Clinical trial NCT04949399
Conditions: Platysma Prominence
Keywords: Platysma Prominence OnabotulinumtoxinA BOTOX
Sponsor: AbbVie
Start date: 2021-07-08; Completion date: 2022-12-20
Enrollment: 408 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the safety and effects of onabotulinumtoxinA (BOTOX) for the temporary improvement in the appearance of platysma prominence.

Study doctors will randomize participants into 1 of the 2 groups, called treatment arms. There is a 1 in 2 chance that a participant will be assigned to placebo. Around 400 participants will be enrolled in the study in the United States and Canada.

Participants will receive a single treatment of intramuscular injection of onabotulinumtoxinA (BOTOX) or placebo on Day 1 during this 4 month long study.

Participants will attend regular monthly visits during the study at the study site.

Detailed description:

Arms: arm 1: BOTOX (OnabotulinumtoxinA) was injected into the platysma muscle on Day 1 arm 2: Placebo will be injected into the platysma muscle on Day 1
Interventions: intervention 1: OnabotulinumtoxinA intervention 2: Placebo
Intervention descriptions: intervention 1: Injection intervention 2: Saline Injection

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
10
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
10
3.2
PRIMARY ENDPOINTS
14
3.3
SECONDARY ENDPOINTS
15
3.4
ADDITIONAL ENDPOINTS
15
3.5
SAFETY ENDPOINTS
16
4
INVESTIGATIONAL PLAN
16
4.1
OVERALL STUDY DESIGN AND PLAN
16
4.2
DISCUSSION OF STUDY DESIGN
17
5
STUDY ACTIVITIES
18
5.1
ELIGIBILITY CRITERIA
18
5.2
CONTRACEPTION RECOMMENDATIONS
21
5.3
PROHIBITED MEDICATIONS AND THERAPY
23
5.4
PRIOR AND CONCOMITANT THERAPY
23
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
24
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
26
5.7
STUDY DRUG
26
5.8
RANDOMIZATION/DRUG ASSIGNMENT
29
5.9
PROTOCOL DEVIATIONS
30
5.10 DATA MONITORING COMMITTEE
30
6
SAFETY CONSIDERATIONS
30
6.1
COMPLAINTS AND ADVERSE EVENTS
30
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
34
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7.1
STATISTICAL AND ANALYTICAL PLANS
34
7.2
DEFINITION FOR ANALYSIS POPULATIONS
34
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
35
7.4
STATISTICAL ANALYSES FOR EFFICACY
36
7.5
STATISTICAL ANALYSES FOR SAFETY
37
7.6
INTERIM ANALYSIS
38
7.7
OVERALL TYPE I ERROR CONTROL
38
7.8
SAMPLE SIZE DETERMINATION
39
8
ETHICS
39
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
39
8.2
ETHICAL CONDUCT OF THE STUDY
40
8.3
SUBJECT CONFIDENTIALITY
40
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
40
10 DATA QUALITY ASSURANCE
40
11 COMPLETION OF THE STUDY
40
12 REFERENCES
41
LIST OF TABLES
TABLE 1.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY EFFICACY ENDPOINTS
11
TABLE 2.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE SECONDARY ENDPOINTS
12
TABLE 3.
STUDY FORMULATIONS AND DILUTION INSTRUCTIONS
28
LIST OF FIGURES
FIGURE 1.
THE PLATYSMA MUSCLE: ANTERIOR AND POSTERIOR MARGINS OF THE PLATYSMA MUSCLE
SHEETS
7
FIGURE 2.
STUDY SCHEMATIC
17
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
43
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
45
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
46
APPENDIX D.
ACTIVITY SCHEDULE
47
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
49
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
BOTOX was first approved for aesthetic treatment of glabellar lines in 2001, lateral canthal lines (crow's 
feet lines) in 2013, and forehead lines in 2017.  BOTOX is one of the most common nonsurgical 
procedures in aesthetic medicine1.
 the medical literature has described the use of BOTOX to improve the 
appearance of the lower face and neck.  Numerous publications specifically report the use of BOTOX to 
improve the appearance of the lower face by minimizing the effects of platysma muscle contraction. 
The platysma muscle complex is composed of 2 separate, superficial muscle sheets that originate from 
the fascia of the upper thoracic region and pass upward over both sides of the neck, crossing over the 
mandibular border and inserting into the overlying skin of the neck and lower face.  When relaxed, the 
platysma muscle smoothly drapes the jawline, neck, and clavicle to create a firm, fitted, and uniform 
appearance (Figure 1). 
Figure 1.
The Platysma Muscle: Anterior and Posterior Margins of the Platysma Muscle 
Sheets
Source:  4.
 
 
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Allergan sponsored a Phase 2 study (1936-201-008) designed to evaluate BOTOX for the treatment of 
platysma prominence.  This was a 4-month, multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging study, comparing the efficacy and safety between a single treatment of BOTOX high dose 
 or BOTOX low dose 
 versus placebo in 171 subjects with moderate to severe 
platysma prominence.
Subjects were adults ≥18 years old 
and moderate to severe 
platysma prominence, as rated at maximum contraction by both the investigator and subject using 
Allergan's platysma prominence scales.  Subjects were excluded from the study if 
had increased medical risk with exposure to BOTOX.  Subjects received a single treatment at baseline 
(Day 1) and were followed for approximately 120 days.
The primary and secondary efficacy endpoints, ≥1-grade improvement from baseline in platysma 
prominence severity at Day 14, assessed independently by Clinician Allergan Platysma Prominence Scale
(C-APPS) and Participant Allergan Platysma Prominence Scale (P-APPS), respectively, were achieved.  
Both high and low dose BOTOX results were statistically significant compared with placebo (p < 0.0001).  
Similar results were observed with other study endpoints, which included patient reported outcome 
(PRO) measures 
, corroborating the C-APPS and P-APPS data.  
The safety profile observed was consistent with that reported in the medical literature and with the 
known pharmacological effects of BOTOX.  The most frequently reported AEs related to the study 
procedure were balanced across all treatment groups and included injection site hemorrhage (6/169, 
3.6%) and injection site bruising (11/169, 6.5%).  
 
 
 
 
While AbbVie does not consider coronavirus disease 2019 (COVID-19) to be a safety concern for BOTOX 
due to its mechanism of action and route of administration, the sponsor is monitoring COVID-19 events 
during the pandemic closely. A recent review of COVID-19 events for the periodic safety update report 
(PSUR) 
 did not identify any new or significant 
safety findings for the subjects receiving BOTOX treatment. Overall, the clinical course and presentation 
of patients with COVID-19 infection coincident with BOTOX is consistent with what has been described 
for the general population.
Considering the COVID-19 pandemic, based on the limited information to date, no additional risk to 
study participants is anticipated with the use of BOTOX.
For further details, please see findings from completed studies, including safety data in the current 
BOTOX Investigator's Brochure.
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3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
The study objective is to compare the safety and efficacy of BOTOX with placebo for the treatment of 
platysma prominence in adult subjects with moderate to severe platysma prominence at maximum 
contraction.
The clinical hypothesis is that BOTOX is a safe and effective treatment for the temporary improvement 
in the appearance associated with moderate to severe platysma prominence in adults.
Estimands: Primary Endpoints
The attributes of the estimands corresponding to the primary efficacy endpoints are summarized in 
Table 1.
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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Variable 
(Endpoint)
Population
Handling of 
Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
primary 
endpoint 
Single dose 
of BOTOX 
 
 
or 
placebo 
Composite 
achievement of a
Grade 1 or 2 
(Minimal or Mild) 
and at least a
2-grade 
improvement 
from baseline 
based on both 
investigator's 
assessment using 
the C-APPS and 
subject's self-
assessment using 
the P-APPS at 
maximum 
contraction at 
Day 14
Intent-to-treat 
(ITT) (all 
randomized)
Subjects who 
discontinue study 
prior to Day 14 
assessments or who 
do not have Day 14 
C-APPS or P-APPS 
assessments will be 
included in the 
analysis as a 
hypothetical 
scenario in which 
the assessments 
were conducted as 
per protocol
Response rates and 
rate differences 
between BOTOX 
and placebo 
treatment groups; 
Cochran-Mantel-
Haenszel (CMH) test 
 
 
 
 
 
Hypothetical 
estimand for 
coprimary 
endpoints 
Single dose 
of BOTOX 
 
 
or 
placebo
Achievement of at 
least a 2-grade 
improvement 
from baseline 
based on the 
following:

Investigator's 
assessment 
using C-APPS 
at maximum 
contraction 
at Day 14, 
and 

Subject's self-
assessment 
using P-APPS 
at maximum 
contraction 
at Day 14
Modified 
intent-to-treat 
(mITT)
 
 
 
Subjects who 
discontinue study 
prior to Day 14 
assessments or who 
do not have Day 14 
C-APPS or P-APPS 
assessments will be 
included in the 
analysis as a 
hypothetical 
scenario in which 
the assessments 
were conducted as 
per protocol
Response rates and 
rate differences 
between BOTOX 
and placebo 
treatment groups; 
CMH test
 
 
 
 
Estimands: Secondary Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are summarized in 
Table 2.  Treatment is the same as for the primary efficacy endpoints.  For the US FDA 
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variables/endpoints, the population is the ITT population (all randomized); for the EU 
variables/endpoints, the population is the mITT population 
 
.  The variables/endpoints listed have the same handling 
of intercurrent events and statistical summary (including population-level summary and analysis 
methods) within their respective analysis populations for the US FDA and EU, as indicated in the 
estimand label.
Table 2.
Summary of the Estimand Attributes of the Secondary Endpoints
Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoint 
 
Achievement of a Grade 
1 or 2 (Minimal or Mild) 
according to 
investigator's 
assessment using 
C-APPS at maximum 
contraction over time
Subjects who discontinue study 
or who do not have C-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH
test 
 
 
  
 
 
.
Hypothetical 
estimand for 
secondary 
categorical 
endpoint 
 
Achievement of a Grade 
1 or 2 (Minimal or Mild) 
according to subject's 
self-assessment using 
P-APPS at maximum 
contraction over time
Subjects who discontinue study 
or who do not have P-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
  
 
 
.
Hypothetical 
estimand for 
secondary 
categorical 
endpoint
Achievement of a rating 
of Minimal or Mild 
according to subject's 
self-assessment using 
P-APPS at maximum 
contraction at Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 P-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Satisfied or 
Very satisfied on the 
ANLFQ: Satisfaction 
(Follow-up) Item 5 
(effect of treatment) at 
Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 ANLFQ: 
Satisfaction (Follow-up) Item 5 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Not at all 
bothered or A little 
bothered on the BAS-PP 
Item 2 (jawline) at 
Day 14 
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 BAS-PP 
Item 2 assessments will be 
included in the analysis as a 
hypothetical scenario in which 
the assessments were conducted 
as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Not at all 
bothered or A little 
bothered on the BAS-PP 
Item 1 (vertical neck 
bands) at Day 14 
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 BAS-PP 
Item 1 assessments will be 
included in the analysis as a 
hypothetical scenario in which 
the assessments were conducted 
as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
Hypothetical 
estimand for 
secondary 
continuous 
endpoints 
 
Change from baseline on 
the ANLFQ: Impacts 
summary score at 
Day 14 
Subjects who discontinue study 
prior to applicable timepoints or 
who do not have Day 14 ANLFQ: 
Impacts summary score will be 
included in the analysis as a 
hypothetical scenario in which 
the assessments were conducted 
as per protocol
Mean change from 
baseline and mean 
differences between 
BOTOX and placebo 
treatment groups; 
analysis of variance 
 
 
 
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
continuous 
endpoints 
 
Change from baseline on 
the ANLFQ: Impacts 
summary score at 
Days 30, 60, and 90
Subjects who discontinue study 
prior to applicable timepoints or 
who do not have Day 30, 60, and 
90 ANLFQ:  Impacts summary 
score will be included in the 
analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Mean change from 
baseline and mean 
differences between 
BOTOX and placebo 
treatment groups; 
analysis of variance 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical 
endpoint 
 
Achievement of at least 
a 1-grade improvement 
from baseline based on 
investigator's 
assessment using 
C-APPS at maximum 
contraction over time
Subjects who discontinue study 
or who do not have C-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
  
 
 
.
Hypothetical 
estimand for
secondary 
categorical 
endpoint 
 
Achievement of at least 
a 1-grade improvement 
from baseline based on 
subject's self-
assessment using 
P-APPS at maximum 
contraction over time
Subjects who discontinue study 
or who do not have P-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the 
assessments were conducted as 
per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
  
 
 
.
3.2 Primary Endpoints
For the FDA, the composite primary efficacy endpoint is achievement of a Grade 1 or 2 (Minimal or Mild) 
and at least a 2-grade improvement from baseline based on both investigator's assessment using the C-
APPS and subject's self-assessment using P-APPS at maximum contraction at Day 14.
For EU regulatory agencies, the coprimary efficacy endpoints are the achievement of at least a 2-grade 
improvement from baseline based on the following: (1) investigator's assessment using C-APPS at 
maximum contraction at Day 14, and (2) subject's self-assessment using P-APPS at maximum contraction 
at Day 14.
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3.3 Secondary Endpoints
For US FDA:

Achievement of Grade 1 or 2 (Minimal or Mild) according to investigator's assessment using 
C-APPS at maximum contraction over time

Achievement of Grade 1 or 2 (Minimal or Mild) according to subject's self-assessment using 
P-APPS at maximum contraction over time

Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction (Follow-up) Item 5 (effect of 
treatment) at Day 14

Responses of Not at all bothered or A little bothered on the BAS-PP Item 2 (jawline) at Day 14  

Responses of Not at all bothered or A little bothered on the BAS-PP Item 1 (vertical neck bands) 
at Day 14 

Change from baseline on the ANLFQ: Impacts summary score at Day 14

Achievement of at least a 1-grade improvement from baseline based on investigator's 
assessment using C-APPS at maximum contraction over time

Achievement of at least a 1-grade improvement from baseline based on subject's self-
assessment using P-APPS at maximum contraction over time
For EU regulatory agencies: 

Achievement of a rating of Minimal or Mild according to subject's self-assessment using P-APPS 
at maximum contraction at Day 14

Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction (Follow-up) Item 5 (effect of 
treatment) at Day 14

Responses of Not at all bothered or A little bothered on the BAS-PP Item 2 (jawline) at Day 14 

Responses of Not at all bothered or A little bothered on the BAS-PP Item 1 (vertical neck bands) 
at Day 14

Change from baseline on the ANLFQ: Impacts summary score at Day 14

Change from baseline on the ANLFQ: Impacts summary score at Days 30, 60, and 90
3.4 Additional Endpoints
 
 
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3.5 Safety Endpoints
The safety endpoint is the incidence of AEs for the entire study population.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 4-month, multicenter, randomized, double-blind, placebo-controlled Phase 3 study designed to 
assess the safety and efficacy of BOTOX treatment in adult subjects with moderate to severe platysma 
prominence. 
To be eligible for enrollment, subjects must be at least 18 years of age, 
 
, and with either moderate (Grade 3) or severe 
(Grade 4) platysma prominence
 
 
.  Eligible subjects will be randomized on Day 1 in a 1:1 ratio to receive BOTOX or 
placebo.  
Approximately 400 subjects will be randomized at up to 35 sites in the United States and Canada. 
. 
 
  
Seven scheduled visits are planned: screening (Day -14 to Day -7), randomization/study drug (Day 1), 
follow-up visits (Days 14, 30, 60, 90), and study exit (Day 120).  On Day 1, the study drug will be 
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Anything other than a positive response to the questions below will result in screen failure.  
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study specific procedures
2. Are willing and able to comply with procedures required in this protocol
Demographics
3. Adult male or female, at least 18 years old at the time of signing the informed consent
Condition
6. Either moderate (Grade 3) or severe (Grade 4) platysma prominence 
 as determined at maximum
contraction 
 by the investigator using the C-APPS
7. Either moderate (Grade 3) or severe (Grade 4) platysma prominence 
 as determined at maximum 
contraction 
 by the subject using the P-APPS
Subject History
11. Good health as determined by medical history, physical examination, vital signs, and 
investigator's judgment
12. No abnormal variations and abnormal anatomical features in the lower face, neck, or 
décolletage area
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13. No history of dermatological disease, 
15. No medical condition that may put the subject at increased medical risk with exposure to 
BOTOX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral 
sclerosis, or any other condition that might interfere with neuromuscular function
16. No lower facial and neck hair, scarring
17. No tattoos, jewelry, or clothing that cannot be removed, and that obscure the target area of 
interest
18. No history of body weight change 
 prior to screening or 
anticipated body weight change 
 during the study period
19. No known immunization or hypersensitivity to any botulinum toxin serotype
20. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class
21. No history of clinically significant (per investigator's judgment) drug or alcohol abuse
22. No plans for an extended absence away from the immediate area of the study site 
23. No history of clinically significant medical conditions
24. No known active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection.  
26. Subject is not an employee or immediate relative of an employee of the sponsor, any of its 
affiliates or partners, or the study center or its affiliates
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1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:
 
 
 
2.
Postmenopausal female
 
 
 
 

Females, of Childbearing Potential

Review and document pregnancy avoidance recommendations with females of childbearing 
potential 

Females of childbearing potential must avoid pregnancy during the study.

Females must commit to one of the following methods of birth control:
 
 
 
 
 
 
 
 
 
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Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
5.3 Prohibited Medications and Therapy
The decision to administer any prohibited medication/treatment during the study period is done with 
the safety of the subject as the primary consideration.  Additionally, the medication/treatment listed 
below are prohibitive due to the potential confounding impact to efficacy assessment and not due to 
any potential safety risk to the subject.  When possible, the sponsor is to be notified before the 
prohibited medication/treatment is administered.
Prohibited treatments and procedures include, but are not limited to:
 
 
 
 
 
Site staff must notify the sponsor if a subject is administered or has taken any concomitant 
medications/procedures not permitted by the protocol.  
5.4 Prior and Concomitant Therapy
Any medication or vaccine 
 
 that the subject is receiving at the time of enrollment or receives during the study 
must be recorded from 30 days prior to study drug administration through study exit.  See below for 
details on special handling for the COVID-19 vaccine.
The use of any medication during the study 
 
 is to be recorded on the subject's electronic case report form 
(eCRF) at each visit along with the reason the medication is taken, dates of use, and dosing regimen.  
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Concurrent procedures will also be collected at each visit.  Concomitant medications and concurrent 
procedures will be tabulated and listed.
Non-live vaccines may be used during screening or treatment periods, if not contraindicated or 
medically inappropriate.  
 
 
Any questions regarding concomitant or prior therapy should be raised to the AbbVie nonemergency 
contact.  Information regarding potential drug interactions with BOTOX are in the BOTOX Investigator's 
Brochure.
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., messenger RNA, non-replicating 
viral vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during 
screening, the treatment period, or follow-up, as long as components of the vaccine are not 
contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
 
 
 
 
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any AEs associated with the COVID-19 vaccine.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time
 
  
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COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it may be necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care. 
 
The investigator should contact the AbbVie nonemergency contact before discontinuing a subject from 
the study for a reason other than described in the protocol to ensure all acceptable mitigation steps 
have been explored.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for safety and efficacy assessments, subjects should continue to be followed 
for all regularly scheduled visits, unless subjects have decided to discontinue the study participation 
entirely
 
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
 
5.7 Study Drug 
BOTOX and matching placebo will be packaged in vials with quantities sufficient to accommodate study 
design (Table 3).  Study drug provided by AbbVie should not be substituted or alternately sourced unless 
otherwise directed by AbbVie.  
 
 
 
 
 
 Study drug will only be used for the conduct of this study.
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Sites are responsible for maintaining the investigational study drug and devices according to 
the storage conditions specified 
 
 
 
 
 
 
 
 
  Dosing will be determined based on the baseline C-APPS 
score on Day 1 
:
 
 
 
 
 
 
 
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Table 3.
Study Formulations and Dilution Instructions
Investigational Medicinal 
Product
BOTOX
Placebo
Dose Formulation
BOTOX (botulinum toxin type A) purified 
neurotoxin complex 
 
 
 
 
 
 
Dilution Instructions
 
 
 
Packaging and Labeling
 
 
 
 
Storage
Manufacturer
Allergan
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5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule.
 
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  The IRT will provide 
access to unblinded subject treatment information in the case of a medical emergency.
At each study site, designated staff member(s) will serve as the Independent Drug Reconstitutor (IDR).  
This person will be unblinded and will be responsible for study drug preparation and documentation.  
 
 
 
 
 
 
 
 
 
Blinding is critical to the integrity of the clinical trial.  The IRT will be programmed with blind-breaking 
instructions.  
 
 
 
the investigator is to make every effort to contact AbbVie prior to unblinding a subject's study drug 
assignment unless this could delay emergency treatment of the subject.  
 
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  The date 
and reason that the blind was broken must be recorded in the source documentation and case report 
form, as applicable.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  
 
 
5.10 Data Monitoring Committee
A data monitoring committee is not planned for this study.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
 
 
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
  
Reporting will be done via electronic data capture (EDC).  
 
  A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue.  
 
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Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
 
 
 
Upon identification and awareness of 1 or more of these events, the investigator must document and 
report the event by completing an AE eCRF, and must notify the AbbVie nonemergency contact and 
assigned clinical research associate by email or telephone call within 72 hours of awareness (if 
non-serious).  The SAE form is not needed unless the AESI is serious.  If the AESI meets SAE criteria 
(which are listed above), it must be reported within 24 hours of awareness per the sponsor's SAE 
reporting requirements 
Adverse Event Severity and Relationship to Study Drug
The investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's usual 
activities.
Severe
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life threatening.
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The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  
 
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
Possible Distant Spread of Toxin
Possible distant spread of toxin (PDSOT) is defined as a possible pharmacologic effect of botulinum toxin 
at sites noncontiguous and distant from the site of injection.  Utilizing a standardized methodology to 
assess for PDSOT, Medical Dictionary for Regulatory Activities PTs that may be associated with 
botulinum toxin effects have been prospectively identified 
 
 
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary analyses.  
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan.
7.2 Definition for Analysis Populations
The ITT population consists of all randomized subjects.  
Baseline analyses and efficacy analyses for US FDA will be performed on the ITT population, consisting of 
all randomized subjects.
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For EU regulatory agencies only, baseline analyses and efficacy analyses will be performed on the mITT 
population,
 
. 
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  All safety 
analyses will be performed with subjects analyzed by their actual treatment received.  The Safety 
Analysis Set will be used for all safety analyses.
7.3 Handling Potential Intercurrent Events for the Primary and 
Secondary Endpoints
The primary composite endpoint for the FDA and the coprimary endpoint for the EU regulatory agencies 
(defined in Section 3.2) will be analyzed based on the ITT population and the mITT population, 
respectively, and the following methods will be used to address potential intercurrent events:

Subjects who did not receive any dose of study drug but are randomized will still be included in 
the ITT population. 
 

Subjects who are randomized but prematurely discontinued the study before assessment of the 
primary endpoints will be considered as part of the ITT population. 
 
 

Subjects who die before assessment of the primary endpoint will count as though they 
hypothetically continued in the study.

Subjects who are lost to follow-up and are missing data for the primary endpoint will count as 
though they hypothetically continued in the study.

Subjects who are missing assessments or data due to the COVID-19 pandemic and are missing 
data for the primary composite or coprimary endpoints will count as though they hypothetically 
continued in the study.

Subjects who are missing data for any other reason for the primary endpoint will count as 
though they hypothetically continued in the study.
The efficacy analysis of secondary endpoints (defined in Section 3.3) will be analyzed based on the same 
populations as above with similar methods for addressing potential intercurrent events.
Missing values will be imputed per the below.
Missing data will be imputed using the following methods for the efficacy analyses:

Multiple Imputation:  The Multiple Imputation approach will be used as a primary analysis for 
the primary endpoint, as well as for all secondary endpoints.  For the primary endpoint (US: 
composite endpoint; EU: coprimary endpoints) and the primary measure through Day 120, 
 
 
 
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EU regulatory agencies:  In addition, the coprimary responder endpoints for at least a 2-grade 
improvement in the C-APPS and P-APPS separately will be analyzed using the CMH method 
 
. 
The evaluation of the equality of the proportions of responders for the primary endpoint at Day 14 will 
be based on the CMH test stratified by baseline C-APPS score on Day 1 and by investigator site.  A 2-
sided p-value < 0.05 will be claimed as statistically significant. 
 
 The 95% CI for 
the treatment risk differences will be constructed using the normal approximation to the binary 
distribution.
Sensitivity analyses of the primary efficacy variables will be performed to establish their consistency and 
robustness as well as to further characterize the extent of subjects' responses. 
 
Summary and Analysis of Secondary Endpoints
Analysis of the secondary endpoints will be conducted on the ITT population based on treatment as 
randomized for the US FDA analyses and on the mITT population based on treatment as randomized for 
the EU regulatory agencies.
For the secondary endpoints, the proportion of responders will be analyzed using the CMH test 
 
  The continuous variables will be analyzed using analysis of 
covariance
 
 
7.5 Statistical Analyses for Safety
The safety analyses will be performed using the safety population.  The safety parameters will include 
incidence of AEs and change from baseline in vital signs.  
 
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose of study drug.  
An overview of AEs will be presented consisting of the number and percentage of subjects experiencing 
at least one event for each of the following AE categories:

Any TEAE

Any TEAE related to study treatment according to the investigator

Any TEAE related to study procedure according to the investigator

Any TEAE related to study drug according to the investigator
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
Any severe TEAE

Any serious TEAE

Any TEAE leading to death

Any AESI

Any PDSOT AE

All deaths
Treatment-emergent AEs will be summarized by system organ class (SOC) and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no reasonable 
possibility) and SOC and PT; by maximum severity and SOC and PT; and by subject number and SOC and 
PT.  Specific TEAEs will be counted once for each subject for calculating percentages, unless stated 
otherwise.  In addition, if the same AE occurs multiple times within a subject, the highest severity and 
level of relationship to investigational product will be reported.
 
 
  
Vital sign measurements will be summarized for changes from baseline at each assessment timepoint.
7.6 Interim Analysis
Interim analyses are not planned for this study.  
7.7 Overall Type I Error Control
Analyses will be conducted using a gated hierarchical testing procedure to preserve a familywise Type I 
error rate of α = 0.05.  
To control the family-wise Type I error rate at 0.05 for multiplicity across the primary and secondary 
analyses, a hierarchical testing strategy23 will be used.  
 
 
 
 
 
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 Nominal p-values will then be provided.
7.8 Sample Size Determination
Approximately 400 subjects will be randomized into the study in a 1:1 ratio yielding approximately 
200 subjects in the BOTOX group and 200 subjects in the placebo group in the treatment period. 
 
 
For the US FDA primary analysis, an estimated sample size of 360 subjects will give a power of greater 
than 99% to detect a difference in responder rates between the BOTOX and placebo groups, assuming a 
10% dropout rate by Day 14. 
 
 
The primary analysis for EU regulatory agencies only will be performed on the mITT population, 
 
  
a sample size of 180 will 
result in a power of greater than 99% to detect a difference between BOTOX and placebo in the 
proportion of subjects achieving at least a 2-grade improvement from baseline according to both 
investigator's assessment using C-APPS and subject's self-assessment using P-APPS at maximum 
contraction at Day 14.  
 
 
All calculations are based on a 2-sided Type I error rate of 0.05.  The power calculation is based on a 
2-sample test of independent proportions, as implemented in the commercial software nQuery 
version 7.0.  
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, Investigator Brochure, informed consent form(s), recruitment materials, and all subject 
materials will be submitted to the IEC/IRB for review and approval.  Approval of both the protocol and 
the informed consent form(s) must be obtained before any subject is enrolled.  Any amendment to the 
protocol will require review and approval by the IEC/IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form(s) will be IEC/IRB approved.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.  Investigators should notify AbbVie if any urgent safety measures are taken to protect the 
subjects against any immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated images will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good clinical practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote data review/verification may be employed if 
allowed by the local regulatory authority, IEC/IRB, and the study site.
10 DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11 COMPLETION OF THE STUDY
The end-of-study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.
A subject is considered to have completed the study if he/she has completed all phases of the study 
including the Study Exit visit.
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12 REFERENCES
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ANLFQ
Appearance of Neck and Lower Face Questionnaire
AO
as observed
BAS-PP
Bother Assessment Scale - Platysma Prominence
BMI
body mass index
C-APPS
Clinician Allergan Platysma Prominence Scale
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease – 2019
eCRF
electronic case report form
EDC
electronic data capture
EU
European Union
FDA
Food and Drug Administration
GCP
good clinical practice
HA
hyaluronic acid
HRT
hormone replacement therapy
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IDR 
Independent Drug Reconstitutor 
IEC
independent ethics committee
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
NRI
non-responder imputation
P-APPS
Participant Allergan Platysma Prominence Scale
PDSOT
possible distant spread of toxin
PGIS
Participant Global Impression of Severity
PRO
patient reported outcome
PSUR
Periodic Safety Update Report
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Abbreviation
Definition
PT
preferred term
RSI
reference safety information
SAE
serious adverse event
SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
US
United States
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-309:  A Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety and Efficacy of BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex for the Treatment of 
Platysma Prominence 
Protocol Date:  22 November 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
regulations and guidelines governing the study at the site location.  In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Independent Ethics Committee (IEC)/Institutional Review Board (IRB), except when necessary 
to protect the subject from immediate harm. 
2.
Personally conducting or supervising the described investigation(s). 
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments. 
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie. 
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s). 
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments. 
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie. 
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments. 
9.
Reporting promptly to AbbVie, the ethics committee/institutional review boards (as required) and other 
appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Therapeutic Area
Statistics 
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 1.0
Administrative Change 1
Version 2.0
Version 3.0
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
1
Statistical Analysis Plan for Study M21-309
A Phase 3 Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Safety and 
Efficacy of BOTOX® (Botulinum Toxin Type A) 
Purified Neurotoxin Complex for the Treatment of 
Platysma Prominence
Date:  12 May 2021
Version 1.0
 
NCT04949399


BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses and Estimands .....................................................5
2.2
Study Design Overview .............................................................................9
2.3
Treatment Assignment and Blinding .......................................................10
2.4
Sample Size Determination......................................................................10
3.0
Endpoints................................................................................11
3.1
Primary Endpoints ...................................................................................11
3.2
Secondary Endpoints ...............................................................................12
3.3
Other Efficacy Endpoints.........................................................................13
3.4
Safety Endpoint........................................................................................13
3.5
Additional Endpoints ...............................................................................14
4.0
Analysis Populations .............................................................14
5.0
Subject Disposition................................................................14
6.0
Study Drug Duration and Compliance................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................15
7.1
Demographics and Baseline Characteristics............................................15
7.2
Medical History and Prior and Concomitant Procedures ........................15
7.3
Prior and Concomitant Medications ........................................................16
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints..............................16
9.0
Efficacy Analyses...................................................................17
9.1
General Considerations............................................................................17
9.2
Handling of Missing Data........................................................................18
9.3
Primary Efficacy Endpoints and Analyses ..............................................20
9.3.1
Primary Efficacy Endpoints.....................................................................20
9.3.2
Main Analysis of Primary Efficacy Endpoints ........................................22
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoints .................................................................................................22
9.4
Secondary Efficacy Endpoints and Analyses ..........................................23
 


BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
3
9.4.1
Secondary Efficacy Endpoints.................................................................23
9.4.2
Main Analyses of Secondary Efficacy Endpoints....................................24
9.4.3
Sensitivity and Supplementary Analyses for Secondary Efficacy 
Endpoints .................................................................................................25
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses........................25
9.5
Additional Efficacy Analyses ..................................................................25
9.6
Efficacy Subgroup Analyses....................................................................26
10.0
Safety Analyses ......................................................................26
10.1
General Considerations............................................................................26
10.2
Adverse Events ........................................................................................26
10.2.1
Treatment-Emergent Adverse Events ......................................................27
10.2.2
Adverse Event Overview .........................................................................27
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................28
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................28
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................28
10.2.6
Adverse Events of Special Interest and Possible Distant Spread of 
Toxin Adverse Events..............................................................................28
10.3
Analysis of Laboratory Data....................................................................29
10.4
Analysis of Vital Signs ............................................................................29
10.5
Safety Subgroup Analyses .......................................................................29
10.6
Other Safety Analyses..............................................................................29
11.0
Other Analyses.......................................................................29
12.0
Interim Analyses....................................................................29
12.1
Data Monitoring Committee....................................................................29
13.0
Overall Type-I Error Control ..............................................30
14.0
Version History......................................................................31
15.0
References...............................................................................32
List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy
Endpoints ...................................................................................................6
 


BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
4
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints ...................................................................................................7
Table 3.
SAP Version History Summary...............................................................31
List of Figures
Figure 1.
Study Schematic.......................................................................................10
List of Appendices
Appendix A.
Protocol Deviations..................................................................................33
 


BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M21-309:
A Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety and Efficacy of BOTOX (Botulinum Toxin Type A) Purified Neurotoxin 
Complex for the Treatment of Platysma Prominence.
Study M21-309 examines the safety and efficacy of BOTOX or botulinum toxin type A in 
subjects.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC 27513) or later under the Linux operating system.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The study objective is to compare the safety and efficacy of BOTOX with placebo for the 
treatment of platysma prominence in adult subjects with moderate to severe platysma 
prominence at maximum contraction.
The clinical hypothesis is that BOTOX is a safe and effective treatment for the temporary 
improvement in the appearance associated with moderate and severe platysma 
prominence in adults.
Estimands: Primary Endpoints
The attributes of the estimands corresponding to the primary efficacy endpoints are 
summarized in Table 1.  In addition, the attribute of treatment is a single dose of BOTOX 
 or placebo.
 


BOTOX (botulinum toxin type A) 
M21-309 – Statistical Analysis Plan
Version 1.0 – 12 May 2021
6
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimand
Variable (Endpoint)
Population
Handling of 
Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
primary 
composite 
endpoint 
 
Achievement of at least a 
2-grade improvement 
from baseline based on 
both investigator's 
assessment using the C-
APPS and subject's self-
assessment using the P-
APPS at maximum 
contraction at Day 14
intent-to-treat 
(ITT) (all 
randomized)
Subjects who 
discontinue study 
prior to Day 14 
assessments or who 
do not have Day 14 
C-APPS or P-APPS 
assessments will be 
included in the 
analysis as a 
hypothetical scenario 
in which the 
assessments were 
conducted as per 
protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; 
Cochran-Mantel-
Haenszel (CMH) test 
 
 
 
 
Hypothetical 
estimand for 
coprimary 
endpoints
Achievement of at least a 
2-grade improvement 
from baseline based on 
the following:

Investigator's 
assessment using 
C-APPS at 
maximum 
contraction at 
Day 14, and

Subject's self-
assessment using 
P-APPS at maximum 
contraction at Day 14
Modified intent-
to-treat (mITT) 
 
 
 
 
Subjects who 
discontinue study 
prior to Day 14 
assessments or who 
do not have Day 14 
C-APPS or P-APPS 
assessments will be 
included in the 
analysis as a 
hypothetical scenario 
in which the 
assessments were 
conducted as per 
protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
.
Estimands: Secondary Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2. Treatment is the same as for the primary efficacy endpoints. For 
the US FDA variables/endpoints, the population is the ITT population (all randomized); 
for the EU variables/endpoints, the population is the mITT population 
 
 The 
variables/endpoints listed have the same handling of intercurrent events and statistical 
 


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summary (including population-level summary and analysis methods) within their 
respective analysis populations for the US FDA and EU, per estimand label.
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints
Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Achievement of at least a 
2-grade improvement 
from baseline based on 
investigator's assessment 
using C APPS at 
maximum contraction at 
Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 C-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the assessments 
were conducted as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical endpoint 
Achievement of a rating 
of Minimal or Mild
according to subject's 
self-assessment using 
P-APPS at maximum 
contraction at Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 P-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the assessments 
were conducted as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Satisfied or 
Very satisfied on the 
ANLFQ: Satisfaction 
(Follow-up) Item 5 (effect 
of treatment) at Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 ANLFQ: 
Satisfaction (Follow-up) Item 5 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the assessments 
were conducted as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
 


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Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints (Continued)
Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Not at all 
bothered or A little 
bothered on the BAS-PP 
Item 1 (vertical neck 
bands) at Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 BAS-PP 
Item 1 assessments will be 
included in the analysis as a 
hypothetical scenario in which 
the assessments were conducted 
as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
Hypothetical 
estimand for 
secondary 
categorical 
endpoints 
 
Responses of Not at all 
bothered or A little 
bothered on the BAS-PP 
Item 2 (jawline) at
Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 BAS-PP 
Item 2 assessments will be 
included in the analysis as a 
hypothetical scenario in which 
the assessments were conducted 
as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
Hypothetical 
estimand for 
secondary 
continuous 
endpoints 
 
Change from baseline on 
the ANLFQ: Impacts 
summary score at Day 14
Subjects who discontinue study 
prior to Day 14 assessment of 
ANLFQ: Impacts summary score 
will be included in the analysis as 
a hypothetical scenario in which 
the assessments were conducted 
as per protocol
Mean change from 
baseline and mean 
differences between 
BOTOX and placebo 
treatment groups; analysis 
of variance 
 
 
 
 
 


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Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints (Continued)
Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints
 
Achievement of a rating 
of Minimal or Mild
according to investigator's 
assessment using C-APPS 
at maximum contraction 
at Day 14
Subjects who discontinue study 
prior to Day 14 assessments or 
who do not have Day 14 C-APPS 
assessments will be included in 
the analysis as a hypothetical 
scenario in which the assessments 
were conducted as per protocol
Response rates and rate 
differences between 
BOTOX and placebo 
treatment groups; CMH 
test 
 
 
 
 
 
Hypothetical 
estimand for 
secondary 
continuous 
endpoints 
Change from baseline on 
the ANLFQ: Impacts
summary score at Days 
30, 60, and 90
Subjects who discontinue study 
prior to applicable timepoints or 
who do not have Day 14 
ANLFQ: Impacts summary score 
will be included in the analysis as 
a hypothetical scenario in which 
the assessments were conducted 
as per protocol
Mean change from 
baseline and mean 
differences between 
BOTOX and placebo 
treatment groups; analysis 
of variance 
 
 
 
 
 
2.2
Study Design Overview
The schematic of the study is shown in Figure 1 for this study (DBPC [double-blind 
placebo-controlled]) as it leads into the open label study extension.
 


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Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
Subjects will be randomized to BOTOX or placebo in a 1:1 ratio.  Randomization will be 
stratified at each investigational site by baseline C-APPS on Day 1 
 
 
  The same block will not be shared across sites or by baseline C-APPS.
2.4
Sample Size Determination
Approximately 400 subjects will be randomized into the study in a 1:1 ratio yielding 
approximately 200 subjects in the BOTOX group and 200 subjects in the placebo group in 
the treatment period.  
 
 
 
The primary analysis for FDA will be performed on the ITT population.  For the US FDA 
primary analysis, an estimated sample size of 360 subjects will give a power of greater 
than 99% to detect a difference in responder rates between the BOTOX and placebo 
groups, assuming a 10% dropout rate by Day 14.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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The primary analysis for EU regulatory agencies only will be performed on the mITT 
population, 
 
 
 a sample size of 180 will result in a power of greater than 99% to 
detect a difference between BOTOX and placebo in the proportion of subjects achieving 
at least a 2-grade improvement from baseline according to both investigator's assessment 
using C-APPS and subject's self-assessment using P-APPS at maximum contraction at 
Day 14.  
 
 
.
Sample size calculations were based on the two group χ2 two-sided test of equal 
proportions using nQuery (Version 7.0) at a 0.05 level of significance.
3.0
Endpoints
3.1
Primary Endpoints
For the FDA, the primary composite efficacy endpoint is achievement of at least a 2-grade 
improvement from baseline based on both investigator's assessment using the C-APPS 
and subject's self-assessment using P-APPS at maximum contraction at Day 14.
For EU regulatory agencies, the coprimary efficacy endpoints are the achievement of at 
least a 2-grade improvement from baseline based on the following: (1) investigator's 
assessment using C-APPS at maximum contraction at Day 14, and (2) subject's self-
assessment using P-APPS at maximum contraction at Day 14.
 


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3.2
Secondary Endpoints
For US FDA:
●
Achievement of at least a 2-grade improvement from baseline based on 
investigator's assessment using C-APPS at maximum contraction at Day 14
●
Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction (Follow-
up) Item 5 (effect of treatment) at Day 14
●
Responses of Not at all bothered or A little bothered on the BAS-PP Item 1
(vertical neck bands) at Day 14
●
Responses of Not at all bothered or A little bothered on the BAS-PP Item 2 
(jawline) at Day14
●
Change from baseline on the ANLFQ: Impacts summary score at Day 14
●
Achievement of a rating of Minimal or Mild according to investigator's
assessment using C-APPS at maximum contraction at Day 14
For EU regulatory agencies:
●
Achievement of a rating of Minimal or Mild according to subject's self-
assessment using P-APPS at maximum contraction at Day 14
●
Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction (Follow-
up) Item 5 (effect of treatment) at Day 14
●
Responses of Not at all bothered or A little bothered on the BAS-PP Item 1
(vertical neck bands) at Day 14
●
Responses of Not at all bothered or A little bothered on the BAS-PP Item 2 
(jawline) at Day14
●
Change from baseline on the ANLFQ: Impacts summary score at Day 14
●
Change from baseline on the ANLFQ: Impacts summary score at Days 30, 60, 
and 90
 


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3.3
Other Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
3.4
Safety Endpoint
The safety endpoint is the incidence of AEs for the entire study population.
 


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3.5
Additional Endpoints
Not applicable.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Intent-to-Treat (ITT) Population includes all randomized subjects.  Subjects will be 
included in the analysis according to the treatment groups to which they were randomized.
Baseline analyses and efficacy analyses for US FDA will be performed on the ITT 
population, consisting of all randomized subjects.
For EU regulatory agencies only, baseline analyses and efficacy analyses will be 
performed on the mITT population, 
 
.  Subjects will be included in
the analysis according to the treatment groups to which they were randomized.
The Safety Analysis Set consists of all subjects who were treated with at least 1 dose of 
study drug.  All safety analyses will be performed with subjects analyzed by their actual 
treatment received.  The Safety Analysis Set will be used for all safety analyses.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and treated will 
be summarized for ITT and mITT populations separately.  Reasons for exclusion, 
including screen failure, will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled (randomized) in the study;
●
Subjects treated with at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
 


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●
Subjects who prematurely discontinued study (with reason);
●
Subjects in each analysis population.
For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period will be summarized overall and by treatment group.
6.0
Study Drug Duration and Compliance
For the safety population, the number of subjects treated will be presented by treatment 
group.  If a subject does not receive the full dose, this will be indicated; significant 
deviations to dosing will be reported.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT and mITT populations overall 
and by treatment group. Categorical variables will be summarized with the number and 
percentage of subjects; percentages will be calculated based on the number of non-
missing observations. Continuous variables will be summarized with descriptive statistics 
(number of non-missing observations, mean and standard deviation, median, minimum 
and maximum).
7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI). Categorical demographic and baseline variables include sex, ethnicity, race, age
group 
 C-APPS grade, P-APPS grade, Fitzpatrick Skin 
Phototype.
7.2
Medical History and Prior and Concomitant Procedures
Medical history data will be reported and summarized separately from prior procedures 
data for the ITT and mITT populations.  Medical history data and prior procedure data 
 


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will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
actual version of the MedDRA coding dictionary will be noted in the statistical tables and 
clinical study report. The number and percentage of subjects in each medical history 
category (by MedDRA system organ class and preferred term) will be summarized overall 
and by treatment group. Similarly, the number and percentage of subjects in each prior 
procedures category will be summarized overall and by treatment group.  The system 
organ class (SOC) will be presented in alphabetical order, and the preferred terms will be 
presented in alphabetical order within each SOC. Subjects reporting more than one
condition/diagnosis will be counted only once in each row (SOC or preferred term).
In addition, any concomitant procedures, defined as any procedure performed on or after 
the date of first treatment, will be summarized by SOC and PT in each treatment group for 
the ITT and mITT populations.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name for the ITT and 
mITT populations. A prior medication is defined as any medication taken prior to the 
date of the first dose of study drug. A concomitant medication is defined as any 
medication that started prior to the date of the first dose of study drug and continued to be 
taken after the first dose of study drug or any medication that started on or after the date 
of the dose of study drug, but not after the date of the last visit assessment. The number 
and percentage of subjects taking medications will be summarized by generic drug name 
based on the World Health Organization (WHO) Drug Dictionary for both prior and 
concomitant medications.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The primary efficacy endpoint of the primary and coprimary endpoints for the FDA and 
for the EU regulatory agencies (defined in Section 3.1), respectively, will be analyzed 
based on the ITT population for the US and the mITT population for the EU, and the 
following methods will be used to address potential intercurrent events:
 


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●
Subjects who did not receive any dose of study drug but are randomized will 
still be included in the ITT population.  
 
 
●
Subjects who are randomized but prematurely discontinued the study before 
assessment of the primary endpoints will be considered as part of the ITT 
population. 
 
 
●
Subjects who die before assessment of the primary endpoint will count as 
though they hypothetically continued in the study.
●
Subjects who are lost to follow-up and are missing data for the primary 
endpoint will count as though they hypothetically continued in the study.
●
Subjects who are missing data for any other reason for the primary endpoint 
will count as though they hypothetically continued in the study.
The secondary efficacy analysis of secondary endpoints (defined in Section 3.2) will be 
analyzed based on the same populations as above with similar methods for addressing 
potential intercurrent events.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the ITT Population for the US and the mITT 
Population for the EU regulatory agencies.
Analyses will be conducted using a gated hierarchical testing procedure to preserve a 
familywise Type I error rate of α = 0.05.
To control the family-wise Type I error rate at 0.05 for multiplicity across the primary and 
secondary analyses, a hierarchical testing strategy1 will be used. 
 
 
 
 


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 Nominal p-values will 
then be provided.
The Primary Analysis will be performed after all ongoing subjects have completed the 
Double Blind (DB) Period and the database has been locked.  This will be the only and 
final analysis for the primary composite, coprimary and secondary efficacy endpoints, as 
well as all other efficacy endpoints in DB Period.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test,
. Continuous variables will 
be analyzed using analysis of covariance (ANCOVA) 
 
.
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the subject's actual stratum.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.  The change from baseline values 
will be computed as the post-baseline value minus the baseline value.
9.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses:
●
Multiple Imputation: The Multiple Imputation approach will be used as a 
primary analysis for the primary endpoint, as well as for all secondary 
 


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endpoints.  For the primary endpoint (US: primary composite endpoint; EU: 
coprimary endpoints) and the primary and secondary measures through 
Day 120, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
●
Non-responder Imputation (NRI): The NRI analysis will categorize any subject 
who does not have evaluation during a specific visit window as a non-
 


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responder for that visit.  The NRI will be one of the sensitivity analysis 
approaches in the analyses of categorical variables for efficacy.
●
As Observed (AO): The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the AO analysis for that visit. AO will include all 
values collected in the study, and will be used for sensitivity analyses of 
efficacy endpoints.
9.3
Primary Efficacy Endpoints and Analyses
9.3.1
Primary Efficacy Endpoints
Clinician Allergan Platysma Prominence Scale (C-APPS): The sponsor developed the 
C-APPS as a clinician's assessment tool for evaluation of platysma prominence at 
maximum contraction.  
 
 
 
 
.
Prior to enrolling subjects, investigators (or sub-investigators when applicable) will be 
trained in grading platysma prominence severity using the C-APPS.
The C-APPS is to be performed by the same trained and qualified (MD/DO) evaluator 
throughout the study 
 
 
 
Platysma prominence 
 will be assessed live, independently, at 
maximum contraction by the investigator using the C-APPS (1 = Minimal, 2 = Mild, 
3 = Moderate, 4 = Severe, 5 = Extreme).
 


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There are no pandemic or natural disaster-related protocol modifications for the C-APPS 
procedure. If a site visit is missed at which this assessment was planned, the assessment 
will be skipped for that timepoint.
Participant Allergan Platysma Prominence Scale (P-APPS): The P-APPS has been 
developed as a subject self-assessment tool 
 
 for evaluation of platysma prominence at maximum contraction. 
Subjects will use the P-APPS (1 = Minimal, 2 = Mild, 3 = Moderate, 4 = Severe, 
5 = Extreme)
to self-assess the severity of 
their 
 platysma prominence at maximum contraction 
 
There are no pandemic or natural disaster-related protocol modifications for the P-APPS
procedure. If a site visit is missed at which this assessment was planned, the assessment 
will be skipped for that timepoint.
 
 
 
 
 responder for C-APPS will be defined as a subject with an improvement 
of at least 2 grades in C-APPS at Day 14 from baseline; similarly, a responder for P-APPS 
will be defined as a subject with an improvement of at least 2 grades in P-APPS at Day 14 
from baseline 
.  A composite responder will be defined as being a responder 
for both C-APPS and P-APPS at the same visit assessment.
 


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9.3.2
Main Analysis of Primary Efficacy Endpoints
The attributes of the estimands corresponding to the primary and coprimary efficacy 
endpoints for the US and EU regulatory agencies are summarized in Table 1 (see 
Section 2.1).
Analysis of the primary endpoint will be conducted on the ITT population based on 
treatment as randomized for the US FDA analyses and on the mITT population based on 
treatment as randomized for the EU regulatory agencies.
US FDA: The primary composite responder endpoint for at least a 2-grade improvement 
will be analyzed using the CMH method 
 
.
EU regulatory agencies: The coprimary responder endpoints for at least a 2-grade
improvement in the C-APPS and P-APPS will be analyzed separately using the CMH 
method 
 
.
The evaluation of the equality of the proportions of responders for the primary endpoint at 
Day 14 will be based on the CMH test 
 
 
 
. The 95% CI for the treatment risk 
differences will be constructed using the normal approximation to the binary distribution.
9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoints
Sensitivity analyses of the primary efficacy variables will be performed to establish their 
consistency and robustness as well as to further characterize the extent of subjects' 
responses. As-observed data analysis, as well as missing as non-responder (using NRI) 
 


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analysis, 
 
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
Bother Assessment Scale - Platysma Prominence (BAS-PP): BAS-PP is a 2-item PRO 
measure that asks subjects to rate how bothered they are by the appearance of their 
vertical neck bands (Item 1) and jawline (Item 2) 
 
 
.
Appearance of Neck and Lower Face Questionnaire (ANLFQ): ANLFQ-Impacts is a 
7-item PRO measure that assesses the psychosocial impact of the appearance of the neck 
and lower face from the subject perspective.
 
 
  Scores from the individual items are summed 
 
 where higher scores indicate greater negative impact from the 
appearance of the neck and lower face.
ANLFQ-Satisfaction is a PRO measure that assesses treatment expectations and 
satisfaction with platysma prominence from the subject perspective. 
 
 
 
 
 
 
 
 
 
 
 


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9.4.2
Main Analyses of Secondary Efficacy Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2 (see Section 2.1).
Analysis of the secondary endpoints will be conducted on the ITT population based on 
treatment as randomized for the US FDA analyses and on the mITT population based on 
treatment as randomized for the EU regulatory agencies.
For the secondary endpoints, the proportion of responders will be analyzed using the 
CMH test 
 
 
 
.
 


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9.4.3
Sensitivity and Supplementary Analyses for Secondary 
Efficacy Endpoints
Additional sensitivity analyses may be performed as needed to assess impact of missing 
data for secondary endpoints due to a pandemic or natural disaster.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
Not applicable.
9.5
Additional Efficacy Analyses
 
 
 
 
 
 
 
 
 
 


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9.6
Efficacy Subgroup Analyses
Not applicable.
10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  Safety summaries will be 
presented by treatment group.  For the safety analysis, subjects are assigned to a treatment 
group based on the treatment actually received, regardless of the treatment randomized.
The safety parameters will include incidence of AEs and change from baseline in vital 
signs. For each safety parameter evaluating change from baseline, the last nonmissing 
safety assessment before study drug administration will be used as the baseline for all 
analyses of that parameter.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
 


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coding dictionary used for the study at the time of database lock. The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAEs) are defined as any AE with the onset that is after the 
first dose of study drug. Events where the onset date is the same as the study drug start 
date are assumed to be treatment-emergent. All TEAEs will be summarized overall, as 
well as by primary MedDRA SOC and PT. The SOCs will be presented in alphabetical 
order, and the PTs will be presented in alphabetical order within each SOC.
The number and percentage of subjects experiencing treatment-emergent AEs will be 
summarized.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any related TEAE
○
Any TEAE related to study drug according to the investigator
○
Any TEAE related to study procedure according to the investigator
●
Any severe TEAE
○
Any severe TEAE related to study treatment according to the investigator
●
Any serious TEAE
○
Any serious TEAE related to study treatment according to the investigator
●
Any TEAE leading to death
●
Any treatment-emergent adverse event of special interest (AESI)
 


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●
Any possible distant spread of toxin (PDSOT) TEAE
●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
TEAEs will be summarized by SOC and PT; by maximum relationship to study drug as 
assessed by the investigator (e.g., reasonable possibility or no reasonable possibility) and 
SOC and PT; by maximum severity and SOC and PT; and by subject number and SOC 
and PT. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to study drug
will be reported.
In addition, TEAEs will be summarized by PT and sorted by decreasing frequency for the 
total active group.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Not applicable.
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Serious AEs (including deaths) and AEs leading to study discontinuation will be 
summarized by SOC and PT and in listing format.
10.2.6
Adverse Events of Special Interest and Possible Distant 
Spread of Toxin Adverse Events
Treatment-emergent adverse events of special interest (AESIs) will be summarized by PT. 
 
 
 


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Possible distant spread of toxin (PDSOT) TEAEs will be summarized by PT.  
 
 
 
Tabular listings of AESIs and PDSOT TEAEs will be provided.
10.3
Analysis of Laboratory Data
Not applicable.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and 
respiratory rate, and changes from baseline at each assessment timepoint will be 
summarized by treatment group.
10.5
Safety Subgroup Analyses
Not applicable.
10.6
Other Safety Analyses
Not applicable.
11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
No interim analysis is planned for this study.
12.1
Data Monitoring Committee
No data monitoring committee (DMC) will be used for this study.
 


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13.0
Overall Type-I Error Control
To control the family-wise Type I error rate at 0.05 for multiplicity across the primary and
secondary analyses, a hierarchical testing strategy1 will be used.  
 
 
 
 
 
 
 
 
The hierarchical testing order follows for US FDA:
1.
Primary composite: Achievement of at least a 2-grade improvement from baseline 
based on both investigator's assessment using the C-APPS and subject's self-
assessment using P-APPS at maximum contraction at Day 14
2.
Secondary: Achievement of at least a 2-grade improvement from baseline based on 
investigator's assessment using C-APPS at maximum contraction at Day 14
3.
Secondary: Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction 
(Follow-up) Item 5 (effect of treatment) at Day 14
4.
Secondary: Responses of Not at all bothered or A little bothered on the BAS-PP 
Item 1 (vertical neck bands) at Day 14
5.
Secondary: Responses of Not at all bothered or A little bothered on the BAS-PP 
Item 2 (jawline) at Day 14 
6.
Secondary: Change from baseline on the ANLFQ: Impacts summary score at 
Day 14 
7.
Secondary: Achievement of a rating of Minimal or Mild according to investigator's 
assessment using C-APPS at maximum contraction at Day 14
 


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The hierarchical testing order follows for EU regulatory agencies:
1.
Coprimary: Achievement of a rating of at least a 2-grade improvement from 
baseline based on the following:
●
Investigator's assessment using C-APPS at maximum contraction at Day 14, 
and 
●
Subject's self-assessment using P-APPS at maximum contraction at Day 14
2.
Secondary: Achievement of a rating of Minimal or Mild according to subject's self-
assessment using P-APPS at maximum contraction at Day 14
3.
Secondary: Responses of Satisfied or Very satisfied on the ANLFQ: Satisfaction 
(Follow-up) Item 5 (effect of treatment) at Day 14 
4.
Secondary: Responses of Not at all bothered or A little bothered on the BAS-PP 
Item 1 (vertical neck bands) at Day 14 
5.
Secondary: Responses of Not at all bothered or A little bothered on the BAS-PP 
Item 2 (jawline) at Day 14 
6.
Secondary: Change from baseline on the ANLFQ: Impacts summary score at 
Day 14
7.
Secondary: Change from baseline on the ANLFQ: Impacts summary score at Days 
30, 60, and 90
14.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
12 May 2021
Original version
 


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15.0
References
 
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study treatment.
●
Subject took prohibited concomitant medication.
 


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