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
Phase: PHASE3
Conditions: Platysma Prominence
Sponsor: AbbVie



  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
9
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
11
3.2
PRIMARY ENDPOINTS
16
3.3
SECONDARY ENDPOINTS
16
3.4
ADDITIONAL ENDPOINTS
17
3.5
SAFETY ENDPOINTS
17
4
INVESTIGATIONAL PLAN
17
4.1
OVERALL STUDY DESIGN AND PLAN
17
4.2
DISCUSSION OF STUDY DESIGN
18
5
STUDY ACTIVITIES
20
5.1
ELIGIBILITY CRITERIA
20
5.2
CONTRACEPTION RECOMMENDATIONS
23
5.3
PROHIBITED MEDICATIONS AND THERAPY
24
5.4
PRIOR AND CONCOMITANT THERAPY
25
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
26
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
27
5.7
STUDY DRUG
28
5.8
RANDOMIZATION/DRUG ASSIGNMENT
30
5.9
PROTOCOL DEVIATIONS
31
5.10 DATA MONITORING COMMITTEE
31
6
SAFETY CONSIDERATIONS
31
6.1
COMPLAINTS AND ADVERSE EVENTS
31
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
36
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7.1
STATISTICAL AND ANALYTICAL PLANS
36
7.2
DEFINITION FOR ANALYSIS POPULATIONS
36
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
37
7.4
STATISTICAL ANALYSES FOR EFFICACY
38
7.5
STATISTICAL ANALYSES FOR SAFETY
39
7.6
INTERIM ANALYSIS
40
7.7
OVERALL TYPE I ERROR CONTROL
40
7.8
SAMPLE SIZE DETERMINATION
41
8
ETHICS
41
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
41
8.2
ETHICAL CONDUCT OF THE STUDY
42
8.3
SUBJECT CONFIDENTIALITY
42
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
42
10 DATA QUALITY ASSURANCE
43
11 COMPLETION OF THE STUDY
43
12 REFERENCES
43
LIST OF TABLES
TABLE 1.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY EFFICACY ENDPOINTS
12
TABLE 2.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE SECONDARY ENDPOINTS
13
TABLE 3.
STUDY FORMULATIONS AND DILUTION INSTRUCTIONS
29
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LIST OF FIGURES
FIGURE 1.
THE PLATYSMA MUSCLE: ANTERIOR AND POSTERIOR MARGINS OF THE PLATYSMA MUSCLE
SHEETS
8
FIGURE 2.
STUDY SCHEMATIC
18
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
45
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
47
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
48
APPENDIX D.
ACTIVITY SCHEDULE
49
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
51
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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 neck2,3.  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 they 
 
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 
variables/endpoints, the population is the ITT population (all randomized); for the EU 
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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 
 
 
  
 
 
.
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
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 
 
 
 
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 
 
 
 
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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 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 
 
 
 
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 
 
 
  
 
 
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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.
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
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
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
 
 
 
 
 
 
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
 
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  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 global study sites. 
 
 
  
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 
administered in the platysma muscle.  Dosing will be determined based on the baseline C-APPS score on 
Day 1 (see Section 5.7).
The schematic of the study is shown in Figure 2.  
 
Figure 2.
Study Schematic
4.2 Discussion of Study Design
Choice of Control Group
Placebo was chosen as a control because there are no FDA-approved drugs for platysma prominence.
Appropriateness of Measurements
The primary efficacy measure used in this study (C-APPS) was developed and validated by Allergan 
 
 
supporting its acceptability for use in the present study.  Allergan also developed 
and validated PROs for this program in accordance with global recommendations set forth by the United 
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States Food and Drug Administration18 and the European Medicines Agency19.  These PROs include the 
P-APPS to assess platysma prominence severity, the BAS-PP to assess bother from vertical neck bands 
and jawline, and the ANLFQ: Satisfaction and Impacts modules to assess treatment expectations, 
satisfaction, and psychosocial impact related to platysma prominence.  These PROs will be used to 
assess treatment efficacy from the patient perspective.  All clinical procedures in this study are standard 
and generally accepted.
Suitability of Subject Population
The study population will include male and female adults with moderate to severe platysma prominence 
at maximum contraction.  Study subjects should be in good health 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the eligibility criteria in order to be included in the study.  Screen failures can 
occur during the screening period up to the Day 1 Visit.  
 Any attempt to rescreen a subject must 
only occur after agreement with the sponsor.
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
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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
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
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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:
 
 
 
 
 
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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.  
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.
 
 
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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.  
 
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If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance as an SAE. 
 
 
 
 
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject. 
 
 
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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 per the SAE reporting requirements described 
above.
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.
For EU regulatory agencies only, baseline analyses and efficacy analyses will be performed on the mITT 
populatio
 
 
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.
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  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 
 
 
 
 
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

Any severe TEAE

Any serious TEAE

Any TEAE leading to death

Any AESI
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
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 strategy 23 will be used.  
 
 
 
 
 
 
 
 
 
 
 Nominal p-values will then be provided.
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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
For personal data that AbbVie controls and maintains, AbbVie has developed a robust security program 
to protect subject personal data focused on due diligence in design, managed change, and information 
security governance.  Information security policies govern the information security functions including 
identity and access management, operations, infrastructure, application, and third-party security 
requirements.  The risk-based AbbVie Data Classification Tool dictates the level of scrutiny and control 
required for the relevant activities per AbbVie's information security policies taking into account the 
sensitivity of the data.
Before subject data is shared with AbbVie, the study doctor and staff will replace any information that 
could directly identify a patient (such as name, address, and contact information) with a generic code 
which AbbVie cannot link to that subject's identity to protect the confidentiality of the data. 
AbbVie has a data protection impact assessment (DPIA) program to ensure and document the 
appropriate controls and safeguards stated above are in place for clinical trial data that it controls and 
maintains, and these processing activities respect the privacy of clinical trial subjects.  AbbVie also 
maintains robust security incident response policies and procedures, including requirements for the 
containment of any data related incidents, the mitigation measures where needed, and notification to 
authorities or affected individuals where required. 
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.
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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 M21-310:  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 (within 1 calendar day) 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 1.1 (Germany Only)
Version 2.0
Administrative Change 2
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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