A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of MT10109L (NivobotulinumtoxinA) for the Treatment of Lateral Canthal Lines With or Without Concurrent Treatment of Glabellar Lines
Phase: PHASE3
Conditions: Lateral Canthal Lines, Glabellar Lines
Sponsor: Medy-Tox



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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 4
September 2020
Amendment 3
March 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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Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes Table .........................................................................3
Table of Contents...........................................................................................................................4
List of Tables ...................................................................................................................................7
List of Figures..................................................................................................................................7
1.
Protocol Summary..........................................................................................................8
1.1.
Synopsis............................................................................................................................8
1.2.
Schema............................................................................................................................12
1.3.
Schedule of Activities (SoA)..........................................................................................13
2.
Introduction...................................................................................................................17
2.1.
Study Rationale...............................................................................................................17
2.2.
Background.....................................................................................................................17
2.3.
Benefit/Risk Assessment ................................................................................................18
3.
Objectives and Endpoints ............................................................................................20
4.
Study Design..................................................................................................................22
4.1.
Overall Design................................................................................................................22
4.1.1.
Clinical Hypotheses ........................................................................................................23
4.2.
Scientific Rationale for Study Design ............................................................................23
4.3.
Justification for Dose......................................................................................................23
4.4.
End of Study Definition..................................................................................................24
5.
Study Population...........................................................................................................25
5.1.
Inclusion Criteria ............................................................................................................25
5.2.
Exclusion Criteria ...........................................................................................................26
Rationale for Inclusion and Exclusion Criteria..............................................................................28
5.3.
Lifestyle Considerations .................................................................................................28
5.4.
Screen Failures................................................................................................................29
6.
Study Intervention........................................................................................................30
6.1.
Study Interventions Administered ..................................................................................30
6.1.1.
Study Supplies ................................................................................................................30
6.1.2.
Instructions for Use and Administration.........................................................................31
6.2.
Preparation/Handling/Storage/Accountability................................................................34
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................34
6.4.
Study Intervention Compliance ......................................................................................35
6.5.
Concomitant Therapy .....................................................................................................35
6.5.1.
Prohibited Interventions..................................................................................................35
6.5.2.
Permitted Interventions...................................................................................................36
6.5.3.
Rescue Medicine.............................................................................................................36
6.6.
Dose Modification ..........................................................................................................37
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9.4.1.
Efficacy Analyses ...........................................................................................................52
9.4.1.1.
Primary Efficacy Endpoints ...............................................................................52
9.4.1.2.
Primary Analyses ...............................................................................................52
9.4.1.3.
Secondary Efficacy Endpoints ...........................................................................54
9.4.1.4.
Secondary Analyses ...........................................................................................55
9.4.1.5.
Exploratory Efficacy Endpoints.........................................................................56
9.4.1.6.
Exploratory Efficacy Analyses...........................................................................57
9.4.2.
Safety Analyses...............................................................................................................57
9.4.2.1.
Adverse Events...................................................................................................57
9.4.2.2.
Vital Signs..........................................................................................................58
9.4.2.3.
Electrocardiograms.............................................................................................58
9.4.2.4.
Hematology/Chemistry Laboratory Testing.......................................................58
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
10.1.9.
Publication Policy...........................................................................................................64
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.........................................................................................................................70
10.4.
Appendix 4: Abbreviations.............................................................................................71
10.5.
Appendix 5: Standard Discontinuation Criteria..............................................................73
10.6.
Appendix 6: Study Tabular Summary............................................................................75
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................77
Definitions: ....................................................................................................................................77
Contraception Guidance: ...............................................................................................................77
Pregnancy Testing:.........................................................................................................................79
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1.3.
Schedule of Activities (SoA)
All Participants
Only Participants Meeting Retreatment Criteriaa
All 
Participants
Study Period
Screeningb
Randomization
Treatment
(Day 1)c
Follow
-up
(Day 7
and 
Day 
14)
Days 
30, 
60, 
90, 
120, 
150
Day 
180
Days 
210, 
240, 
270, 
300, 
330
Retreatment
1 and 
Retreatment 
2 (from Day 
180 through 
Day 330)c,d,e
Follow-up
(Day 7 and 
Day 14 after 
each 
retreatment)
Follow-up 
(Day 30
after each 
retreatment)e
Follow-up 
(Day 90
after each 
retreatment)e
End of 
Study 
(Day 360 or
Early Exit)
Visit Windows
Days −28
to −1
-
± 3 
days
± 7 
days
± 7 
days
± 7 
days
-
± 3 days
± 7 days
± 7 days
± 7 days
Consent/
Authorization
X
Demographics, 
Weight/ Height
X
Inclusion/
Exclusion 
Criteria
X
X
Medical/
Surgical History
X
FLO-11©
X
X
X
X
X
X
X
X
X
X
FLSQ©
(Baseline)f
X
FLSQ (Follow-
up)
X
X
X
X
X
X
X
X
X
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GRD-CLN-T-01-01 v2.0
Note: Participants completing this study through Day 360 will be eligible to enroll into a 2-year open-label extension study (Study MT10109L-004).
ECG = electrocardiogram; FLO-11 = 11-item Facial Line Outcomes Questionnaire; FLSQ = Facial Line Satisfaction Questionnaire; FWS = Facial Wrinkle Scale with Photonumeric Guide; 
GL = glabellar lines; LCL = lateral canthal lines (or crow’s feet lines)
a Participants who meet retreatment criteria will receive up to 2 blinded study interventions of the same study intervention that they received on Day 1. 
b All screening procedures must be completed up to 28 days before Day 1, and the results must be available to the investigator before randomization on Day 1
c All assessments (including photography and immunogenicity samples, if applicable) must be completed before administration of study intervention.
d Retreatment 1 cannot be administered earlier than the Day 180 visit; Retreatment 2 cannot be administered earlier than 84 days since administration of Retreatment 1 and no later than Day 330.
e If a procedure or assessment has already been performed as part of a scheduled visit, it must not be repeated.
f LCL at maximum smile and at rest; GL at maximum frown and at rest.
g To be randomized into the study, participants must meet Inclusion Criterion 2.01 both at the Screening Visit and prior to randomization at the Day 1 Visit.
h
i Vital sign measurements are pulse rate, respiration rate, and blood pressure. Participants are to be seated for at least 2 minutes before measurements are collected.
j Only on Days 30 and 120
k Women of childbearing potential must have a negative pregnancy test. Investigator may ask participant to perform urine pregnancy test at any visit. At each visit, the investigator must discuss 
compliance with contraceptive use with women of childbearing potential.
l Single ECG traces will be taken with the participant in a semirecumbent position for ≥10 minutes before starting the tracing.
n Participants must be observed for ≥30 minutes after each study intervention for adverse events.
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
Photographic equipment (including headbands and drapes) will be provided by a qualified 
third-party vendor

Laboratory sample kits (for immunogenicity and hematology/chemistry sampling) will be 
provided by a qualified third-party vendor

Electrocardiogram equipment and supplies will be provided by a qualified third-party vendor

Tablets for electronic PRO administration will be provided by a qualified third-party vendor
The following will be provided by the investigator:

Urine pregnancy test kits (sensitivity of 25 mIU/mL)

Cotton pads and make-up remover

Appropriately sized sterile needles fitted to 1 mL sterile syringes with 0.01 mL demarcations 
for extraction of liquid study intervention from vial

Half-inch 30-gauge sterile needles for study intervention injection

Alcohol wipes

Protective gloves 

Penlight

Covered container for medical waste (sharps box) 

Refrigerator to store study intervention with a temperature between 2° and 8°C

Internet connection (high speed connection for eCRF completion)

Monitor and DVD player for viewing participant instructions

Centrifuge for separation of serum 

Freezer, that does not automatically defrost, to store blood samples at a temperature of −20°C 
or colder
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 LCL and GL 
injections are provided to investigators via a video recording from a board-certified plastic 
surgeon with injection demonstration, and review of injection techniques as outlined in the 
protocol. The video is available on the training portal for injectors to access at any time as a 
refresher course. The investigator must maintain documentation of training records for all study 
personnel.
There will be up to 3 treatments in the study. In the first treatment period (Day 1 to Day 180), all 
participants will receive blinded treatment on Day 1, either MT10109L 24 U, 44 U, or placebo. 
In the retreatment period (from Day 180 through Day 330), all participants will receive up to 
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2 interventions of MT10109L 24 U, 44 U, or placebo (same as blinded Treatment 1) based on 
meeting the retreatment criteria.
The LCL study interventions will be administered as bilaterally symmetrical IM injections at 
3 injection sites in the lateral aspect of each orbicularis oculi (Figure 6-1A). 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 (Figure 6-3A). Lateral canthal lines and GL 
will be treated together, following the appropriate injection technique for each area, as described 
below.
Participants must be observed for adverse events for ≥30 minutes after each study intervention.
Lateral Canthal Line Injection Technique
Each injection volume is 0.1 mL, for a total of 0.6 mL. Lateral canthal lines injections must be 
given with the needle-tip bevel up and oriented away from the eye. The first injection will be 
made into the orbicularis oculi at the level of the lateral canthus, ≥1.5 to 2.0 cm temporal to the 
lateral canthus and just temporal to the lateral orbital rim (Figure 6-1B, Point A). The second and
third injections will be made 1.0 to 1.5 cm above and below the first injection site, each at an 
approximate 30angle medially. Repeat this procedure for the contralateral side.
If the lines in the lateral canthal area are primarily below the lateral canthus, injection sites may 
be given in a line that angles from anteroinferior to superposterior, but the most anterior injection 
will be lateral to a line drawn vertically from lateral canthus, and the most inferior injection will
be superior to the maxillary prominence (Figure 6-2). Repeat this procedure for the contralateral 
side.
Figure 6-1
(A) The Orbicularis Oculi (Lateral Canthal Line Area) on 1 Side of the Face and 
(B) Injection Pattern when Lateral Canthal Lines are Distributed Above and Below the 
Lateral Canthus 
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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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
At the Screening Visit, each participant who provides informed consent will be assigned a 
participant number that will serve as the participant identification number on all study 
documents.
An automated IWRS will be used to manage the randomization and study intervention
assignment based on a randomization scheme prepared by the sponsor’s biostatistics department. 
Before administering study intervention, the site must contact the IWRS and enter the site 
number and the participant’s enrollment stratification information 
 
The IWRS will then randomly assign participants to receive 
MT10109L 24 U, 44 U, or placebo in a 2:2:1 ratio. Once a randomization number has been 
assigned, it must not be re-assigned. In addition, withdrawn study participants cannot be 
replaced.
Study intervention will be labeled with study kit numbers. The IWRS system will provide the 
site with the specific medication kit numbers for each randomized participant at the time of 
randomization. Study sites will dispense study intervention according to IWRS instructions. 
Study sites will also contact the IWRS at subsequent retreatment visits (if applicable) to obtain 
study kit numbers for dispensing study intervention. Study sites will receive the IWRS 
confirmation notifications for each transaction. All notifications are to be maintained with the 
study source documents.
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The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s study 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a participant’s 
study intervention assignment unless this could delay emergency treatment of the participant. If a 
participant’s study intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation.
6.4.
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.
6.5.
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 sponsor.
6.5.1.
Prohibited Interventions
The decision to administer a prohibited medication/treatment is done with the safety of the 
participant as the primary consideration. When possible, the sponsor must be notified before the 
prohibited medication/treatment is administered. Co-administration of aminoglycosides or agents 
that could interfere with neuromuscular transmission (eg, curare-like agents) or muscle relaxants 
must be used with caution as the effects of the toxin, theoretically, could be potentiated.
No other facial cosmetic procedures or treatments are to be performed throughout the duration of 
the study. Prohibited treatments and procedures include, but are not limited to:

Oral retinoids

New or changes to regimen of topical hormone cream to the face

New or changes to regimen of topical retinoids to the face

Microdermabrasion to the face
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
Medium depth to deep facial chemical peels (ie, TCA and phenol)

Laser treatment, ultrasound treatment, or resurfacing to the face

Facial lift (mid or full face)

Blepharoplasty

Synthetic implantation (eg, Gore-Tex) to the upper half of the face

Autologous fat transplantation to the face

Dermal fillers to the face

Permanent make-up to the face

Concurrent treatment with botulinum toxin of any serotype for any indication (other than the 
study intervention) is prohibited.
6.5.2.
Permitted Interventions
Any medication or vaccine (including prescription or over-the-counter medication, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor.
The sponsor must be contacted if there are any questions regarding concomitant or prior therapy.
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the end of study visit will be recorded in the eCRF as a concomitant medication; 
any medication started after the end of study visit will not be considered a concomitant 
medication and should not be captured in the eCRF.
6.5.3.
Rescue Medicine
Rescue medicine is not applicable.
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7.
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.
Definitions of the standard terms are provided in Appendix 5.
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
7.1.
Discontinuation of Study Intervention
Study intervention should be discontinued for the following reasons:

Pregnancy (see Appendix 7 and Section 8.3.5)

Other safety criteria (eg, hypersensitivity to the study intervention, failure to continue to meet 
randomization 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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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.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.
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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.

The amount of blood collected from each participant throughout this 12-month study will be
approximately 220 mL. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples.

Blood samples may be stored for a maximum of 5 years following finalization of the study’s 
final CSR. Samples will then be disposed. 

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 LCL at rest and maximum smile
and investigators’ 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
The FWS with investigator-oriented instructions and the FWS with participant-oriented 
instructions will be provided by the sponsor to each study site. Both versions of the FWS provide 
photographic examples of LCL severity at rest and at maximum smile and GL severity at rest 
and maximum frown. Prior to enrolling participants, investigators and appropriate site personnel
will be trained in grading LCL and GL severity using the FWS to ensure that severity is graded 
consistently at each site and across all sites.
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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 (see Section 8.3.6) 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.
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reference safety information or protocol for the study intervention or comparator as applicable. 
See Section 8.4 for information of treatment of overdose.
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol. 
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 not likely 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, 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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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.
If more than 1 adverse event is coded to the same preferred term for the same participant, the 
participant will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarizations by severity and by relationship to study intervention.
The number and percentage of participants reporting TEAEs that are included in the PDSOT 
term list will be tabulated by study intervention. The PDSOT term list will be provided by the 
MSP.
The PDSOT will be reviewed by the MSP in a timely fashion for monitoring severity, frequency, 
and trending.
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.
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. 
QTc interval will be calculated using both Bazett (QTcB = QT/[RR]½) and Fridericia 
(QTcF = QT/[RR]⅓) corrections; if RR is not available, it will be replaced with 60/heart rate in 
the correction formula. 
Data listings, which include ECG basic parameters and ECG abnormalities, will be produced.
9.4.2.4.
Hematology/Chemistry Laboratory Testing
Descriptive statistics (n, mean, SD, median, minimum, and maximum) for clinical laboratory 
values at baseline and change from baseline at postbaseline visits will be summarized in SI units 
by study intervention and by visit.
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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.
9.5.
Interim Analyses
No interim analysis is planned.
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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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10.2.
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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ICH
International Conference on Harmonisation
IEC
institutional ethics committee
IM
intramuscular
IND
investigational new drug application
IRB
institutional review board
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
LCL
lateral canthal lines
LD50
median lethal intraperitoneal dose
LLN
lower limit of normal value provided by the laboratory
MCMC
Markov chain Monte Carlo
mITT
modified intent-to-treat
MSP
medical safety physician
PDSOT
possible distant spread of toxin
PRO
patient-reported outcome
RBC
red blood cell
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
U
unit
UFL
upper facial lines
ULN
upper limit of normal value provided by the laboratory
WBC
white blood cell
WOCBP
woman of childbearing potential
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CDISC Submission Value
CDISC Definition
Protocol deviation
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI)
Recovery
A healing process and/or an outcome implying 
relative health. The term is typically used in the 
context of direct and indirect effects of sickness 
or injury. (NCI)
Screen failure
The potential subject who does not meet one or 
more criteria required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at 
a particular site by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by 
its sponsor (NCI)
Technical problems
A problem with some technical aspect of a 
clinical study, usually related to an instrument 
(NCI)
Withdrawal by parent/guardian
An indication that a study participant has been 
removed from the study by the parent or legal 
guardian
Withdrawal by subject
An indication that a study participant has 
removed itself from the study (NCI)
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Table 10-2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 

Oral 

Intravaginal 

Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral 

Injectable 
Highly Effective Methods That Are User Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

IUD

IUS

Etonogestrel implant (ie, Nexplanon®)
Bilateral tubal occlusion
Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
Table 10-3
Acceptable Contraceptive Methods
Acceptable Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide 

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
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Section No. and Name
Description of Change
Brief Rationale
Appendix 7 (Table 10-3)
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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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; October 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. SAS Institute; Cary, North Carolina: 
2005;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;949-958.
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. Wileys;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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