
 
 
 
 
  
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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. 
 
 
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.
 
 
 
 
 
  
 
 
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 8.2.1.2.3. The subject 
  
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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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6
CLINICAL SUPPLIES
Details of the drug composition and excipients are provided in the current US prescribing 
informaiton.3
6.1
6.1.1
6.1.2
Subject Identification Number (SIN) 
Each study participant who has signed the ICF will be entered into the eCRF system and a subject 
number will be assigned via the eCRF system.  
  
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All subjects who have signed the ICF should be listed. Sufficient information to link the eCRF to 
the medical records should be recorded in the source documentation. 
For the duration of the entire study, the subject will be identified using the subject number for all 
documentation and discussion.
6.1.3
Method of Treatment Assignment
Not applicable; this is an open-label study.
6.1.4
Kit Number/Randomization Number
Not applicable; this is an open-label study.  
6.1.5
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
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6.1.5.1
6.1.5.2
6.1.5.3
  
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6.2
Study Drug(s) Packaging and Labeling
The carton will contain a label indicating the protocol number and that the product is for a clinical 
study. 
6.3
Supplies Management
6.3.1
Accountability
Upon receipt of the study drug(s), the Investigator or designee will maintain accurate records of 
the study drug(s) delivery to the clinical study center, the inventory at the clinical study center, the 
use by each subject, the reconciliation of all study drug(s) received from the Sponsor’s designee, 
and the return to the Sponsor’s designee for disposal of used and unused study drug(s).
All study drug(s) sent to the Investigator/Institution will be accounted for and no unauthorized use 
is permitted.
6.3.2
Storage of Study Drug(s)
Study drug(s) must be stored in a safe and secure area with restricted access, under the storage 
conditions specified by the Sponsor (see Table 3).
  
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6.3.3
Dispensing and Return 
All study drug must be inventoried and a record of the dispensing for each subject must be 
appropriately documented by the Investigator or designee. Any dispensing errors must be reported 
to the Sponsor/CRO and properly documented.
In the event of early termination/suspension of the clinical study, a rapid recall of study drug(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
 
 
 
 
 
 
 
 
6.4
Dose Modification 
Dose modifications are not permitted.
6.5
Blinding
Not applicable; this is an open-label study.
  
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7
EFFICACY ASSESSMENTS 
7.1
Overall Subject Satisfaction by Direct Questioning
 
 
 
 
.
7.2
 
 
 
 
 
 
 
 
 
 
 
  
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8
SAFETY ASSESSMENTS
A safety assessment will be conducted for all subjects at the screening visit (from the Informed 
consent signature) and at subsequent visits as outlined in the schedule of assessments (Table 2). 
Safety parameters include an evaluation of AES and focused physical examination findings.
8.1
Focused Physical Examination
At all study visits (prior to treatment, as applicable), the Investigator or designee will perform a 
physical examination of the subject that includes the face, head, and neck. Further details are 
provided in Appendix 4.
 
 
 
 
The Investigator may choose to investigate any other sign that he/she observes during the physical 
examination and should assess all abnormal findings for clinical significance. 
Clinically significant abnormal findings at the screening/baseline visit are exclusionary, and the 
subject should not be enrolled in the study. If the abnormality is not clinically significant, capture 
it as medical history. 
For any clinically significant changes from the screening/baseline visit, an AE is to be recorded.
8.2
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.
8.2.1.1
Definitions
8.2.1.1.1
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 
  
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sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (study) product, whether or not related to the medicinal (study) 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 8.2.1.2.3.
8.2.1.1.2
Treatment Emergent Adverse Events (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.
8.2.1.1.3
Serious Adverse Events (SAE)
An 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.
  
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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).
8.2.1.1.4
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., medicinal package 
insert/summary of product characteristics for an approved study product).
8.2.1.1.5
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.  
8.2.1.1.6
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.
8.2.1.1.7
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.
  
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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 and the AE.

The clinical study protocol procedure (injection related trauma, etc.) and the AE. 
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.
8.2.1.2
Reporting Procedures
8.2.1.2.1
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.  
  
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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 8.2.1.2.2) and pregnancies (see Section 8.2.1.2.3), 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 8.2.1.2.2).
8.2.1.2.2
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 8.2.1.1.3). 
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 the 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.
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.
  
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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 safety report describing a SAE(s) or 
other specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
file it with the prescribing information and will notify the IRB, if appropriate according to 
local requirements.
9.
Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to the 
IRB.
8.2.1.2.3
Procedures for Reporting Pregnancies
Any pregnancy occurring during the clinical study, where the fetus could have been exposed to the 
study product, must be monitored until its outcome in order to ensure the complete collection of 
safety data.
Pregnancies occurring during the screening period are considered as screening failures; they are 
recorded as such in the eCRF and no pregnancy form is to be completed.
If a subject becomes pregnant after the screening period, the Investigator is to do the following:
1.
The subject does not need to be withdrawn from the clinical study, i.e. she may continue to 
attend the planned study visits, but no invasive procedure should be conducted (e.g. no 
sample taken for lab test).
2.
Complete the Pregnancy Surveillance form – Part I: History and Start of Pregnancy, as fully 
as possible.  Send by e-mail this pregnancy form along with the exit form (if applicable)
within 24 hours of receipt of the information to the Safety Mailbox listed above (see 
Section 8.2.1.2.2).
3.
Monitor and record the progress of the pregnancy until its outcome.  Contact the subject’s 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask regular follow-up information.
4.
Inform the Sponsor of the progress by tri-monthly updates until the final outcome of the 
pregnancy by completing the Pregnancy Surveillance form – Part I.  For all the additional 
evaluations, send by e-mail the additional follow-up information to the Safety Mailbox within 
24 hours of receipt of the information.  If the subject can no longer be reached (lost to 
  
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follow-up), documentation of the non-response/contact with two phone calls and a letter 
(certified with return receipt) is required.
5.
At the outcome of the pregnancy, complete the Pregnancy Surveillance form – Part II: Course 
and Outcome of Pregnancy, as fully as possible. Inform the Sponsor by sending this 
pregnancy form to the Safety Mailbox within 24 hours of receipt of the information.
6.
If the pregnancy leads to an abortion (voluntary abortion, spontaneous abortion or therapeutic 
abortion), in utero death or congenital anomaly, follow the procedure for declaration of an 
SAE (see Section 8.2.1.2.2).
8.3
8.3.1
l 
 
 
Pregnancy Test
For all women of childbearing potential a urine pregnancy test will be performed prior to treatment 
at screening/baseline and month 6, and month 12 (if optional re-treatment is performed). A negative 
pregnancy test is required for study inclusion. The result will be documented.
8.4
Appropriateness of Measurements
The subject satisfaction question and questionnaire are tools that have been developed in order for 
the Sponsor to better understand the subject’s needs and expectations with respect to 
abobotulinumtoxinA treatment and the treatment regimen.
 
 
 
  
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9
CLINICAL STUDY VISITS DESCRIPTIONS AND PROCEDURES
9.1
Description of Clinical Study Visits
Please refer to the schedule of assessment table (Table 2).
A written, signed ICF (inclusive of HIPAA and photo consent) must be obtained prior to 
performing any clinical study-related evaluations and/or procedures. The subject must be provided 
with a fully completed, dated and signed copy.
 
 
 
 
 
 
 
 
 
 
  
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,
 
 
 
 
 
 
 
  
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e
  
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4.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
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10
STATISTICAL METHODS PLANNED
10.1.2.4
Safety Population
The safety population includes all subjects who were administered the study product. 
  
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10.1.2.5
Imputation of Missing Data
All analyses will be carried out based on the observed cases (OC). However, if there are a 
substantial amount of missing data for the primary efficacy endpoint, a sensitivity analysis to assess 
the impact of the missing data might be done by using, for example, the hot deck method. 
10.1.3
Data Presentation and Graphics
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.
All efficacy variables will be summarized by visit.  
10.1.3.1
Safety
A summary of all AEs will be provided, which will include:
•
number of subjects who did not have an AE
•
number of subjects with at least one AE and number of events
•
number of subjects with at least one TEAE and number of events
•
number of subjects with at least one related TEAE and number of events
•
number of subjects with at least one TEAE by causality
•
number of subjects with at least one TEAE by maximum intensity
•
number of subjects with at least one TEAE leading to discontinuation
•
number of subjects with at least one serious TEAE.
All TEAEs, treatment emergent SAEs, TEAEs by maximum intensity, TEAEs by causality, TEAEs 
by maximum intensity and causality, and TEAEs leading to discontinuation will be summarized 
  
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by SOC and PT including number of subjects with at least one event, percentages, and number of 
events. All related TEAEs will also be summarized by time to onset and duration.
The results of the urine pregnancy tests will be listed.
10.1.4
Withdrawals and Deviations
All withdrawn subjects will be listed individually, including at least subject number, date and 
reason for withdrawal, and last visit performed.
10.1.5
10.2
Sample Size Determination
  
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10.3
11
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE
11.1
Personnel Training
Investigators and other responsible persons should be listed together with their function on the 
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.
11.2
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.
11.3
Data Management
All data management procedures will be detailed in a Data Management Plan (DMP). 
11.4
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).
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.  
  
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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.
11.5
  
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12
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS
12.1
Institutional Review Board (IRB)
This clinical study protocol and all amendments will be reviewed and approved by the appropriate 
IRBs.
12.2
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. 
12.3
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).
12.4
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 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 
  
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the study. Such consent shall include the consent to the transfer of Personal Data to government 
authorities located in countries outside the US. 
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.
12.5
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.
12.6
Data Collection and Archiving
12.6.1
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.
12.6.2
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.  
  
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12.6.3
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 
securely in Sponsor/CRO/Investigator/Institution archives for the legally required duration for 
archiving.
The Investigator/Institution should maintain the essential clinical study documents as specified in 
Section 8 of ICH-GCP, and according to the applicable regulatory requirements.
The Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
If the Principal Investigator retires, relocates, or withdraws from the responsibility of keeping the 
clinical study records for any other reasons, custody must be transferred to a person who will accept 
the responsibility.  The Sponsor/CRO must be notified in writing of the name and address of the 
new custodian.
12.7
Insurance
A certificate attesting Third Party coverage of CRO/Sponsor will be provided upon request.
a Defining the role of authors and contributors, compiled by the International Committee of Medical Journal Editors 
(ICMJE) (http://www.icmje.org).
  
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12.9
  
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13
LITERATURE REFERENCE LIST
1. Monheit GD, Pickett A. AbobotulinumtoxinA: A 25-Year History. Aesthet Surg J. 2017 May
1;37(suppl_1):S4-S1.
2. Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic
applications. J Cosmet Laser Ther. 2007 Sep;9(3):186-92.
3. Rzany B, Dill-Müller D, Grablowitz D, et al. 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. 2007 Jan;33(1 Spec No.):S18-25.
4. DYSPORT®
(abobotulinumtoxinA)
for injection, for intramuscular use [Prescribing
Information]. Wrexham, UK: Ipsen Biopharm Ltd: 12/2016.
5.
  
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?
  
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SIGNATURES PAGE
  
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