A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Evaluate the Safety and Efficacy of MT10109L (NivobotulinumtoxinA) for the Treatment of Glabellar Lines
Phase: PHASE3
Conditions: Glabellar Lines
Sponsor: Medy-Tox

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Title Page
Protocol Title: A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group 
Study to Evaluate the Safety and Efficacy of MT10109L (NivobotulinumtoxinA) for the 
Treatment of Glabellar Lines
Protocol Number: MT10109L-001
Amendment Number: Amendment 4
Product: MT10109L (NivobotulinumtoxinA)
Brief Protocol Title: MT10109L in the Treatment of Glabellar Lines
Development Phase: 3
Sponsor Name and Legal Registered Address:
Allergan Sales LLC
 
Regulatory Agency Identifying Numbers: IND Number 121473;
EudraCT Number 2014-005300-16
Sponsor Signatory:
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 4
September 2020
Amendment 3
February 2019
Amendment 2
November 2018
Amendment 1
September 2018
Original Protocol
May 2018
Amendment 4 (September 2020)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The overall rationale of this protocol amendment was to integrate feedback and 
recommendations from a health authority.
Section No. and Name
Description of Change
Brief Rationale
Title Page
Updated sponsor signatory
Administrative
 
11 References
Added references
References added to Section 9.4.1.2
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Table of Contents
Title Page ....................................................................................................................................... 1
Protocol Amendment Summary of Changes Table......................................................................... 2
Table of Contents .......................................................................................................................... 3
List of Tables................................................................................................................................... 6
List of Figures................................................................................................................................. 6
Protocol Summary ......................................................................................................... 7
Synopsis........................................................................................................................... 7
Introduction.................................................................................................................. 14
Study Rationale.............................................................................................................. 14
Background.................................................................................................................... 14
Benefit/Risk Assessment................................................................................................ 15
Objectives and Endpoints............................................................................................ 17
Study Design................................................................................................................. 19
Overall Design............................................................................................................... 19
4.1.1
Clinical Hypotheses ....................................................................................................... 20
End of Study Definition................................................................................................. 21
Study Population.......................................................................................................... 22
Inclusion Criteria ........................................................................................................... 22
Exclusion Criteria .......................................................................................................... 23
Lifestyle Considerations ................................................................................................ 25
Screen Failures............................................................................................................... 26
Study Intervention ....................................................................................................... 27
6.1.2
Instructions for Use and Administration........................................................................ 28
Preparation/Handling/Storage/Accountability............................................................... 29
Study Intervention Compliance ..................................................................................... 31
Concomitant Therapy .................................................................................................... 31
6.5.3
Rescue Medicine............................................................................................................ 32
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Dose Modification ......................................................................................................... 32
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................... 34
Discontinuation of Study Intervention........................................................................... 34
Participant Discontinuation/Withdrawal from the Study............................................... 35
Lost to Follow Up.......................................................................................................... 35
Study Assessments and Procedures............................................................................ 36
Efficacy Assessments..................................................................................................... 36
8.1.1
Facial Wrinkle Scale With Photonumeric Guide (FWS) ............................................... 36
 
Safety Assessments........................................................................................................ 38
8.2.1
Adverse Events .............................................................................................................. 38
8.2.2
Physical Examination..................................................................................................... 38
8.2.4
Vital Signs...................................................................................................................... 39
8.2.5
Electrocardiograms ........................................................................................................ 39
8.2.6
Hematology and Blood Chemistry................................................................................. 40
8.2.7
Urine Pregnancy Tests ................................................................................................... 40
8.2.8
Suicidal Risk Monitoring............................................................................................... 40
Adverse Events and Serious Adverse Events ................................................................ 40
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information .................................................................................................................... 41
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events .............................. 41
8.3.3
Follow-up of Adverse Events and Serious Adverse Events........................................... 41
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events................................. 42
8.3.5
Pregnancy....................................................................................................................... 42
8.3.7
Medication Errors .......................................................................................................... 43
Treatment of Overdose .................................................................................................. 43
Pharmacokinetics........................................................................................................... 44
Pharmacodynamics ........................................................................................................ 44
Genetics ......................................................................................................................... 44
Medical Resource Utilization and Health Economics................................................... 45
Statistical Considerations............................................................................................ 46
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Statistical Hypotheses.................................................................................................... 46
Sample Size Determination ........................................................................................... 47
Populations for Analyses ............................................................................................... 47
Statistical Analyses ........................................................................................................ 48
9.4.1
Efficacy Analyses........................................................................................................... 48
9.4.1.1
Primary Efficacy Endpoints............................................................................... 48
9.4.1.2
Primary Analyses ............................................................................................... 48
9.4.1.3
Secondary Efficacy Endpoints........................................................................... 50
9.4.1.4
Secondary Analyses ........................................................................................... 51
9.4.1.5
Exploratory Efficacy Endpoints......................................................................... 52
9.4.1.6
Exploratory Efficacy Analyses........................................................................... 52
9.4.2
Safety Analyses.............................................................................................................. 52
9.4.2.1
Adverse Events .................................................................................................. 53
9.4.2.2
Vital Signs.......................................................................................................... 53
9.4.2.3
Electrocardiograms ............................................................................................ 54
9.4.3
Other Analyses............................................................................................................... 54
9.4.3.1
Immunogenicity Analyses.................................................................................. 54
Interim Analyses ............................................................................................................ 54
Supporting Documentation and Operational Considerations................................. 55
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 56
10.1.1
Regulatory and Ethical Considerations.......................................................................... 56
10.1.2
Financial Disclosure....................................................................................................... 56
10.1.3
Informed Consent Process ............................................................................................. 57
10.1.4
Data Protection............................................................................................................... 57
10.1.5
Posting Clinical Study Data........................................................................................... 57
10.1.6
Data Quality Assurance.................................................................................................. 58
10.1.7
Source Documents ......................................................................................................... 58
10.1.8
Study and Site Closure................................................................................................... 58
10.1.10 Compliance with Protocol.............................................................................................. 59
Appendix 2: Clinical Laboratory Tests.......................................................................... 60
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 61
Definition of AE............................................................................................................................ 61
Definition of SAE ......................................................................................................................... 63
Recording and Follow-Up of AEs and/or SAEs ........................................................................... 64
Reporting of SAEs ........................................................................................................................ 66
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Appendix 4: Abbreviations............................................................................................ 67
Appendix 10: Protocol Amendment History ................................................................. 92
References..................................................................................................................... 96
List of Tables
Table 8-1
Expected Adverse Reactions for Treatment of Glabellar Lines............................ 40
Table 10-1
Protocol-required Safety Laboratory Assessments ............................................... 60
List of Figures
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Protocol Summary
Synopsis
Protocol Title: A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group 
Study to Evaluate the Safety and Efficacy of MT10109L (NivobotulinumtoxinA) for the 
Treatment of Glabellar Lines
Protocol Number: MT10109L-001
Brief Title: MT10109L in the Treatment of Glabellar Lines
Study Phase: 3
Study Rationale:
The purpose of this placebo-controlled pivotal study is to evaluate the safety and efficacy of 
MT10109L for the treatment of glabellar lines (GL) in participants with moderate to severe GL 
.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy between
20 U MT10109L and placebo for 
the treatment of GL in participants 
with moderate to severe GL
For US FDA:

Composite: The proportion of participants with a ≥2-grade 
improvement from baseline on the Facial Wrinkle Scale With 
Photonumeric Guide (FWS) according to investigator and 
participant assessments of GL severity at maximum frown at Day 30
using the intent-to-treat (ITT) population after a single 
intramuscular (IM) injection of MT10109L or placebo in the GL
For EU regulatory agencies:

 
 
Secondary

To compare the efficacy between 
MT10109L and placebo for the 
treatment of GL in participants 
with moderate to severe GL

To compare the safety between 
MT10109L and placebo for the 
treatment of GL in participants 
with moderate to severe GL
For US FDA:

Secondary: The duration of GL treatment effect, estimated as the 
median time to return to moderate or severe GL at maximum frown, 
in participants who achieved a rating of ≥2-grade improvement 
from baseline in GL severity at maximum frown at Day 30 
according to investigator assessments using the FWS

Secondary: The proportion of responders for investigator 
assessments of GL severity at maximum frown using the FWS, 
where a responder is defined as achieving a ≥2-grade improvement 
from baseline at maximum frown at Day 30

 
 
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
Secondary: The proportion of participants reporting mostly 
satisfied/very satisfied on the Facial Line Satisfaction Questionnaire
(FLSQ) follow-up version Item 5 for GL at Day 60

Secondary: The proportion of responders for investigator 
assessments of GL severity at rest using the FWS among 
participants who were rated at least mild at rest at baseline, where a 
responder is defined as achieving a ≥1-grade improvement from 
baseline at Day 30

Secondary: Incidence of adverse events; change from baseline in 
vital sign and electrocardiogram (ECG) parameters; and presence of 
binding and neutralizing antibodies
For EU regulatory agencies:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Study Design:

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
Phase 3 study to evaluate the safety and efficacy of MT10109L in treating GL. 
 

Participants are adults ≥ 18 years of age with moderate to severe GL at maximum frown 
(assessed by both the investigator and participant using the FWS [investigator and 
participant ratings must be the same for GL]).

The primary efficacy measure is the investigators’ and participants’ assessments of GL at 
maximum frown using the FWS, and the primary timepoint is Day 30 after the first 
intervention.

Participants will attend a Screening Visit up to 28 days before enrollment on Day 1. 
 
 
 
 
 

The first treatment period (Day 1 with follow-up to Day 180) is a double-blind, 
randomized, placebo-controlled, parallel-group, single treatment administration with a 
6-month follow-up.

On Day 1, participants will be randomly assigned in a 2:1 ratio to receive 
MT10109L 20 U or placebo. 
 
 
 
 
 

Participants who complete the study will have an exit visit at Day 360.
 
Number of Participants:
Approximately 225 participants will be enrolled in order to have approximately 190 participants 
complete the study 
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Number of Sites:
Approximately 16 global sites
Intervention Groups and Study Duration:

The total duration of study participation for each participant is approximately 12 months 
(Day 1 randomization/treatment to end of study/Day 360). Participants will attend the 
following visits:
o
Screening (up to 28 days prior to Day 1)
o
Randomization and treatment (Day 1)
o
Follow-up visits on Days 7 and 14 after each intervention
o
Monthly (Days 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, and 330)
o
Exit (Day 360 [completion] or early exit)

On Day 1, participants will receive IM injections of MT10109L 20 U or placebo.

During the retreatment period (Day 180 through Day 330), participants who meet 
retreatment criteria will receive up to 2 open-label interventions of MT10109L 20 U 
 
. Participants who complete the study will 
have an exit visit at Day 360.
Data Monitoring Committee: No
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Introduction
Study Rationale
The purpose of this placebo-controlled, pivotal study is to evaluate the safety and efficacy of 
MT10109L for the treatment of GL in participants with moderate to severe GL 
 
Background
 
 
 
 
 
Glabellar lines are deep furrows or frown lines in the glabellar area of the face, and LCL (or 
CFL) are horizontal smile lines by the sides of the eyes. Both types of facial lines result from the 
repetitive functional action of the underlying mimetic facial musculature during animation 
(Blitzer 1993). When injected at therapeutic doses, MT10109L produces partial chemical 
denervation of the muscle, resulting in localized reduction in muscle activity. Because GL and 
LCL result from muscular activity, the muscle relaxation leads to a temporary relief of facial 
lines. While it was previously thought that these facial lines were structural and permanent, the 
effects of these injections demonstrate the lines are part functional and remain because of 
constant muscle tone (Ferreira 2004; Garcia 1996).
The development of facial lines (such as GL and LCL) is an age-related change of the face that 
occurs because of the repetitive muscle contractions that are associated with common facial 
expressions. Thus, these facial lines can be observed with contraction (dynamic rhytides) or in 
more severe cases in repose (static rhytides). Increasing severity in the appearance of facial lines 
has been associated with a patient’s perception of reduced attractiveness and a negative effect on 
self-esteem and sense of well-being (Koblenzer 1996). Furthermore, the appearance of these 
facial lines can lead to a miscommunication of an emotional state of anger, anxiety, disapproval, 
or sadness (Khan 2001) causing distress and affecting social interactions (Finn 2003).
Evidence supports that unattractive or aging skin is indeed related to psychological and 
psychosocial impacts (Farage 2010).
 
 
 
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The popularity of BoNT/A cosmetic treatment of GL and LCL in adults is related to its proven 
efficacy for reducing moderate to severe facial lines (Beer 2006); well documented safety profile 
(Brin 2009); and positive impact on psychological well-being and the resulting psychosocial 
benefits (Finn 2003).
Benefit/Risk Assessment
Generally, the popularity of BoNT/A cosmetic treatment of GL and LCL in adults is related to its 
proven efficacy for reducing moderate to severe facial lines (Beer 2006); well documented safety 
profile (Brin 2009); and positive impact on psychological well-being and the resulting 
psychosocial benefits (Finn 2003). Compared with the general class of BoNT/A treatments, 
MT10109L provides additional benefits. For one, it is provided as a ready-to-use liquid product. 
Secondly, it is manufactured without human- or animal-derived products. MT10109L also offers 
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potential efficacy and safety advantages in addition to convenience since it does not require 
reconstitution and has shown sustained benefit in the treatment of GL.
 
 
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Objectives and Endpoints
Objectives
Endpoints
Primary

To compare the efficacy between
20 U MT10109L and placebo for the 
treatment of GL in participants with 
moderate to severe GL
For US FDA:

Composite: The proportion of participants with a ≥2-grade 
improvement from baseline on the FWS according to 
investigator and participant assessments of GL severity at 
maximum frown at Day 30 using the ITT population after a 
single IM injection of MT10109L or placebo in the GL
For EU regulatory agencies:

Coprimary: The proportion of participants achieving a rating of 
 
 
Secondary

To compare the efficacy between 
MT10109L and placebo for the 
treatment of GL in participants with 
moderate to severe GL

To compare the safety between 
MT10109L and placebo for the 
treatment of GL in participants with 
moderate to severe GL
For US FDA:

Secondary: The duration of GL treatment effect, estimated as the 
median time to return to moderate or severe GL at maximum 
frown, in participants who achieved a rating of ≥2-grade 
improvement from baseline in GL severity at maximum frown at 
Day 30 according to investigator assessments using the FWS

Secondary: The proportion of responders for investigator 
assessments of GL severity at maximum frown using the FWS, 
where a responder is defined as achieving a ≥2-grade 
improvement from baseline at maximum frown at Day 30

 
 
 

Secondary: The proportion of participants reporting mostly 
satisfied/very satisfied on the FLSQ follow-up version Item 5 for 
GL at Day 60

Secondary: The proportion of responders for investigator 
assessments of GL severity at rest using the FWS among 
participants who were rated at least mild at rest at baseline, 
where a responder is defined as achieving a ≥1-grade 
improvement from baseline at Day 30

Secondary: Incidence of adverse events; change from baseline in 
vital sign and ECG parameters; and presence of binding and 
neutralizing antibodies
For EU regulatory agencies:

 
 
 
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Study Design
Overall Design

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
Phase 3 study conducted across approximately 16 global sites to evaluate the safety and 
efficacy of MT10109L in treating GL. Participants may receive up to 3 study 
interventions (a single double-blind intervention of MT10109L 20 U or placebo and up to 
2 open-label interventions with MT10109L 20 U). 

Participants are adults ≥ 18 years of age with moderate to severe GL at maximum frown 
(assessed by both the investigator and participant using the FWS [investigator and 
participant ratings must be the same for GL]).

The primary efficacy measure is the investigators’ and participants’ assessments of GL 
severity at maximum frown using the FWS, and the primary timepoint is Day 30 after the 
first intervention.

Participants will attend a Screening Visit up to 28 days before enrollment on Day 1. 
 

The first treatment period (Day 1 with follow-up to at least Day 180) is a double-blind, 
randomized, placebo-controlled, parallel-group, single treatment administration with a 
6-month follow-up.

On Day 1, participants will be randomly assigned in a 2:1 ratio to receive 
MT10109L 20 U or placebo. 
 
 
 
 
 

MT10109L 20 U or placebo will be administered as 5 IM injections: 5 to the GL complex 
(2 in each corrugator muscle, 1 in the procerus muscle), 0.1 mL (4 U MT10109L or 0 U 
placebo) per injection.
 
 
 
 

Participants who complete the study will have an exit visit at Day 360.
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
The total duration of study participation for each participant is approximately 12 months 
(Day 1 randomization/treatment to end of study/Day 360). Participants will attend the 
following visits:
o
Screening (up to 28 days prior to Day 1)
o
Randomization and treatment (Day 1)
o
Follow-up visits on Days 7 and 14 after each intervention
o
Monthly (Days 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, and 330)
o
Exit (Day 360 [completion] or early exit)
 

Approximately 225 participants will be enrolled at approximately 16 global sites in order 
to have approximately 190 participants complete the study 
 
 

Participants who prematurely discontinue from the study will not be replaced.
4.1.1
Clinical Hypotheses
MT10109L 20 U is more effective than placebo in treating GL, measured by both investigators’ 
and participants’ assessments of GL severity at maximum frown using the FWS.
MT10109L 20 U has an acceptable safety profile after single and repeat treatments.
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End of Study Definition
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant in the study globally.
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the SoA.
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Study Population
Participants in the current study have moderate to severe GL at maximum frown, as specified in 
Section 5.1.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be ≥18 years of age and considered to be an adult in her/his local 
jurisdiction at the time of signing the informed consent.
2.
Type of Participant and Characteristics
2.01
Moderate to severe GL at maximum frown (as assessed by both the investigator and 
participant; 
) using the FWS
2.02
Participants must have sufficient visual acuity without the use of eyeglasses (contact 
lens use acceptable) to accurately assess their GL lines, in the opinion of the 
investigator.
3.
Sex
3.01
Male and female
4.
Contraceptives
4.01
Female participants willing to minimize the risk of inducing pregnancy for the 
duration of the clinical study and follow-up period
4.02
Female participants of childbearing potential must have a negative urine pregnancy 
test before each study intervention. A female is considered NOT to be of 
childbearing potential if she is premenarchal, postmenopausal (at least 
12 consecutive months without menstruation), or permanently sterilized (eg, tubal 
occlusion, hysterectomy, bilateral oophorectomy).
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5.
Informed Consent
5.01
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol
5.02
Written informed consent from the participant has been obtained prior to any study-
related procedures.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Any condition which precludes a participant’s ability to comply with study requirements, 
including completion of the study visits or inability to read, understand, and/or self-assess 
GL severity using the FWS
1.03
Any medical condition that may put the participant at increased risk with exposure to 
MT10109L including diagnosed myasthenia gravis, Eaton-Lambert syndrome, 
amyotrophic lateral sclerosis, or any other condition that might interfere with 
neuromuscular function
 
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1.09
Any uncontrolled systemic disease
1.11
Anticipated need for treatment with botulinum toxin of any serotype for any reason during 
the study (other than study intervention)
1.12
Anticipated need for surgery or overnight hospitalization during the study
2.
Prior/Concomitant Therapy/Procedures
2.01
Prior exposure to botulinum toxin of any serotype for any reason
 
 
 
 
 
 
 
 
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2.06
Prior facial treatment with permanent soft tissue fillers, synthetic implantation 
(eg, Gore-Tex®), and/or autologous fat transplantation
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study
4.
Other
4.01
Females who are pregnant, nursing, or planning a pregnancy during the study
4.02
Participants who plan for an extended absence away from the immediate area of the study 
site that would preclude them from returning for all protocol specified study visits
 
 
 
 
 
 
 
 
 
 
 
Lifestyle Considerations
No restrictions are required.
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Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from health authorities. Minimal information includes 
demographics, screen failure details, eligibility criteria, and any SAE.
Screen failures can occur during the screening period up to the Day 1 Visit. 
 
 
 
 
 
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Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol.
 
 
 
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6.1.2
Instructions for Use and Administration
Only trained and medically qualified physicians experienced with BoNT/A injections are 
authorized to administer the study interventions. Study-specific training for GL injections are 
provided to investigators 
 
 
 
 
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The GL study interventions will be administered as IM injections at 5 injection sites in the 
glabellar complex, 2 in each corrugator muscle and 1 in the procerus 
.
Participants must be observed for adverse events for ≥ 30 minutes after each study intervention.
 
 
 
 
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only authorized 
site personnel may administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
personnel.
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3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions are 
provided in the study manual.
All unused study intervention and empty vials must be returned to the sponsor at the termination 
of the study. Unit counts will be performed when the study intervention is returned, and all study 
intervention must be accounted for. Unused drug supplies and empty vials will be returned to the 
sponsor.
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Study Intervention Compliance
Participants will receive all doses under the direct supervision of study site personnel. Study 
intervention compliance will not be calculated.
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration.
Concomitant Therapy
The use of any concomitant medication or vaccine (including prescription or over-the-counter 
medication, vitamins, and/or herbal supplements) is to be recorded on the participant’s eCRF at 
each visit along with the reason the medication is taken.
At screening and end of study and upon admission to and discharge from the study site, study 
site personnel will question each participant specifically on the use of concomitant medications. 
Study site personnel must notify the sponsor immediately if a participant consumes any 
concomitant medications not permitted by the protocol. Participants who admit to using 
prohibited concomitant medications may be discontinued from the study at the discretion of the 
investigator or the sponsor.
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6.5.3
Rescue Medicine
Rescue medicine is not applicable.
Dose Modification
This protocol does not allow for alteration from the currently outlined dosing schedule.
 
 
 
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Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and is randomized 
ceases participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures.
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the 
appropriate eCRF.
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used terms:
Commonly Used Terms
Adverse event
Lost to follow-up
Lack of efficacy
Other
Physician decision
Pregnancy
Protocol deviation
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by subject
Discontinuation of Study Intervention
Study intervention should be discontinued for the following reasons:

Pregnancy 

Other safety criteria
 
Women who test positive for urine pregnancy test will NOT receive further treatment and will be 
discontinued from the study. They should complete study exit procedures and be followed up for 
pregnancy outcome. See the SoA for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
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Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

See the SoA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the study site for a required 
study visit:

The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
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Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. 
 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
 
 
Efficacy Assessments
8.1.1
Facial Wrinkle Scale With Photonumeric Guide (FWS)
Investigators’ and participants’ assessments of the severity of GL at rest and maximum frown 
using the validated FWS, based on the following scale:
0 = None
1 = Mild
2 = Moderate
3 = Severe
 
 
 
 
 
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Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1
Adverse Events
The investigator will question the participant to ascertain whether any adverse events were 
experienced since the previous visit. Additionally, at treatment visits, the participants will be 
observed for ≥ 30 minutes following study intervention. All pertinent information regarding 
adverse events (ie, date of onset and stop, duration, outcome, severity, relationship to study 
intervention, action or treatment required) will be obtained and recorded in the source documents 
and appropriate eCRF page.
8.2.2
Physical Examination
Physical examination will be conducted at the Screening Visit
 
 
 
 
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8.2.4
Vital Signs
Pulse rate (beats per minute): Participants are to be seated for at least 2 minutes, and pulse rate 
will be counted over 60 seconds, and recorded in the source document and eCRF as beats per 
minute.
Blood pressure (mm Hg): Participants are to be seated for at least 2 minutes, and 
systolic/diastolic blood pressure will be measured.
Respiration rate (breaths per minute): Participants are to be seated for at least 2 minutes, and 
breaths will be counted for 30 seconds and multiplied by 2.
8.2.5
Electrocardiograms

All participants will undergo conventional 12-lead ECG using standardized equipment and 
electrode placement at the visits outlined in the SoA. Participants are to be in a 
semirecumbent position for at least 10 minutes prior to starting the tracing. During screening, 
a single ECG trace will be taken to assess entry eligibility.

A qualified third-party vendor will read the ECGs and report the findings as normal, 
abnormal, or unable to evaluate.
 
 
 
 
 
 
 
 
 
 

The ECG will be assessed for the following measures: heart rate, QRS duration, QT interval, 
QTcB interval, QTcF interval, ST segment, RR interval, PR interval, and qualitative results.
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8.2.6
Hematology and Blood Chemistry

See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency.

Hematology and nonfasting blood chemistry assays will be performed by a central 
laboratory.

During the Screening Period, the investigator or subinvestigator will assess the clinical 
significance of any values outside the reference ranges provided by the laboratory, and 
participants with abnormalities judged to be clinically significant will be excluded from the 
study.
8.2.7
Urine Pregnancy Tests
Urine dipstick kits will be used to conduct pregnancy tests at the timepoints specified in the SoA, 
or more frequently, at the investigator’s discretion.
8.2.8
Suicidal Risk Monitoring
Suicidal risk monitoring is not applicable for this study.
Adverse Events and Serious Adverse Events
The definitions of an adverse event or SAE can be found in Appendix 3.
Adverse events will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an adverse event or SAE and remain responsible for 
following up adverse events that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7).
Adverse drug reactions for MT10109L have not been established.
 
The following expected adverse drug reactions are based on BOTOX clinical trial data for the 
treatment of GL (Table 8-1).
Table 8-1
Expected Adverse Reactions for Treatment of Glabellar Lines
Expected Adverse Reactionsa
Incidence
Eyelid ptosis 
3%
Facial pain
1%
Facial paresis
1%
Muscular weakness
1%
a Data are based on BOTOX glabellar lines clinical trial data (BOTOX Cosmetic US Package Insert, 2017)
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The adverse drug reactions of eyelid ptosis, facial pain, facial paresis, and muscular weakness
usually are mild in severity, reversible, and have a low incidence. Therefore, no treatment for 
these reactions is recommended. If these reactions are moderate or severe, medical help should 
be sought as needed.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
For participants who received study intervention, all adverse events from the signing of the ICF 
until 30 days after the last study visit will be collected at the timepoints specified in the SoA
 and as observed or reported spontaneously by study participants.
 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the adverse event section of the eCRF.
All SAEs from the signing of the ICF until at least 12 weeks after the last administration of study 
intervention will be collected at the timepoints specified in the SoA (Section 1.3), and as 
observed or reported spontaneously by study participants.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek adverse event or SAE information after 
conclusion of the study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.
The method of recording, evaluating, and assessing causality of adverse events and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire about 
adverse event occurrences.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial adverse event/SAE report, the investigator is required to proactively follow each 
participant who received study intervention at subsequent visits/contacts. All TEAEs/SAEs, 
including AESIs
 will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up 
.
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The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the adverse event or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including 
histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ IECs, and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
8.3.5
Pregnancy

Urine pregnancy testing will be conducted for women of childbearing potential prior to each 
study intervention, and at the study exit visit. See Appendix 7 for detailed information on 
definition of women of childbearing potential, use of contraceptives, and pregnancy.

To minimize the risk of pregnancy, all women of childbearing potential must agree to use a 
highly effective or acceptable contraception method (Appendix 7) consistently and correctly 
throughout the duration of the study. 

Women who test positive for urine pregnancy test will NOT receive further treatment and 
will be discontinued from the study.

Women who test positive for urine pregnancy test should complete end-of-study procedures 
and be followed up for pregnancy outcome.
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
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an elective 
abortion or not) are considered SAEs.
 
8.3.7
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study intervention

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration that is above the maximum recommended dose according to the protocol for the 
study intervention or comparator as applicable. See Section 8.4 for information on the treatment 
of overdose.
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration that is under the minimum recommended dose according to the protocol.
Treatment of Overdose
Overdose of MT10109L is a relative term and depends upon dose, site of injection, and 
underlying tissue properties. Signs and symptoms of overdose are likely not to be apparent 
immediately postinjection. Excessive doses may produce local, or distant, generalized and 
profound neuromuscular paralysis.
Because MT10109L is administered as injections by physicians, for this study, the chance of 
overdose is extremely low. Should accidental injection or oral ingestion occur or overdose be 
suspected, the participant should be medically monitored for up to several weeks for progressive 
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signs or symptoms of systemic muscular weakness that could be local or distant from the site of 
injection, which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness, or 
respiratory failure. For GL or LCL, eyelid ptosis, diplopia, and vision blurred are known local 
effects of the toxin. These participants should be considered for further medical evaluation and 
appropriate medical therapy immediately instituted, which may include hospitalization.
If the musculature of the oropharynx and esophagus is affected, aspiration may occur, which may 
lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or 
sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes 
place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical 
ventilation, in addition to other general supportive care.
In the event of an overdose, the investigator should educate the participant, monitor the course of 
overdose, contact the medical safety physician as needed, document the quantity of the excess 
dose, associated adverse events as well as the duration of the overdose in the eCRF.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
Genetics
Genetics are not evaluated in this study.
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Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.
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Statistical Considerations
Statistical Hypotheses
For US FDA:
The primary efficacy analysis will be performed on the ITT population, which consists of all 
randomized participants. The following hypotheses will be used to compare MT10109L 20 U 
with placebo:

Null hypothesis: MT10109L 20 U and placebo are equally effective in reducing GL severity 
at maximum frown as measured by the proportion of responders with a ≥ 2-grade 
improvement from baseline based on both the investigator- and participant-rated FWS at 
Day 30.

Alternative hypothesis: MT10109L 20 U and placebo are not equally effective in reducing 
GL severity at maximum frown as measured by the proportion of responders with a 
≥2-grade improvement from baseline based on both the investigator- and participant-rated 
FWS at Day 30.
For EU regulatory agencies:
 
 
 
 
 
 
 
 
 
 
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Sample Size Determination
Approximately 225 participants will be randomized into the study in a 2:1 ratio yielding 
approximately 150 participants in the MT10109L 20 U group and 75 participants in the placebo 
group in the first treatment period. The sample size of 225 allows for an adequate safety database 
of participants treated with MT10109L for this indication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Populations for Analyses
Primary and secondary efficacy analyses for the US FDA will be performed on the ITT 
population, consisting of all randomized participants.
 
The safety analyses will be based on the safety population, which will include all participants 
who receive at least 1 injection of study intervention. All safety analyses will be performed with 
participants analyzed by their actual treatment or regimen received.
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Statistical Analyses
The SAP will be developed and finalized before database lock and unblinding and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary, secondary, and exploratory endpoints.
9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Endpoints
For the US FDA, the composite efficacy endpoints are the proportion of participants with a 
≥2-grade improvement from baseline on the FWS according to both investigator and participant 
assessments of GL severity at maximum frown at Day 30 using the ITT population after a single 
IM injection of MT10109L or placebo in the GL.
 
9.4.1.2
Primary Analyses
The primary efficacy analysis will be based on the comparison of GL efficacy for MT10109L 
20 U versus placebo at the primary timepoint of Day 30 of the first treatment period. The 
evaluation of the equality of the proportions of responders will be based on CMH test stratified 
by investigator-assessed baseline GL severity at maximum frown. Relative risk and 95% CI for 
relative risk will be presented. Missing values will be imputed up to Day 180 using multiple 
imputation methods. SAS Proc MI procedure will be used 
 
Seed for all Proc MI procedure is prespecified as 
. 
 
 
 
 
 
 
 
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 The primary efficacy variables will be evaluated across all study visits, with the 
primary timepoint being Day 30 of the first treatment period.
Sensitivity analyses of the primary efficacy variables will be performed to establish their 
consistency and robustness as well as to further characterize the extent of participants’ responses. 
 
9.4.1.3
Secondary Efficacy Endpoints
For US FDA:

The duration of GL treatment effect estimated as the median time to return to moderate or 
severe GL at maximum frown, in participants who achieved a rating of ≥2-grade 
improvement from baseline in GL severity at maximum frown at Day 30 according to 
investigator assessments using the FWS.

The proportion of responders for investigator assessments of GL severity at maximum frown 
using the FWS, where a responder is defined as achieving a ≥2-grade improvement from 
baseline at maximum frown at Day 30
 
 

The proportion of participants reporting mostly satisfied/very satisfied on the FLSQ 
follow-up version Item 5 for GL at Day 60.

The proportion of responders for investigator assessments of GL severity at rest using the 
FWS, among participants who were rated at least mild at rest at baseline, where a responder 
is defined as achieving a ≥ 1-grade improvement from baseline at Day 30.
For EU regulatory agencies:
 
 
 
 
 
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9.4.1.4
Secondary Analyses
All secondary variables will be evaluated for all study visits with the prespecified primary 
timepoint given above, except for duration of treatment effect. The duration of GL treatment 
effect is defined as the time to return to moderate or severe GL at maximum frown, in those 
participants achieving a responder status (for US FDA, responder is defined as participants who 
achieved a rating of ≥2-grade improvement from baseline in GL severity at maximum frown;
 
 
at Day 30 according to investigator assessments using the 
FWS. It will be estimated using the Kaplan-Meier method.
 
A serial gatekeeping strategy will be used to account for multiplicity in testing the primary and 
secondary efficacy variables at the primary timepoint 
 
 
 
 
 
 
 
 
 
The proportion of responders will be analyzed using the CMH test stratified by baseline GL 
severity at maximum frown as assessed by the clinician (investigator or subinvestigator). The 
continuous variables and ordinal variables will be analyzed using ANCOVA
 
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9.4.1.5
Exploratory Efficacy Endpoints
For both the US FDA and EU, analyses for exploratory efficacy endpoints will be performed on 
the ITT population.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.1.6
Exploratory Efficacy Analyses
The proportion of responders will be analyzed using the CMH test
 
9.4.2
Safety Analyses
The safety analysis will be performed using the safety population and are fully defined in the 
SAP. The safety parameters will include:

Adverse events
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
Vital signs

Electrocardiogram

Immunogenicity analyses
9.4.2.1
Adverse Events
An adverse event will be considered a TEAE if:

The adverse event began on or after the date of the first dose of study intervention; or

The adverse event was present before the date of the first dose of study intervention, but 
increased in severity or became serious on or after the date of the first dose of study 
intervention
An adverse event that occurs more than 30 days after study exit will not be counted as a TEAE.
An adverse event will be considered a TESAE if it is a TEAE that additionally meets any SAE 
criteria.
The number and percentage of participants reporting TEAEs in each study intervention group 
will be tabulated by system organ class and preferred term and by system organ class, preferred 
term, and severity.
The number and percentage of participants reporting treatment related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term.
 
The number and percentage of participants reporting TEAEs that are included in the PDSOT 
term list will be tabulated by study intervention group. 
 
 
Summary tables will be provided for participants with SAEs and participants with adverse events 
leading to discontinuation if 5 or more participants reported such events. Listings of all adverse 
events, SAEs, and adverse events leading to discontinuation by participant will be presented.
The definitions of an adverse event and SAE can be found in Appendix 3.
9.4.2.2
Vital Signs
Descriptive summaries (n, mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for vital signs (systolic and diastolic blood pressure, 
pulse and respiration rate). These summaries will be presented by study intervention and by visit.
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9.4.2.3
Electrocardiograms
Descriptive statistics for ECG parameters (eg, heart rate, QRS duration, QT interval, QTc 
intervals, RR interval, and PR interval) at baseline, and changes from baseline at all postbaseline 
timepoints will be presented by study intervention and by visit. For each parameter, only 
participants who had both baseline postbaseline assessments will be included in the summary. 
 
 
9.4.3
Other Analyses 
9.4.3.1
Immunogenicity Analyses
Immunogenicity results, manifested as the presence of binding antibodies and neutralizing 
antibodies to MT10109L, will be summarized in a table.
Interim Analyses
No interim analysis is planned.
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Supporting Documentation and Operational Considerations
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Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
o
Applicable ICH/ISO GCP guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
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10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
10.1.4
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.

The participant must be informed that his/her medical records may be examined by clinical 
quality assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5
Posting Clinical Study Data

 
 

Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required.

Company-sponsored study information and tabular study results will be posted on the US 
National Institutes of Health’s website www.ClinicalTrials.gov and other publicly 
accessible sites.
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10.1.6
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
10.1.7
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study.

Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate.
10.1.8
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.10
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site and 
will ensure the availability of appropriate study personnel and compliance with GCP regulations 
and procedures. Trainings are provided by the sponsor to discuss the protocol procedures and 
study requirements. A representative of the sponsor will make frequent contact with the 
investigator and his/her research staff and will conduct regular monitoring visits at the site to 
review participant and study intervention accountability records for compliance with the 
protocol. Protocol deviations will be discussed with the investigator upon identification. The use 
of the data collected for the participant will be discussed to determine if the data are to be 
included in the analysis. The investigator will enter data that may be excluded from analysis as 
defined by the protocol deviation specifications. Significant protocol deviations will be reported 
to the IRB/IEC according to the IRB/IEC’s reporting requirements.
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Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10-1 will be performed by the central laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10-1
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelets
RBC count
Hemoglobin
Hematocrit
RBC morphology
WBC count with differential (absolute):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry
BUN
Potassium
AST
Total, direct, and indirect bilirubin
Creatinine
Sodium
ALT
Total protein
Glucose
Calcium
Alkaline phosphatase
Chloride
Albumin
Magnesium
Phosphorus
Bicarbonate (carbon dioxide content)
Uric acid
Investigators must document their review of each laboratory safety report.
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Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease); for example:
o
The test result is associated with accompanying symptoms, and/or
o
The test result requires additional diagnostic testing or medical/surgical 
intervention, and/or
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The test result leads to a change in study dosing (outside of any protocol-specified 
dose adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy, and/or
o
The test result is considered to be an AE by the investigator or sponsor.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.

Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AEs or SAEs if they fulfil the definition of an AE 
or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. Merely 
repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not 
require recording as an AE.

The disease/disorder being studied or expected progression, signs, or symptoms 
(clearly defined) of the disease/disorder being studied, unless more severe than 
expected for the participant’s condition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)
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
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen
Definition of SAE
SAEs must meet both the AE criteria described above and the seriousness criteria listed below.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
The term life threatening in the definition of serious refers to an event in which the 
participant 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.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
Recording and Follow-Up of AEs and/or SAEs
AE and SAE Recording

When an AE or SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the AE or SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
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Assessment of Intensity
MILD
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
MODERATE
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm 
to the research participant.
SEVERE
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
An event is defined as serious when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE or SAE.

A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.
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
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Reporting of SAEs
SAE Reporting
 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE form, sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE form within the designated reporting time frames.
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Appendix 4: Abbreviations
Term/Abbreviation
Definition
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase
BoNT/A
botulinum toxin type A 
BUN
blood urea nitrogen
CFL
crow’s feet lines
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
CFR
Code of Federal Regulations
DVD
digital versatile disc
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EU
European Union
FDA
Food and Drug Administration
FLO-11
11-item Facial Line Outcomes questionnaire
FLSQ
Facial Line Satisfaction Questionnaire
FWS
Facial Wrinkle Scale with Photonumeric Guide
GCP
Good Clinical Practices
GL
glabellar lines
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IND
investigational new drug application
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IRB
Institutional Review Board
ITT
intent-to-treat
IUD
intrauterine device
IWRS
interactive web response system
LCL
lateral canthal lines
LLN
lower limit of normal value provided by the laboratory
mITT
modified intent-to-treat
PRO
patient-reported outcome
RBC
red blood cells
SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
SoA
schedule of activities
SUSAR
serious adverse reactions
TCA
trichloroacetic acid
TEAE
treatment-emergent adverse events
U
Units
UFL
upper facial lines
ULN
upper limit of normal value provided by the laboratory
US
United States
WBC
white blood cells
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Appendix 10: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.
Amendment 1 (September 2018)
This amendment is considered to be nonsubstantial 
 
 
The editorial nature of this amendment is intended to provide 
clarity of information throughout the document.
Overall Rationale for the Amendment:
The overall rationale for the changes implemented in the protocol amendment were 
administrative in nature.
Section Number
and Name
Description of Change
Brief Rationale
 
 
 
 
 
Throughout
Minor editorial revisions
Minor, therefore have not been 
summarized
Amendment 2 (November 2018)
This amendment is considered to be nonsubstantial 
 
 
 
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Overall Rationale for the Amendment:
The overall rationale for the change implemented in the protocol was administrative in nature.
Section No.
and Name
Description of Change
Brief Rationale
Title Page
Added Allergan Limited
 
Administrative
Amendment 3 (February 2019)
This amendment is considered to be substantial
 
 
 
Section No. and Name
Description of Change
Brief Rationale
1.1 (Synopsis), 3 (Objectives and 
Endpoints), and 9.4.1.1 (Primary 
Efficacy Endpoints)
Clarified the primary objective and endpoint, added 
secondary objectives, and secondary safety endpoints
Updated per 
recommendation by 
health authority
1.1 (Synopsis), 3 (Objectives and 
Endpoints), and 9.4.1.3 (Secondary 
Efficacy Endpoints)
Added new secondary efficacy endpoints
New addition
 
 
 
 
 
 
 
 
 
 
 
1.3 (Schedule of Activities)
Modified and added footnotes 
Improve clarity
 
 
 
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Section No. and Name
Description of Change
Brief Rationale
 
 
 
 
 
 
 
8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and 
Serious Adverse Event 
Information) and 8.3.3 (Follow-up 
of Adverse Events and Serious 
Adverse Events)
Added text to clarify that collection of adverse events at
follow-up visits only applies to participants who receive 
study intervention
Improve clarity
8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and 
Serious Adverse Event 
Information)
Added a statement to clarify the process for collecting 
adverse events
 
Improve clarity
 
 
 
 
 
 
 
8.3.5 (Pregnancy) and Appendix 7 
(subsection of Collection of 
Pregnancy Information)
Revised the description of which pregnancy outcomes 
are considered serious adverse events (SAEs)
Consistent with the 
new protocol 
template
 
 
 
 
 
 
 
 
 
 
 
9.4.1.5 (Exploratory Efficacy 
Endpoints) and 9.4.1.6 
(Exploratory Efficacy Analyses)
Added a new section (Section 9.4.1.5) and modified 
text in Section 9.4.1.6 to provide details about 
exploratory endpoints and analyses
Updated per 
recommendation by 
health authority
9.4.2.1 (Adverse Events)
Revised the duration after which an adverse event will 
not be counted as a treatment-emergent adverse event 
(TEAE)
Correction
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Section No. and Name
Description of Change
Brief Rationale
9.4.2.1 (Adverse Events)
Added a paragraph describing analysis of TEAEs 
related to possible distant spread of toxin (PDSOT) and 
monitoring of PDSOT
Clarification of 
process
9.4.2.2 (Vital Signs) and 9.4.2.3 
(Electrocardiograms)
Modified the description of analyses for clarity
Improve clarity
Appendix 1 (subsection of 
Compliance with Protocol)
Added text to clarify compliance with GCP regulations 
and procedures, and training of investigators on study 
requirements
Updated per 
recommendation by 
health authority
 
 
Appendix 7
Revised criteria for postmenopausal females who are 
not being considered women of childbearing potential
Improve clarity
Appendix 7 (Table 10-2)
Added text to include as one of the acceptable birth 
control methods the option of male or female condoms 
without spermicide (in addition to male or female 
condoms with spermicide)
Correction
Throughout
Minor editorial revisions
Minor, therefore 
have not been 
summarized
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References
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Koblenzer CS. Psychologic aspects of aging and the skin. Clin Dermatol. 1996;14:171-177.
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O'Kelly M, Ratitch B. Clinical trials with missing data: A guide for practitioner. Statistics in 
Practice. Wiley; 2014.
Wilson EB, Hilferty, MM. The distribution of chi-squared. Proceedings of the National Academy 
of Sciences, Washington. 1931;17:12,684–688.
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