Clinical trial NCT03721016
Conditions: Glabellar Lines Lateral Canthal Lines
Sponsor: Medy-Tox
Start date: 2018-10-26; Completion date: 2021-01-22
Enrollment: 415 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and efficacy of MT10109L for the treatment of glabellar lines (GL) with or without concurrent treatment of lateral canthal lines (LCL) in participants with moderate to severe GL and LCL.

Detailed description:

Arms: arm 1: MT10109L Dose 1 will be injected into the Glabellar Lines (GL) and Placebo into the Lateral Canthal Lines (LCL): initial double-blind treatment on Day 1, and up to 2 additional blinded treatments during the retreatment period. arm 2: MT10109L Dose 1 will be injected into the Glabellar Lines (GL) and MT10109L Dose 2 into the Lateral Canthal Lines (LCL): initial double-blind treatment on Day 1, and up to 2 additional blinded treatments during the retreatment period. arm 3: Placebo will be injected into the Glabellar Lines (GL) and into the Lateral Canthal Lines (LCL): initial double-blind treatment on Day 1, and up to 2 additional blinded treatments during the retreatment period.
Interventions: intervention 1: MT10109L intervention 2: Placebo
Intervention descriptions: intervention 1: MT10109Lwill be injected into either the Glabellar Lines (GL), Lateral Canthal Lines (LCL), or both. intervention 2: Placebo will be injected into either the Glabellar Lines (GL), Lateral Canthal Lines (LCL), or both.

Protocol documents:
Prot_002.pdf: 
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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 With or Without Concurrent Treatment of Lateral Canthal Lines
Protocol Number: MT10109L-005
Amendment Number: Amendment 4
Product: MT10109L (nivobotulinumtoxinA)
Brief Protocol Title: MT10109L in the Treatment of Glabellar Lines With or Without 
Concurrent Treatment of Lateral Canthal Lines
Development Phase: 3
Sponsor Name and Legal Registered Address:
Allergan Sales LLC
Regulatory Agency Identifying Number: IND Number 121473;
EudraCT Number 2014-005301-21
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Refer to the final page of this protocol for electronic signature and date of approval.
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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
August 2018
Original Protocol
June 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
9.4.1.2 Primary Analyses
Added text describing imputation methods
from the statistical analysis plan
Updated per recommendation by health 
authority
11 References
Added references
References added to Section 9.4.1.2
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................39
7.1.
Discontinuation of Study Intervention............................................................................39
7.2.
Participant Discontinuation/Withdrawal From the Study...............................................40
7.3.
Lost to Follow Up...........................................................................................................40
8.
Study Assessments and Procedures.............................................................................41
8.2.
Safety Assessments.........................................................................................................43
8.2.1.
Adverse events................................................................................................................43
8.2.2.
Physical Examination......................................................................................................43
8.2.4.
Vital Signs.......................................................................................................................44
8.2.5.
Electrocardiograms .........................................................................................................44
8.2.6.
Hematology and Blood Chemistry..................................................................................45
8.2.7.
Urine Pregnancy Test......................................................................................................45
8.2.8.
Suicidal Risk Monitoring................................................................................................45
8.3.
Adverse Events and Serious Adverse Events .................................................................45
8.3.1.
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information................................................................................46
8.3.2.
Method of Detecting Adverse Events and Serious Adverse 
Events..............................................................................................................................46
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ...........................................47
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events..................................47
8.3.5.
Pregnancy........................................................................................................................47
8.3.7.
Medication Errors ...........................................................................................................48
8.4.
Treatment of Overdose ...................................................................................................49
8.5.
Pharmacokinetics............................................................................................................49
8.6.
Pharmacodynamics .........................................................................................................49
8.7.
Genetics ..........................................................................................................................49
8.9.
Medical Resource Utilization and Health Economics....................................................50
9.
Statistical Considerations.............................................................................................51
9.1.
Statistical Hypotheses.....................................................................................................51
9.2.
Sample Size Determination ............................................................................................52
9.3.
Populations for Analyses ................................................................................................52
9.4.
Statistical Analyses.........................................................................................................53
9.4.1.
Efficacy Analyses ...........................................................................................................53
9.4.1.1.
Primary Efficacy Endpoints ...............................................................................53
9.4.1.2.
Primary Analyses ...............................................................................................53
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9.4.1.4.
Secondary Analyses ...........................................................................................56
9.4.1.5.
Exploratory Efficacy Endpoints.........................................................................56
9.4.1.6.
Exploratory Efficacy Analyses...........................................................................58
9.4.2.
Safety Analyses...............................................................................................................58
9.4.2.1.
Adverse Events...................................................................................................58
9.4.2.2.
Vital Signs..........................................................................................................59
9.4.2.3.
Electrocardiograms.............................................................................................59
9.4.2.4.
Hematology/Chemistry Laboratory Testing.......................................................59
9.4.3.
Other Analyses................................................................................................................59
9.4.3.1.
Immunogenicity Analyses..................................................................................59
9.5.
Interim Analyses.............................................................................................................59
10.
Supporting Documentation and Operational Considerations..................................60
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................61
10.1.1.
Regulatory and Ethical Considerations...........................................................................61
10.1.2.
Financial Disclosure........................................................................................................61
10.1.3.
Informed Consent Process ..............................................................................................62
10.1.4.
Data Protection................................................................................................................62
10.1.5.
Posting Clinical Study Data............................................................................................62
10.1.6.
Data Quality Assurance ..................................................................................................63
10.1.7.
Source Documents ..........................................................................................................63
10.1.8.
Study and Site Closure....................................................................................................63
10.1.10. Compliance with Protocol...............................................................................................64
10.2.
Appendix 2: Clinical Laboratory Tests...........................................................................65
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................66
Definition of AE ............................................................................................................................66
Definition of SAE ..........................................................................................................................68
Recording and Follow-Up of AEs and/or SAEs............................................................................69
Reporting of SAEs.........................................................................................................................71
10.4.
Appendix 4: Abbreviations.............................................................................................72
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10.10.
Appendix 10: Protocol Amendment History ..................................................................97
11.
References....................................................................................................................103
List of Tables
Table 8-1
Expected Adverse Reactions for Treatment of Glabellar Lines ........................... 45
Table 8-2
Expected Adverse Reactions for Treatment of Lateral Canthal Lines ................. 46
Table 10–1
Protocol-required Safety Laboratory Assessments............................................... 65
List of Figures
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1.
Protocol Summary
1.1.
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 With or Without Concurrent Treatment of Lateral Canthal Lines
Protocol Number: MT10109L-005
Brief Title: MT10109L in the Treatment of Glabellar Lines With or Without Concurrent 
Treatment of Lateral Canthal 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) with or without concurrent treatment of
lateral canthal lines (LCL) in participants with moderate to severe GL and LCL
 
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Number of Participants:
Approximately 375 participants will be enrolled in order to have 318 participants complete the 
study based on an anticipated dropout rate of 15%.
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 before 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 intramuscular injections of MT10109L 20 U 
(MT10109L in GL area, placebo in LCL area), MT10109L 44 U (20 U in GL area and 
24 U in LCL area), or placebo (placebo in both GL and LCL areas). 

During the retreatment period (from Day 180 through Day 330), participants who meet 
retreatment criteria will receive up to 2 blinded interventions of the same study 
intervention received in the first period (MT10109L 20 U, 44 U, or placebo). 
Data Monitoring Committee: No
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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).
2.3.
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. 
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In some cases, botulinum toxin effect may be observed beyond the site of local injection. The 
symptoms may include asthenia, generalized muscle weakness, diplopia, eyelid ptosis, 
dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. Swallowing 
and breathing difficulties can be life threatening, and there have been reports of death related to 
distant spread of toxin effects with other BoNT/A treatments for noncosmetic indications. The 
risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also 
occur in adults treated for spasticity and other conditions. 
Reduced blinking after BoNT/A product injection to the orbicularis muscle can lead to corneal 
exposure, persistent epithelial defect, and corneal ulceration with perforation. In the use of 
another BoNT/A product for treatment of blepharospasm, 1 case of corneal perforation in an 
aphakic eye requiring corneal grafting has occurred because of this effect.
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4.
Study Design
4.1.
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 with or without concurrent treatment of LCL. 
Participants may receive up to 3 interventions. 

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]) and bilaterally symmetrical moderate to 
severe LCL at maximum smile (same grade on both sides of the face as assessed by the 
investigator only).
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
Participants who complete the study will have an exit visit at Day 360.

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 (Day −28 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)
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 (for GL) and 44 U (20 U for GL and 24 U for LCL) have an acceptable safety 
profile after single and retreatments.
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4.4.
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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5.
Study Population
Adult participants in the current study have moderate to severe GL at maximum frown and 
moderate to severe LCL at maximum smile 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.
5.1.
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
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 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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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
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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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6.2.
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.
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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6.5.3.
Rescue Medicine
Rescue medicine is not applicable.
6.6.
Dose Modification
This protocol does not allow for alteration from the currently outlined dosing schedule.
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7.2.
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.
7.3.
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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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

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.

All assessments, including photography, must be completed after the participant removes 
their make-up (if wearing any) and before administration of study intervention.
8.1.
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 
and LCL at rest and maximum smile using the validated FWS, based on the following scale:
0 = None
1 = Mild
2 = Moderate
3 = Severe
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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 (as defined in Section 7.3).
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 
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8.4.
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 
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, or 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.
8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
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8.9.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.
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9.
Statistical Considerations
9.1.
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 
and 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 ≥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 ≥2-grade 
improvement from baseline based on both the investigator- and participant-rated FWS at 
Day 30.
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10.
Supporting Documentation and Operational Considerations
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10.1.
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

Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor. 

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 
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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10.2.
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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10.4.
Appendix 4: Abbreviations
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
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
DVD
digital versatile disc
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EU
European Union
FDA
US Food and Drug Administration
FHL
forehead lines
FLO-11
11-Item Facial Line Outcomes
FLSQ
Facial Line Satisfaction Questionnaire
FSH
follicle-stimulating hormone
FWS
Facial Wrinkle Scale With Photonumeric Guide
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GL
glabellar lines
HEENT
head, eyes, ear, nose, and throat
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormonal replacement therapy
IB
investigator’s brochure
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Section No. and Name
Description of Change
Brief Rationale
1.3 (Schedule of 
Activities)
Vital sign measurements, electrocardiogram (ECG) 
assessments, and collection of blood samples for 
hematology and chemistry testing were added for 
Days 30 and 120
Updated per 
recommendation 
by health 
authority
1.3 (Schedule of 
Activities)
New columns were added for 30 and 90 days after 
retreatment
Improve clarity
1.3 (Schedule of 
Activities)
Vital sign measurements were added for 30 days 
after each retreatment; ECG assessments were 
added for the days of Retreatments 1 and 2 and 30 
days after each retreatment
Updated per 
recommendation 
by health 
authority
1.3 (Schedule of 
Activities)
Modified and added footnotes 
Improve clarity
3 (Objectives and 
Endpoints)
Added statement to provide additional detail on 
exploratory endpoints
Updated per 
recommendation 
by health 
authority
5.4 (Screen Failures)
Rescreening criteria were clarified
Improve clarity
6.1.2 (Instructions for 
Use and 
Administration)
Added text to clarify required qualification and 
training of physicians
Updated per 
recommendation 
by health 
authority
8 (Study Assessments 
and Procedures)
Updated the amount of blood collected during the 
study for each participant
Update
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
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11.
References
Beer KR. Comparative evaluation of the safety and efficacy of botulinum toxin type A and 
topical creams for treating moderate-to-severe glabellar rhytids. Dermatol Surg. 
2006;32:184-192.
Blitzer A, Brin MF, Keen MS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional 
lines of the face. Arch Otolaryngol Head Neck Surg. 1993;119:1018-1022.
BOTOX® Cosmetic (onabotulinumtoxinA) for injection [package insert]. Irvine, CA: Allergan, 
Inc; September 2017.
Brin MF, Boodhoo TI, Pogoda JM, James LM, Demos G, Terashima Y, et al. Safety and 
tolerability of onabotulinumtoxinA in the treatment of facial lines: A meta-analysis of individual 
patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol. 
2009;61:961-970.e1-11.
Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W. Gatekeeping strategies. In: Analysis 
of clinical trials using SAS: a practical guide. Cary, NC: SAS Institute; 2005. p. 104-108.
Finn CJ, Cox SE, Earl ML. Social implications of hyperfunctional facial lines. Dermatol Surg. 
2003;29:450-455. 
Farage MA, Miller KW, Berardesca E, Maibach HI. Psychological and Social Implications of 
Aging Skin: Normal Aging and the Effects of Cutaneous Disease. In: Farage MA, Miller KW, 
Maibach HI, editors. Textbook of Aging Skin. Springer; New York, New York: 2010;949-957.
Ferreira MC, Salles AG, Gimenez R, Soares MFD. Complications with the use of botulinum 
toxin type A in facial rejuvenation: report of 8 cases. Aesthet Plast Surg. 2004;28:441-444.
Garcia A, Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum 
toxin: A dose-response study. Dermatol Surg. 1996;22:39-43. 
Khan JA. Aesthetic surgery: Diagnosing and healing the miscues of human facial expression. 
Ophthal Plastic Reconstr Surg. 2001;17:4-6.
Koblenzer CS. Psychologic aspects of aging and the skin. Clin Dermatol. 1996;14:171-177.
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.
Approval Date: 30-Sep-2020 22:55:16 (GMT)


Electronic Signatures
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SAP_003.pdf: 
Page 1
MT10109L-005
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1.0
TITLE PAGE
MT10109L-005
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 with or without Concurrent Treatment of Lateral Canthal Lines
STATISTICAL ANALYSIS PLAN - Clinical Study Report
[Final]: [18 NOV 2020]
Confidentiality Statement
This document is the property of Allergan, Inc., and may notin full or partbe passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, Inc.




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15.8
Missing Date Information for Adverse Events................................................................................35
15.9
Missing Date Information for Prior or Concomitant Medications ..................................................36
17.0
REFERENCES..............................................................................................................................................38
18.0
HISTORY OF CHANGES............................................................................................................................39


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse events of special interest
ALT
Alanine Aminotransferase
ANCOVA
analysis of covariance
AST
Aspartate Aminotransferase
CMH
Cochran-Mantel-Haenszel
CRF
case report form
ECG
electrocardiogram, electrocardiographic
EU
European Union
eCRF
electronic case report form
FLO-11
Facial Line Outcomes Questionnaire
FLSQ
Facial Line Satisfaction Questionnaire
FWS
Facial Wrinkle Scale
GL
glabellar lines
ITT
intent to treat
LCL
lateral canthal lines
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
PDSOT
possible distant spread of toxin
Q1
25th percentile
Q3
75th percentile
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
RBC
Red blood cell


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SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SI
Le Système International d’Unités (International System of Units)
TEAE
treatment-emergent adverse event
UFL
upper facial line
WBC
White blood cell




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C
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5.0
OBJECTIVES
The objectives of this study are to evaluate the safety and efficacy of MT10109L versus placebo 
in the treatment of participants of GL with or without concurrent treatment of LCL.




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7.0
PARTICIPANT DISPOSITION
The number and percentage of participants in the 3 study populations (ITT, 
safety) 
will be summarized by treatment group and overall; the number of participants screened and 
randomized will be summarized by study center.
The number of participants screened will be summarized overall. The number and percentage of 
participants who were randomized, treated, or who completed the study and prematurely 
discontinued will be presented for each treatment group and pooled across treatment groups. A 
frequency table showing participant disposition (continuing, entered to the next cycle, 
completed, discontinued) will also be provided for all analysis populations for each treatment 
cycle.
Tabulation of the numbers and percentages of participants in each exit status category (i.e., 
adverse event, pregnancy, lost to follow-up, personal reasons, protocol violations and other) will 
be provided for each treatment group for entire study and by treatment cycle for all analysis 
populations. Discontinued participants will be listed along with the corresponding reason(s) for 
early withdrawal from the study.




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9.0
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
EXTENT OF EXPOSURE
Participants’ exposure to study intervention will be summarized by total duration of treatment 
exposure and by cycle
 
 and by number of treatments received.




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The following hypothesis will be used to compare the MT10109L groups 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-rated and participant-rated 
FWS at Day 30 of Treatment Cycle 1.

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-rated and 
participant-rated FWS at Day 30 of Treatment Cycle 1.


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Analyses of the secondary efficacy variables will be performed for all study visits using observed 
data, with the primary time-point at Day 30 of the Treatment Cycle 1
 


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11.2
CLINICAL LABORATORY PARAMETERS
Study baseline is defined to be the data measured before dosing on Day 1. Descriptive statistics 
(n, mean, standard deviation, minimum, median, and maximum) for clinical laboratory values at 
baseline, and change from baseline at post-baseline visits will be summarized, in SI units 
(System of International Units), for all continuous clinical laboratory parameters specified 
below. 
The clinical laboratory parameters include the following:
Hematology:
Hemoglobin, hematocrit, red blood cell count (RBC), RBC morphology,
white blood cell count (WBC), neutrophils, lymphocytes, monocytes, 
basophils, eosonophils, and platelets




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11.7
PREGNANCY TESTS
Urine pregnancy tests are performed prior to treatment and at exit visit for females of 
childbearing potential. Participants with positive pregnancy test results will be listed by 
treatment group, including urine sample collection date, and days since most recent treatment.
11.8
IMPACT DUE TO COVID-19
Participants discontinued related to COVID-19 will be listed.
The description of impact to visit assessment due to COVID-19 (missed, remote audio visit, etc.)
will be listed.
For participants affected by COVID-19, their COVID-19 status, COVID-19 supplemental signs
and symptoms will be listed.


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12.0
INTERIM ANALYSIS
No interim analysis is planned for this study.




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14.0
STATISTICAL SOFTWARE
Statistical analyses will be performed using version 9.3 (or newer) of SAS on a Linux operating 
system.


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15.5
REPEATED 
OR 
UNSCHEDULED 
ASSESSMENTS 
OF 
SAFETY 
PARAMETERS
If a participant has repeated assessments before the start of the first treatment, the results from 
the final nonmissing assessment made prior to the start of the study intervention will be used as 
baseline. If end-of-study assessments are repeated or if unscheduled visits occur, the last 
nonmissing postbaseline assessment will be used as the end-of-study assessment for generating 
summary statistics.
15.6
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned. If severity is missing for an AE that started on or after the 
date of the first dose of study intervention, an intensity of severe will be assigned. The imputed 
values for severity assessment will be used for the incidence summary; the values will be shown 
as missing in the data listings.
15.7
MISSING CAUSAL RELATIONSHIP TO STUDY INTERVENTION FOR 
ADVERSE EVENTS
If the causal relationship to the study intervention is missing for an AE that started on or after the 
date of the first dose of study intervention , a causality of yes will be assigned. The imputed 
values for causal relationship to study intervention will be used for the incidence summary; the 
values will be shown as missing in the data listings.
15.8
MISSING DATE INFORMATION FOR ADVERSE EVENTS
Partial adverse event onset date will be imputed as follows: 1) if day is missing but month is not, 
impute the date as the first day of the month; 2) if both day and month are missing, impute the 
date as 01 Jan; 3) if imputed onset date is before the first treatment, yet the corresponding 
adverse event was not observed pre-treatment, then impute the onset date as the first treatment 
date. Imputed partial adverse event onset date will only be used to determine the adverse event 
onset cycle.
Other partial adverse event dates will not be imputed. All partial dates will be listed “as is” in the 
data listings.


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15.9
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT 
MEDICATIONS
There will be no imputation for missing or partially reported medication start and/or end dates. 
However, reported partial information will be utilized in classification of prior and concomitant 
medications, when appropriate. For example, a medication may be classified as a pre-study 
medication if the partial end date provided is determined to definitively have occurred prior to 
the study intervention date (for example, the partial end date provided is “2017”, and Day 1 
occurred on August 29, 2018).
If start and/or stop dates for medications are only partially reported but can be classified as 
having occurred prior to Day 1, then the medications will be included in this summary of prior
medications.
If stop dates for medications are only partially reported and cannot be definitively classified as 
having occurred prior to Day 1, then the medications will be included in this summary of
concomitant medications.


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17.0
REFERENCES
Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W. Gatekeeping strategies. In: Analysis 
of clinical trials using SAS: a practical guide. Cary, NC: SAS Institute; 2005. p. 104-108.
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.




Electronic Signatures