Clinical trial NCT05134649
Conditions: Platysma Prominence
Keywords: Platysma Prominence BOTOX OnabotulinumtoxinA
Sponsor: AbbVie
Start date: 2021-11-16; Completion date: 2023-08-18
Enrollment: 292 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, open-label extension study to evaluate the long-term safety of repeat BOTOX treatments in adult participants with Platysma Prominence. Participants who completed the lead-in Phase 3 Study M21-309 and met eligibility requirements could enroll in this open-label extension study.

Planned study enrollment was approximately 270 participants. Participants who met treatment criteria could receive up to 3 administrations of BOTOX. Day 1 (study entry) was the same day as Day 120/study exit visit of the lead-in Phase 3 study. The first administration of study drug could occur at the Day 1 visit, and the last administration of study drug could occur at the Day 180 visit (60 days prior to Day 240/study exit). Once a subject was enrolled in this study, monthly follow-up visits occurred.

Detailed description:

Arms: arm 1: BOTOX (OnabotulinumtoxinA) will be injected into the platysma muscle for up to 3 Cycles during study M21-323
Interventions: intervention 1: OnabotulinumtoxinA
Intervention descriptions: intervention 1: Intramuscular Injection

Protocol documents:
Prot_000.pdf: 


  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
6
2.1
BACKGROUND AND RATIONALE
6
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
9
3.2
PRIMARY ENDPOINT
9
3.3
SECONDARY ENDPOINT(S)
9
3.4
ADDITIONAL EFFICACY ENDPOINTS
9
3.5
SAFETY ENDPOINTS
10
4
INVESTIGATIONAL PLAN
10
4.1
OVERALL STUDY DESIGN AND PLAN
10
4.2
DISCUSSION OF STUDY DESIGN
12
5
STUDY ACTIVITIES
13
5.1
ELIGIBILITY CRITERIA
13
5.2
CONTRACEPTION RECOMMENDATIONS
15
5.3
PROHIBITED MEDICATIONS AND THERAPY
16
5.4
PRIOR AND CONCOMITANT THERAPY
17
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
18
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
20
5.7
STUDY DRUG
20
5.8
RANDOMIZATION/DRUG ASSIGNMENT
23
5.9
PROTOCOL DEVIATIONS
23
5.10 DATA MONITORING COMMITTEE
24
6
SAFETY CONSIDERATIONS
24
6.1
COMPLAINTS AND ADVERSE EVENTS
24
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
28
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7.1
STATISTICAL AND ANALYTICAL PLANS
28
7.2
DEFINITION FOR ANALYSIS POPULATIONS
29
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY ENDPOINTS
29
7.4
STATISTICAL ANALYSES FOR EFFICACY
29
7.5
STATISTICAL ANALYSES FOR SAFETY
30
7.6
INTERIM ANALYSIS
31
7.7
OVERALL TYPE I ERROR CONTROL
31
7.8
SAMPLE SIZE DETERMINATION
31
8
ETHICS
31
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
31
8.2
ETHICAL CONDUCT OF THE STUDY
32
8.3
SUBJECT CONFIDENTIALITY
32
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
32
10 DATA QUALITY ASSURANCE
32
11 COMPLETION OF THE STUDY
32
12 REFERENCES
33
LIST OF TABLES
TABLE 1.
STUDY FORMULATIONS AND DILUTION INSTRUCTIONS
22
LIST OF FIGURES
FIGURE 1.
THE PLATYSMA MUSCLE:  ANTERIOR AND POSTERIOR MARGINS OF THE PLATYSMA MUSCLE 
SHEETS
6
FIGURE 2.
STUDY SCHEMATIC
11
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
35
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
37
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
38
APPENDIX D.
ACTIVITY SCHEDULE
39
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
40
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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 medicine.1
 the medical literature has described the use of BOTOX to improve the 
appearance of the lower face and neck.2,3  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
Primary
The study objective is to evaluate the long-term safety of repeat treatments of BOTOX in subjects with 
moderate to severe platysma prominence at maximum contraction.
The clinical hypothesis is that BOTOX is a safe treatment after repeat treatment in adult subjects with 
moderate to severe platysma prominence.
Secondary
There are no secondary objectives in the current study.
3.2 Primary Endpoint
For both FDA and European Union (EU) regulatory agencies, the primary endpoint of the study is 
incidence of AEs.  No estimands are provided.
3.3 Secondary Endpoint(s)
There are no secondary endpoints in the current study.
3.4 Additional Efficacy Endpoints
 
 
 
 
 
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3.5 Safety Endpoints
The safety endpoint evaluated in the current study is the primary endpoint of incidence of AEs 
(Section 3.2).
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is an 8-month, multicenter, open-label extension study to evaluate the long-term safety of BOTOX 
repeat treatment for platysma prominence.  In this study, subjects may receive up to 3 administrations 
of study drug based on meeting treatment criteria (Section 5.7) 
 
.  The first administration of study drug may occur at the 
Day 1 visit, and the last administration of study drug may occur at the Day 180 visit (60 days prior to 
Day 240/study exit).  No treatment is allowed after the Day 180 visit. 
Subjects who complete all phases of the lead-in Phase 3 study may be eligible to enroll into this open-
label extension study.
For subjects who choose to participate in this study and qualify for enrollment, Day 1 (study entry) must 
be same day as Day 120/study exit visit of the lead-in Phase 3 study.  Once a subject is enrolled in this 
study, monthly follow-up visits will occur.  During follow-up, if the subject meets treatment criteria, the 
subject will receive study drug.  
 
 Based on individual 
variability in time to meet treatment criteria, retreatment timepoints are not expected to be 
synchronized among all study subjects.
The total duration of study participation for each subject is approximately 8 months.  Visits include study 
entry (Day 1), scheduled monthly visits (Days 30, 60, 90, 120, 150, 180, 210), Day 14 after each study 
drug administration, and study exit (Day 240 or premature discontinuation).  Up to 12 scheduled visits 
are planned.  Administration of study drug is not permitted after the Day 180 visit.  Study exit (Day 240 
visit/completion) or premature discontinuation must occur at least 60 days after the subject's last 
administration of study drug.
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5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects who complete the lead-in Phase 3 study may be eligible to enroll into this 8-month open-label 
extension study.
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an Institutional 
Review Board (IRB), prior to the initiation of any study-specific procedures
2. Are willing and able to comply with procedures required in this protocol
Type of Subject and Characteristics
3. Completion of all phases of the lead-in Phase 3 study (Screening Period, Treatment Period 
[randomization/treatment with 4-month follow-up visit] and Study Exit visit)
Subject History
6. 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
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5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Nonchildbearing Potential

Females do not need to use birth control during or following study drug treatment if considered 
of nonchildbearing potential due to meeting any of the following criteria:
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 study 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.  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., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during the 
treatment period, 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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Sites are responsible for maintaining the investigational study drug and devices according to 
the storage conditions specified
 
 
 
 
During the treatment period of this study (Day 1 through Day 180), subjects may receive up to 
3 administrations of study drug, if all the following treatment criteria are met:

 
 

No treatment is allowed in subjects who are experiencing active AESIs of any severity, or who, at 
the discretion of the investigator, are in a situation which may put the subject at increased 
medical risk with additional treatments

 

Subject has either moderate (Grade 3) or severe (Grade 4) platysma prominence 
 
 as determined at 
maximum contraction by the investigator using the C-APPS

Subjects with confirmed (viral test positive) or suspected COVID-19 infection must meet 
COVID-19 viral clearance criteria before dosing (see Section 5.5)

Females of childbearing potential must have a negative pregnancy test prior to treatment
If the subject does not meet treatment criteria, he/she will be assessed the following month for 
treatment eligibility.  No treatment is allowed after the Day 180 visit.  No treatment is allowed if subject 
has extreme (Grade 5) platysma prominence 
, as determined at maximum 
contraction by the investigator using the C-APPS.  These subjects will return at the next monthly visit to 
be reassessed for treatment eligibility. 
For each subject meeting treatment criteria, superficial intramuscular injections will be administered to 
 
 Dosing will be determined 
based on the baseline C-APPS score on treatment day 
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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.  
 
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  Product 
complaints occurring during the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
 
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The investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
 
 
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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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 the primary analysis.  Complete and 
specific details of the statistical analysis will be described in the Statistical Analysis Plan (SAP).
  
 
 
 
 
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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 discontinuation of study drug

Any TEAE leading to death

Any AESIs

Any PDSOT AEs

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.
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Safety analyses will take into account both study drug groups (e.g., placebo or BOTOX in the lead-in 
Phase 3 study, BOTOX in this study) and BOTOX treatment cycles from both the lead-in Phase 3 study 
and this study.  Adverse events will be summarized by treatment cycle and for the overall study. 
  
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
Not applicable for this study.
7.8 Sample Size Determination
No formal statistical power or sample size calculation was performed for this study.  Approximately 
270 subjects (or up to 400 subjects) are anticipated to be enrolled into this study.  
 
 
 
 
 
Due to local guidelines to prevent and mitigate the effects of a pandemic or natural disaster, it is 
understood that some subjects may not be able to complete all visits in clinic as indicated per protocol.  
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
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, IRB/IEC, 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
BAS-PP
Bother Assessment Scale - Platysma Prominence
C-APPS
Clinician Allergan Platysma Prominence Scale
CI
confidence interval
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
IEC
independent ethics committee
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
mITT
modified intent-to-treat
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
PT
preferred term
RSI
reference safety information
SAE
serious adverse event
SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Abbreviation
Definition
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
US
United States
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STUDY M21-323  |  Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-323:  Phase 3, Multicenter Open-label Extension Study to Evaluate the Safety 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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STUDY M21-323  |  Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Therapeutic Area
Statistics 
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STUDY M21-323  |  Version 4.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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)
M21-323 – Statistical Analysis Plan
Version 3.0 – 17 July 2023
1
Statistical Analysis Plan for Study M21-323
Phase 3, Multicenter Open-label Extension Study to 
Evaluate the Safety of BOTOX® (Botulinum Toxin 
Type A) Purified Neurotoxin Complex for the 
Treatment of Platysma Prominence
Date:  17 July 2023
Version 3.0
 
NCT05134649


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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.......................................................................... 5
2.3
Treatment Assignment and Blinding....................................................... 6
2.4
Sample Size Determination .................................................................... 6
3.0
Endpoints...............................................................................6
3.1
Primary Endpoint ................................................................................... 6
3.2
Secondary Endpoint ............................................................................... 7
3.3
Other Efficacy Endpoints ....................................................................... 7
3.4
Safety Endpoints .................................................................................... 8
3.5
Additional Endpoint(s) ........................................................................... 8
4.0
Analysis Populations .............................................................8
5.0
Subject Disposition................................................................9
6.0
Study Drug Duration...........................................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................10
7.1
Demographics and Baseline Characteristics.......................................... 10
7.2
Medical History and Prior and Concurrent Procedures.......................... 10
7.3
Prior and Concomitant Medications...................................................... 11
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................11
9.0
Efficacy Analyses.................................................................12
9.1
General Considerations......................................................................... 12
9.2
Handling of Missing Data..................................................................... 13
9.3
Primary Efficacy Endpoint and Analyses.............................................. 13
9.3.1
Primary Efficacy Endpoint ................................................................... 13
9.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 13
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint............................................................................................... 14
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 14
 


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9.4.1
Key Secondary Efficacy Endpoints....................................................... 14
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints .......................... 14
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 14
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 14
9.5
Efficacy Endpoints and Analyses.......................................................... 14
9.6
Efficacy Subgroup Analyses................................................................. 18
10.0
Safety Analyses....................................................................18
10.1
General Considerations......................................................................... 18
10.2
Adverse Events..................................................................................... 18
10.2.1
Treatment-Emergent Adverse Events.................................................... 19
10.2.2
Adverse Event Overview...................................................................... 19
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 20
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 20
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 20
10.2.6
Adverse Events of Special Interest and Possible Distant Spread of 
Toxin Adverse Events .......................................................................... 21
10.3
Analysis of Laboratory Data................................................................. 21
10.4
Analysis of Vital Signs......................................................................... 21
10.5
Safety Subgroup Analyses.................................................................... 22
10.6
Other Safety Analyses .......................................................................... 22
11.0
Other Analyses ....................................................................22
12.0
Interim Analyses..................................................................22
12.1
Data Monitoring Committee................................................................. 23
13.0
Overall Type-I Error Control.............................................23
14.0
Version History ...................................................................23
15.0
References............................................................................23
List of Tables
Table 1.
Criteria for Potentially Clinically Important Vital Sign Values ............. 22
 


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Table 2.
SAP Version History Summary ............................................................ 23
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 24
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for BOTOX 
(Botulinum Toxin Type A) for Study M21-323, entitled "Phase 3, Multicenter Open-label 
Extension Study to Evaluate the Safety of BOTOX® (Botulinum Toxin Type A) Purified 
Neurotoxin Complex for the Treatment of Platysma Prominence."
Study M21-323 examines the long-term safety of repeated BOTOX (Botulinum Toxin 
Type A) treatments of platysma prominence in subjects who have previously completed a 
lead-in pivotal Phase 3 study. 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 evaluate the long-term safety of repeat treatments of BOTOX in 
subjects with moderate to severe platysma prominence at maximum contraction.
The clinical hypothesis is that BOTOX is a safe treatment after repeat treatment in adult 
subjects with moderate and severe platysma prominence.
As the objective is to evaluate safety, no formal testing will be conducted and no 
estimands are provided.
2.2
Study Design Overview
The schematic is shown in Figure 1 with the current M21-323 open-label study (OLS) as 
an extension of the M21-309 double-blind placebo-controlled (DBPC) lead-in study.
 


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Figure 1.
Study Schematic
2.3
Treatment Assignment and Blinding
This study is an open-label study with no control group and no randomization. Study drug 
(BOTOX) will be unblinded.
2.4
Sample Size Determination
No formal statistical power or sample size calculation was performed for this study. 
Approximately 270 subjects are anticipated to be enrolled or rolled-over into this study. 
 
 
 
 
 
3.0
Endpoints
3.1
Primary Endpoint
For both US FDA and European Union (EU) regulatory agencies, the primary endpoint of 
the study is incidence of adverse events.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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3.2
Secondary Endpoint
Not applicable.
3.3
Other Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4
Safety Endpoints
The primary endpoint is the incidence of adverse events (AEs). Safety parameters include 
AEs and vital signs. Safety analyses will be performed by study drug group (e.g., lead-in 
study treatment, along with BOTOX treatments in this study) and number of BOTOX 
cycles (i.e., total number of treatment cycles up to 4, including BOTOX treatment from 
the lead-in study).
3.5
Additional Endpoint(s)
Not applicable.
4.0
Analysis Populations
The following population sets will be used for the analyses.
 


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For US FDA analyses, efficacy variables will be analyzed based on the intent-to-treat 
(ITT) population. The ITT population consists of all subjects who enrolled in this study.
For EU regulatory agencies only, the efficacy analyses will be performed on the modified 
intent-to-treat (mITT) population,
 
Safety analyses will be based on the Safety Analysis Set (safety population), which 
consists of all subjects who received at least 1 dose of study drug either in the lead-in 
study or in this study. Subjects will be analyzed by actual study drug received, including 
both the lead-in study, as well as during this study.
Subject data from the current study will be integrated with the corresponding subject data 
from the lead-in study.
5.0
Subject Disposition
The total number of subjects who were enrolled and treated 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 (including 
from the lead-in study):
●Subjects enrolled in the study;
●Subjects who took at least one dose of study drug;
●Subjects who completed the study;
●Subjects who prematurely discontinued study drug;
●Subjects in each analysis population, as applicable.
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 and 
treatment cycles.
 


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6.0
Study Drug Duration
For the safety population, the number of subjects treated will be presented by treatment 
received for the lead-in study and for this study, as well as by number of cycles within this 
study. 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 and disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the ITT and mITT populations overall 
and by treatment group (including lead-in study) based on the lead-in study baseline data.
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, BAS-PP Items 1 and 2, ANLFQ-Satisfaction (Baseline) Item 5, and ANLFQ-
Impacts domain based on the lead-in study data.
7.2
Medical History and Prior and Concurrent 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 will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The actual 
 


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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. 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).   Similarly, the number and percentage of subjects in each 
prior procedure category will be summarized overall and by treatment group by MedDRA 
high level term and preferred term.
In addition, any concurrent procedures, defined as any procedure performed on or after 
the date of first treatment in this study, will be summarized by MedDRA high level term 
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 in this study. A concomitant medication is defined as any 
medication that started prior to the date of the first dose of study drug in this study 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
For the primary endpoint, AEs will be reported as observed, without additional handling 
of potential intercurrent events.
There are no secondary endpoints in this study.
 


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9.0
Efficacy Analyses
9.1
General Considerations
Summary and Analysis of the Primary Endpoint
There are no primary efficacy endpoints. The primary endpoint is safety, and the analyses 
related to the primary endpoint of incidence of AEs are described in Section 10.0.
Summary and Analysis of Efficacy Endpoints
In general, the proportions of subjects who achieve the efficacy endpoints will be 
summarized with frequency tables. The 95% confidence intervals for response will be 
estimated based on the observed data by study drug group and by BOTOX treatment cycle 
(both lead-in study as well as this study). No missing data imputation or statistical testing 
will be performed.
For the US FDA, efficacy measures will be summarized using descriptive statistics using 
the ITT population based on the observed data. For the EU efficacy measures, descriptive 
statistics will be reported for the mITT population based on observed data. Continuous 
measures will be reported by timepoint using the number observed, mean, standard 
deviation, median, 25th and 75th quartiles, minimum and maximum. Categorical 
measures will be reported by time point using the number observed, counts for each 
category, and percentages. In addition, for the responder definitions, the 95% CIs will be 
included.
 
 
 
 
 


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9.2
Handling of Missing Data
In general, no missing data will be imputed for the efficacy analyses. If a score (C-APPS 
or P-APPS) is missing for one side, then the average will be based on the score of the 
other side (see Section 9.1). If both scores are missing for both sides, then the score will 
be missing.
9.3
Primary Efficacy Endpoint and Analyses
9.3.1
Primary Efficacy Endpoint
There is no primary efficacy endpoint. The primary endpoint is incidence of AEs (safety).
9.3.2
Main Analysis of Primary Efficacy Endpoint
Not applicable.
 


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9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint
Not applicable.
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Key Secondary Efficacy Endpoints
Not applicable.
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints
Not applicable.
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints
Not applicable.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
Not applicable.
9.5
Efficacy Endpoints and 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. For the safety analysis, 
subjects are assigned to a treatment group based on the treatment actually received and 
will be presented by treatment groups and by treatment cycle, including number of 
BOTOX treatment cycles (up to 4, including the lead-in study). Safety analyses will take 
into account both study drug groups and number of BOTOX treatment cycles (e.g., 
placebo or BOTOX in the lead-in Phase 3 study, BOTOX in this study up to 3 treatment 
cycles) from both the lead-in Phase 3 study and this study.
The safety parameters will include incidence of AEs and change from lead-in study
baseline in vital signs. For each safety parameter evaluating change from lead-in study 
baseline, the last nonmissing safety assessment before study drug administration of the 
lead-in study will be used as 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 
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 
 


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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. For the lead-in study, the TEAEs will already be defined, and will 
be counted in the overall group presentation of events. TEAEs collected for this study will 
be counted as TEAEs of the previous study if the first dose of study drug was not 
administered in this study; otherwise, they will be counted as TEAEs in this study after 
the first dose of study drug in this study. 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 TEAE related to study treatment
○
Any TEAE related to study drug according to the investigator
○
Any TEAE related to study procedure according to the investigator
●
Any mild TEAE
○
Any mild TEAE related to study treatment according to the investigator
●
Any moderate TEAE
○
Any moderate TEAE related to study treatment according to the 
investigator
 


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●
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 TEAE leading to discontinuation of study treatment
●
Any treatment-emergent adverse event of special interest (AESI)
●
Any possible distant spread of toxin (PDSOT) TEAE
●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events 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 investigational product will be reported.
In addition, treatment-emergent adverse events 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
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
 


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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. 
 
 
Possible distant spread of toxin (PDSOT) AEs will be summarized by PT. 
 
 
Tabular listings of AESIs and PDSOT AEs 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 lead-in study baseline at each assessment timepoint 
will be summarized by treatment group. In addition, potentially clinically important vital 
sign values will be summarized.
 


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10.5
Safety Subgroup Analyses
 
 
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.
 




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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 did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose for study treatment.
●
Subject received prohibited concomitant medication or procedure.
 


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