Conditions: Forehead Lines
Keywords: Forehead Lines OnabotulinumtoxinA X
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
Facial lines that develop from repeated facial expression, such as forehead lines (FHL), are typically treated by selectively weakening specific muscles with small quantities of botulinum toxin. OnabotulinumtoxinA X is being investigated as another form of treatment to treat FHL by inhibiting the release of the neurotransmitter that causes the overactivity of the muscles responsible for the severity of these facial lines. The purpose of this study is to evaluate the safety and change in condition of 3 doses of OnabotulinumtoxinA X for the treatment of moderate to severe forehead lines.

Study doctors will determine if a subject is eligible for the study. If so, the subject will be randomized into 1 of the 4 groups, called treatment arms. There is a 1 in 4 chance that a participant will be assigned to placebo. Around 120 adult participants with FHL will be enrolled in the study in approximately 10 sites in the United States.

Participants will receive either intramuscular injections of onabotulinumtoxinA X or placebo.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular monthly visits during the study at the study site.

Detailed description:

Arms:
arm 1: Placebo will be injected into the forehead on Day 1. arm 2: OnabotulinumtoxinA X will be injected into the forehead on Day 1. arm 3: OnabotulinumtoxinA X will be injected into the forehead on Day 1. arm 4: OnabotulinumtoxinA X will be injected into the forehead on Day 1.

Interventions: intervention 1: OnabotulinumtoxinA X intervention 2: Placebo
Intervention descriptions: intervention 1: Intramuscular Injection intervention 2: Intramuscular Injection

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
OBJECTIVE AND ENDPOINTS
9
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
9
3.2
PRIMARY ENDPOINT
9
3.3
SECONDARY ENDPOINTS
10
3.4
ADDITIONAL EFFICACY ENDPOINTS
10
3.5
SAFETY ENDPOINTS
12
4
INVESTIGATIONAL PLAN
12
4.1
OVERALL STUDY DESIGN AND PLAN
12
4.2
DISCUSSION OF STUDY DESIGN
14
5
STUDY ACTIVITIES
15
5.1
ELIGIBILITY CRITERIA
15
5.2
CONTRACEPTION RECOMMENDATIONS
18
5.3
PROHIBITED MEDICATIONS/THERAPY AND PROCEDURES
20
5.4
PRIOR AND CONCOMITANT MEDICATIONS/THERAPY
20
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
22
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
23
5.7
STUDY DRUG
23
5.8
RANDOMIZATION/DRUG ASSIGNMENT
24
5.9
PROTOCOL DEVIATIONS
25
5.10 DATA MONITORING COMMITTEE
25
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
29
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7.1
STATISTICAL AND ANALYTICAL PLANS
29
7.2
DEFINITION FOR ANALYSIS POPULATIONS
29
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY EFFICACY ENDPOINT
29
7.4
STATISTICAL ANALYSES FOR EFFICACY
30
7.5
STATISTICAL ANALYSES FOR SAFETY
31
7.6
INTERIM ANALYSIS
31
7.7
OVERALL TYPE I ERROR CONTROL
32
7.8
SAMPLE SIZE DETERMINATION
32
8
ETHICS
32
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
32
8.2
ETHICAL CONDUCT OF THE STUDY
33
8.3
SUBJECT CONFIDENTIALITY
33
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
33
10 DATA QUALITY ASSURANCE
33
11 COMPLETION OF THE STUDY
34
12 REFERENCES
34
LIST OF TABLES
TABLE 1.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY EFFICACY ENDPOINT
9
TABLE 2.
STUDY DRUG IDENTIFICATION
23
TABLE 3.
STUDY ACTIVITIES TABLE (SITE VISITS)
41
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMA
14
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
36
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APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
38
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
39
APPENDIX D.
ACTIVITY SCHEDULE
40
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
43
APPENDIX F.
OPERATIONS MANUAL
44
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
Botulinum toxins act selectively at the neuromuscular or neuroglandular junction to reversibly block 
presynaptic acetylcholine release. OnabotulinumtoxinA is the active drug substance in BOTOX/BOTOX 
Cosmetic and in OnabotA X. BOTOX® (onabotulinumtoxinA) was first approved for aesthetic treatment 
in the United States for glabellar lines (GL) in 2002 and for forehead lines (FHL) in 2017, and is one of the 
most common nonsurgical procedures in aesthetic medicine.1
OnabotA X is an onabotulinumtoxinA investigational product being developed for the treatment of 
moderate to severe upper facial lines. Hyperfunctional facial lines that develop from repeated facial 
expression, such as GL and FHL, are typically treated by selectively weakening specific muscles with 
small quantities of botulinum toxin.2-6
Resting eyebrow position results from a balance between eyebrow elevator muscles, primarily the 
frontalis, and eyebrow depressor muscles, including the procerus, corrugators, and orbicularis oculi. 
Thus, isolated weakening of the frontalis muscle with cosmetic botulinum toxins treatment may result in 
eyebrow ptosis due to an imbalance between eyebrow elevators and depressors. Most clinicians agree 
that concurrent treatment of the glabellar area is recommended to reduce the risk of undesirable 
aesthetic outcomes (e.g., eyebrow malposition and eyebrow or eyelid ptosis).7,8 As a result, the 
treatment regimen proposed for this FHL study is the treatment of the frontalis muscle in conjunction 
with the glabellar complex.
 
 
 
 
 
 
2.2 Benefits and Risks to Subjects
OnabotulinumtoxinA is the active drug substance in BOTOX/BOTOX Cosmetic and in OnabotA X; 
therefore, safety data from prior studies of BOTOX are relevant to the benefit/risk assessment for 
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The clinical safety and efficacy profile of BOTOX has also been demonstrated in multiple Allergan and 
non-Allergan sponsored clinical trials across several indications, with favorable benefit/risk profiles.  In 
general, adverse reactions occur within the first few days following injection of BOTOX, and while 
generally transient, may have a duration of several months or, in rare cases, longer. Below is a brief 
summary of safety for BOTOX utilized in the treatment of FHL, multiple facial areas (including FHL, GL, 
and lateral canthal lines [LCL]), and GL. More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events (AEs) of OnabotA X may be found in the 
Investigator's Brochure (IB) and the subject's informed consent form (ICF).
Safety data for BOTOX treatment of FHL come from 3 double-blind, placebo-controlled trials conducted 
in North America and Europe (
 
). A total of 1260 subjects were exposed to at least 1 BOTOX treatment
), the majority 
of whom received either 40 U (N = 749) or 64 U (N = 746), the doses approved for treatment of FHL and 
of FHL and LCL, respectively.
The most frequently reported treatment-emergent adverse events (TEAEs) were commonly occurring 
conditions in the general population (e.g., headache [11.1% of all BOTOX-treated subjects, 
] 
and nasopharyngitis [7.9%, 
]) or events commonly occurring following injections to 
vascularized areas (e.g., injection site bruising [6.9%, 
]). Most of these events were mild or 
moderate in severity.
 
 
 
 
 
 
 
 
For further details, please see findings from completed studies, including safety data in the current 
OnabotA X Investigator's Brochure.
Considering the coronavirus disease – 2019 (COVID-19) pandemic, and based on the information to 
date, no additional risk to study participants is anticipated with the use of OnabotA X.  While AbbVie 
does not consider COVID-19 to be a safety concern for OnabotA X due to its mechanism of action and 
route of administration, the Marketing Authorization Holder is monitoring COVID-19 events during the 
pandemic closely. A recent review of COVID-19 events for the period of 01 January 2019 through 
31 December 2021 did not identify any new or significant safety findings for the patients receiving 
BOTOX (onabotulinumtoxinA) treatment. Overall, the clinical course and presentation of patients with 
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COVID-19 infection coincident with BOTOX (onabotulinumtoxinA) is consistent with what has been 
described for the general population.
3 OBJECTIVE AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The objective of this study is to evaluate the safety and efficacy of 3 doses of OnabotA X for the 
treatment of moderate to severe FHL.
3.2 Primary Endpoint
The primary efficacy endpoint is the achievement of ≥ 1-grade improvement from baseline on the 
investigator-rated Facial Wrinkle Scale (FWS-FHL) at maximum contraction (also known as eyebrow 
elevation or surprise) at Day 30.
Estimand attributes of the primary efficacy endpoint are detailed in Table 1.
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical 
Summary
Hypothetical 
estimand for 
primary 
endpoint
OnabotA X 
or 
placebo
Achievement of 
≥1-grade improvement 
from baseline on the 
investigator-rated FWS-
FHL at maximum 
contraction at Day 30
ITT (All 
randomized)
Missing data will be 
imputed using 
multiple 
imputation.
Difference in 
response 
proportions 
between each 
active treatment 
group and 
placebo, after MI 
using CMH test 
stratified by 
baseline 
investigator-
rated FWS-FHL at 
maximum 
contraction
CMH = Cochran-Mantel-Haenszel; FWS-FHL = Facial Wrinkle Scale; Forehead Lines; ITT = intent-to-treat; MI = multiple 
imputation; OnabotA X = onabotulinumtoxinA X
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3.3 Secondary Endpoints
Secondary Endpoints
No secondary endpoints are identified in this study.
 
 
 
 
 
 
 
 
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3.5 Safety Endpoints
Primary Safety Endpoints include:

Incidence of adverse events (AEs) 
 

Change from baseline in vital signs (body temperature, pulse rate, respiratory rate, and blood 
pressure [systolic and diastolic]).
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 180-day, multicenter, randomized, placebo-controlled, Phase 2 study to evaluate the safety and 
efficacy of 3 doses of OnabotA X for the treatment of moderate to severe FHL. To be eligible for 
enrollment, subjects must have symmetrical moderate to severe FHL at maximum contraction as 
assessed by both investigator and subject using the FWS-FHL at screening and on Day 1 prior to study 
treatment. Both investigator and subject assessments must match.  Additionally, subjects must have GL 
of moderate or severe rating at maximum contraction as assessed by investigator using the FWS-GL at 
screening and on Day 1 prior to study treatment.
 
Approximately 120 subjects will be 
randomized to 4 treatment groups in a 1:1:1:1 ratio. At Day 1, all randomized subjects will receive a 
fixed dose of 
 of OnabotA X in the glabellar complex, followed by injections in the frontalis. The 
dose injected in the frontalis will vary depending on the treatment group the subject is assigned to, as 
follows:
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Figure 1.
Study Schema
4.2 Discussion of Study Design
Choice of Control Group
A placebo control group is the gold standard for comparative evaluations of safety and efficacy in clinical 
trials.  The control group will be used in this study in order to optimally evaluate the safety and efficacy 
of 3 different OnabotA X doses for treatment of moderate to severe FHL, defined as treatment of the 
frontalis muscle with simultaneous treatment of the glabellar complex.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All safety and 
efficacy-related measurements in this study are appropriate for assessing a novel formulation of a 
neuromodulator.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
Suitability of Subject Population
The study population will include adults with moderate to severe FHL at maximum contraction and GL at 
maximum contraction, assessed by using FWS.
There is an important interplay between the frontalis and other main muscular components of the 
upper face, including glabellar complex muscles.
 
As a result, the treatment regimen proposed for 
use in this study is a single treatment of FHL, composed of injections in the frontalis muscle, with 
simultaneous treatment of GL, composed of  injections in the procerus and corrugator muscles. Hence, 
subjects must meet the criteria for moderate to severe for both FHL and GL to be suitable to participate 
in this study.
In addition, the selection of subjects in general good health is standard for safety studies.
 
 
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Selection of Doses in the Study
OnabotulinumtoxinA is approved as a safe and effective treatment for GL and FHL at doses of 
 each 
and FHL treated simultaneously with GL (
). However, facial lines and wrinkles are strongly 
influenced by individual differences in anatomy and muscle activity, with some individuals requiring a 
higher dose to meet desired results.21 In the literature, higher cosmetic neurotoxin doses were reported 
to show greater efficacy and longer duration of effect in treating facial aesthetic indications including 
FHL.18-20,22
 
 
 
 
 
 
Considering the importance of the aesthetic evaluation, musculature variables among patients within 
same or different gender, a patient's desired outcome, and potential retreatment intervals, high and low 
doses will be tested to assess an optimal safe dose.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
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. Screen 
failures can occur during the screening period up to the point prior to randomization on Day 1.  
Rescreening is not allowed for individuals who do not meet key safety or efficacy Eligibility Criteria: 
  Any attempt to rescreen a subject must only occur after 
agreement with the sponsor.
Consent
1. Subjects must voluntarily sign and date an informed consent approved by an institutional 
review board (IRB), prior to the initiation of any screening or study-specific procedures.
2. Subject is willing and able to comply with procedures required in this protocol.
Demographic and Other Assessments
3. Adult male or female, ≥ 18 years of age, at the time of signing the informed consent.
4. Subject must have sufficient visual acuity without the use of eyeglasses (contact lens use is 
acceptable) to accurately assess their facial lines.
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5. Subject must be able to follow study instructions and complete study assessment tools 
without any assistance or alterations to the assessment tools, and complete all required study 
procedures.
6. Subject is in good health as determined by medical history, vital signs, and investigator's 
judgment, including no known active pandemic infection.
Condition Activity
7. Subject must have symmetrical moderate to severe FHL at maximum contraction
 
 
8.
Subject History
9. No history of known immunization to any botulinum toxin serotype.
10. No history of known hypersensitivity to any botulinum toxin serotype,
 
, or any other constituents of the study drug or its excipients, and/or other 
products in the same class.
 
 
13. No presence or history of any medical condition that may place the subject at increased risk 
following exposure to OnabotA X or interfere with the study evaluation, including:

Diagnosed myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, or 
any other significant disease that might interfere with neuromuscular function;

Facial nerve palsy;

Infection or dermatological condition at the site of study drug injection;
 
 
 
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Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
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5.3 Prohibited Medications/Therapy and Procedures
In addition to the medications listed in the eligibility criteria, no other facial cosmetic procedures or 
treatments are to be performed throughout the duration of the study.
 
 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:

Concurrent treatment with botulinum neurotoxin of any serotype for any indication (other than 
the study intervention)

Medium depth to deep facial chemical peels 
 to the face

Energy-based treatments
 
to the face

Microneedling to the face

Facial lift or cosmetic/surgical suspension threads (upper facial area or full face)

Rhinoplasty

Blepharoplasty
During the study, all other investigational drugs are prohibited.
5.4 Prior and Concomitant Medications/Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) 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 (including prescription or over-the-counter medication, 
vitamins, and/or herbal supplements) is to be recorded on the subject's 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. Study site personnel must notify the sponsor immediately if a subject uses a 
concomitant medication or has a concurrent procedure that is prohibited per protocol (see Section 5.3).  
Subjects who use prohibited concomitant medications or have a prohibited concurrent procedure may 
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be discontinued at the discretion of the investigator or sponsor. 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.  When possible, study drug should be given at least ± 7 days from vaccine 
administration.
 
Systemic and topical hormones and their derivatives (i.e., sex steroids - androgens, estrogens, 
progesterone) should be maintained throughout study period to avoid changes in skin, including but not 
limited to:

Oral birth control

IUDs/implants/injections

Oral supplements including testosterone & estrogens and their derivatives, 
dehydroepiandrosterone (DHEA), etc.

Topicals (anywhere on the body) including testosterone & estrogens and their derivatives, 
DHEA, etc.
 
Subjects must maintain their standardized skin care regimen throughout the study period.
Any questions regarding concomitant or prior medications/therapy and concomitant procedures should 
be raised to the AbbVie non-emergency contact.  Information regarding potential drug interactions with 
OnabotA X can be located in the OnabotA X Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications as described in the eligibility 
criteria.  Subjects must be consented for the study prior to discontinuing any prohibited medications for 
the purpose of meeting study eligibility.
 
 
 
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5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:  
 

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.
 

Subject is significantly noncompliant with study procedures.
This is a single dose study and treatment will be administered on Day 1 only. In case of pregnancy or AE 
during the study, after study treatment is provided, the subject should continue in the study for safety 
follow-up.
In case the subject has a desire to end his/her participation, or is discontinued for any reason, the 
Premature Discontinuation Visit procedures should be completed.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor's non-emergency medical contact before discontinuing a 
subject from the study for a reason other than described in the protocol, to ensure all acceptable 
mitigation steps have been explored.
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5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for safety and efficacy assessments, subjects who prematurely discontinue 
study drug treatment on Day 1 should continue to be followed for all regularly scheduled visits, unless 
subjects have decided to discontinue the study participation entirely (withdrawal of informed consent).  
Subjects should be advised on the continued scientific importance of their data even if they discontinue 
treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after the last 
dose of study drug may be completed to ensure all treatment-emergent AEs/SAEs have been resolved.
5.7 Study Drug
OnabotA X is an intramuscular injectable 
 and will be prepared and administered on Day 1 
only, as a single treatment.  All components of the investigational product admixture will be supplied 
unblinded and labeled as required per US FDA requirement. Components will be packaged as three kits, 
as per Table 2. 
 
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5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
5.10 Data Monitoring Committee
An independent DMC will be instituted to review interim safety and efficacy data to provide a dose 
  The interim analysis will occur after the majority of
subjects have completed the Day 90 visit or prematurely discontinued.  A snapshot will include all data 
collected up to the data cutoff date. Study sites, study team and subjects will remain blinded for the 
duration of the study.
The details of the interim analyses are included in Section 7.6.
The DMC will review the results of the interim analyses and make a recommendation to the sponsor in 
accordance with the DMC Charter.
A separate DMC charter will be prepared outside of the protocol and will further describe the roles and 
responsibilities of the DMC members, frequency and scope of the data reviews, and expectations for 
blinded communications.
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).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
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Medical Complaints/Adverse Events and Serious Adverse Events:  OnabotA X
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.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
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 or Clinical Research Organization (as appropriate) as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the SAE (refer to 
Section 4.2 of the Operations Manual [Appendix FAppendix E] for reporting details and contact 
information):
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.
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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.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event along with any suspected transmission of an 
infectious agent via a medicinal product if no other serious criterion 
is applicable.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration will be collected for at least 30 days after 
the last dose of study drug or until the last follow-up visit, whichever is longer, whether solicited or 
spontaneously reported by the subject.  In addition, study procedure-related serious and nonserious AEs 
will be collected from the time the subject signs the study-specific informed consent.
 
 
 
 
 
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
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7.5 Statistical Analyses for Safety
The safety analyses will be performed using the safety population.  Safety evaluations include AEs, 
abbreviated physical examination, neurological assessment, and change from baseline in vital signs
(body temperature, pulse rate, respiratory rate, and blood pressure [systolic and diastolic]).  Safety 
endpoints will be summarized using descriptive statistics and/or shift tables, as applicable.  For each 
safety endpoint evaluating change from baseline, the last nonmissing safety assessment before study 
intervention administration will be used as the baseline for all analyses of that endpoint.
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose of study 
drug.  Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent.
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 treatment-emergent AE

Any treatment-emergent AE related to study treatment according to the investigator

Any treatment-emergent AE related to study procedure according to the investigator

Any treatment-emergent AE related to study drug according to the investigator

Any severe treatment-emergent AE

Any serious treatment-emergent AE

Any treatment-emergent AE leading to death

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 treatment-emergent AEs 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 closest relationship to investigational product will be reported.
SAEs (including deaths) will be summarized by SOC and PT and in listing format.
PDSOT AEs will be identified in the SAP and summarized by PT.  
Vital sign will be summarized for changes from baseline at each assessment timepoint.
7.6 Interim Analysis
An interim analysis is planned to occur after the majority of subjects have completed the Day 90 visit or 
prematurely discontinued.  The interim analyses will be unblinded to a group of AbbVie personnel who 
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are not directly involved in ongoing day-to-day study conduct.  Further details are provided in DMC 
Charter. 
Key efficacy analyses will be performed for the interim analysis, as well as summaries of key safety 
variables.
The SAP will describe the planned interim analyses in detail.  No separate SAP will be prepared for the 
interim analyses.
7.7 Overall Type I Error Control
Analyses will be conducted using a Type I error rate of α=0.05 for each OnabotA X group.  The p-values 
will be presented as unadjusted p-values that are deemed statistically significant if p≤0.05.
7.8 Sample Size Determination
Approximately 120 subjects will be randomized into the study in a 1:1:1:1 ratio (30 in each group) 
yielding approximately 90 subjects receiving OnabotA X in the frontalis muscle for treatment of FHL.
The sample size of 120 is chosen empirically to allow for an adequate safety data of subjects treated 
with OnabotA X for this indication.
The primary efficacy endpoint is the achievement of ≥ 1-grade improvement from baseline on the 
investigator-rated FWS-FHL at maximum contraction at Day 30. 
 
Assuming 
 
 the sample size of 
N = 30 per group will provide 97% power.
All calculations are based on a 2-sided type I error rate of 0.05.
 
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, 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.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  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 samples 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.
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11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
ASAPS. American Society of Aesthetic Plastic Surgery: Cosmetic surgery national data bank: 
statistics. New York: ASAPS; 2017.
2.
Blitzer A, Binder WJ, Aviv JE, et al. The management of hyperfunctional facial lines with 
botulinum toxin. A collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol 
Head Neck Surg. 1997;123(4):389-92.
3.
Carruthers A, Carruthers J. Botulinum toxin type A for the treatment of glabellar rhytides. 
Dermatol Clin. 2004;22(2):137-44.
4.
Garcia A, Fulton JE, Jr. Cosmetic denervation of the muscles of facial expression with botulinum 
toxin. A dose-response study. Dermatol Surg. 1996;22(1):39-43.
5.
Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: a double-blind, placebo-
controlled study with an electromyographic injection technique. J Am Acad Dermatol. 
1996;35(4):569-72.
6.
Pribitkin E, Greco T, Goode R, et al. Patient selection in the treatment of glabellar wrinkles with 
botulinum toxin type A injection. Arch Otolaryngol Head Neck Surg. 1997;123(3):321-6.
7.
Bulstrode N, Grobbelaar A. Long-term prospective follow-up of botulinum toxin treatment for 
facial rhytides. Aesthetic plastic surgery. 2002;26(5):356-9.
8.
Lorenc ZP, Smith S, Nestor M, et al. Understanding the functional anatomy of the frontalis and 
glabellar complex for optimal aesthetic botulinum toxin type A therapy. Aesthetic plastic 
surgery. 2013;37(5):975-83.
9.
Bhatnagar D, Conkling N, Rafailovich M, et al. An in vivo analysis of the effect and duration of 
treatment with botulinum toxin type A using digital image speckle correlation. Skin Research 
and Technology. 2013;19(3):220-9.
10.
Carruthers J, Rivkin A, Donofrio L, et al. A Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Repeated OnabotulinumtoxinA 
Treatments in Subjects With Crow's Feet Lines and Glabellar Lines. Dermatologic Surgery. 
2015;41(6):702-11.
11.
Carruthers A, Carruthers J. A single-center, dose-comparison, pilot study of botulinum 
neurotoxin type A in female patients with upper facial rhytids: safety and efficacy. Journal of the 
American Academy of Dermatology. 2009;60(6):972-9.
12.
Carruthers J, Carruthers A. Botulinum toxin type A treatment of multiple upper facial sites: 
patient-reported outcomes. Dermatologic surgery. 2007;33:S10-S7.
13.
Chauhan DS, Cariappa K, Guruprasad Y. Botulinum toxin type a for the treatment of hyperkinetic 
lines of the face. Journal of maxillofacial and oral surgery. 2013;12(2):173-83.
14.
Graber EM, Dover JS, Arndt KA. Two cases of herpes zoster appearing after botulinum toxin type 
a injections. The Journal of clinical and aesthetic dermatology. 2011;4(10):49.
15.
Lowe NJ, Shah A, Lowe PL, et al. Dosing, efficacy and safety plus the use of computerized 
photography for botulinum toxins type A for upper facial lines. Journal of Cosmetic and Laser 
Therapy. 2010;12(2):106-11.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
16.
Michaels BM, Csank GA, Ryb GE, et al. Prospective randomized comparison of 
onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport) in the treatment of forehead, 
glabellar, and periorbital wrinkles. Aesthetic surgery journal. 2012;32(1):96-102.
17.
Prager W, Huber-Vorländer J, Taufig AZ, et al. Botulinum toxin type A treatment to the upper 
face: retrospective analysis of daily practice. Clinical, cosmetic and investigational dermatology. 
2012;5:53.
18.
Bowler PJ. A retrospective study in the use of botulinum toxin type-A in a UK multidisciplinary 
cosmetic practice. J Cosmet Dermatol. 2005;4(2):89-92.
19.
Carruthers A, Carruthers J. Prospective, double-blind, randomized, parallel-group, dose-ranging 
study of botulinum toxin type A in men with glabellar rhytids. Dermatol Surg. 2005;31(10):1297-
303.
20.
Carruthers A, Carruthers J, Said S. Dose-ranging study of botulinum toxin type A in the treatment 
of glabellar rhytids in females. Dermatol Surg. 2005;31(4):414-22; discussion 22.
21.
Anido J, Arenas D, Arruabarrena C, et al. Tailored botulinum toxin type A injections in aesthetic 
medicine: consensus panel recommendations for treating the forehead based on individual 
facial anatomy and muscle tone. Clinical, cosmetic and investigational dermatology. 
2017;10:413.
22.
Carruthers A, Carruthers J, Cohen J. A prospective, double-blind, randomized, parallel-group, 
dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead 
rhytides. Dermatologic surgery. 2003;29(5):461-7.
23.
Cox SE, Joseph JH, Fagien S, et al. Safety, pharmacodynamic response, and treatment 
satisfaction with onabotulinumtoxinA 40 U, 60 U, and 80 U in subjects with moderate-to-severe 
dynamic glabellar lines. Toxicon. 2021;190:S14.
24.
Joseph JH, Eaton LL, Robinson J, et al. Does increasing the dose of Abobotulinumtoxina impact 
the duration of effectiveness for the treatment of moderate to severe glabellar lines? J Drugs 
Dermatol. 2016;15(12):1544-9.
25.
Wilson EB, Hilferty MM. The distribution of chi-square. proceedings of the National Academy of 
Sciences of the United States of America. 1931;17(12):684.
26.
O'Kelly M, Ratitch B. Clinical trials with missing data: a guide for practitioners. First ed: John 
Wiley & Sons, Ltd; 2014.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease – 2019
CRF
case report form
DHEA
dehydroepiandrosterone
DMC
data monitoring committee
eCRF
electronic case report form
EDC
electronic data capture
ePRO
electronic patient-reported outcome device
FDA
Food and Drug Administration
FHL
forehead lines
FWS
Facial Wrinkle Scale
FWS-FHL
Facial Wrinkle Scale – Forehead Lines
FWS-GL
Facial Wrinkle Scale – Glabellar Lines
GCP
Good clinical practice
GL
glabellar lines
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IDR 
Independent Drug Reconstitutor 
IEC
Independent ethics committee
IM
intramuscular
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
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Abbreviation
Definition
ITT
intent-to-treat
IU
International units
IUD
intrauterine device
LCL
lateral canthal lines
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
N/A
not applicable
OnabotA X
onabotulinumtoxinA X
PCR
polymerase chain reaction
PDSOT
possible distant spread of toxin
PRO
patient-reported outcomes
PT
preferred term
SAE
Serious adverse event
SAP
Statistical analysis plan
SAR
Serious adverse reactions
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOC
system organ class
SUSAR
Suspected unexpected serious adverse reactions
TCA
trichloroacetic acid
TEAE
treatment-emergent adverse event
U
units
US
United States
VDS
verbal descriptor scale
WOCBP
woman of child-bearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-606:  A Phase 2, Multicenter, Randomized, Placebo-controlled Study to Evaluate the Safety and 
Efficacy of OnabotulinumtoxinA X for Forehead Lines
Protocol Date:  18 July 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 
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 Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary 
to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments.
9.
Reporting promptly to AbbVie, the ethics committee/institutional review boards (as required) and other 
appropriate individuals (e.g., coordinating investigator, institution director): 

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Study Project Manager II
Clinical Study Leadership
Vice President, Head of Clinical 
Development, Aesthetic Medicine
Therapeutic Area
Executive Director, Biostatistics
Statistics
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SAP_001.pdf: 
O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
1
St ati sti c al A n al y si s Pl a n f or St u d y M 2 1 -6 0 6
A P h a s e 2, M ulti c e nt er, R a n d o mi z e d, Pl a c e b o -
c o ntr oll e d St u d y t o E v al u at e t h e S af et y a n d Effi c a c y 
of O n a b ot uli n u mt o xi n A X f or F or e h e a d Li n e s
D at e:  1 2 S e pt e m b er 2 0 2 2
V er si o n 2 . 0
 
N C T 0 5 1 5 2 5 7 6


O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
2
T a bl e of C o nt e nt s
1. 0
I ntr o d ucti o n ...........................................................................5
2. 0
St u d y Desi g n a n d O bjecti ves ................................................5
2. 1
O bject i ves, H yp ot heses a n d Esti ma n ds ................................................... 5
2. 2
St u d y  Desi g n O ver vie w.......................................................................... 6
2. 3
Treat me nt Assi g n me nt a n d Bli n di n g ....................................................... 6
2. 4
S a m ple Si ze Deter mi nat i on .................................................................... 7
3. 0
E n d p oi nts ...............................................................................7
3. 1
Pri mar y E n d p o i nt(s) ............................................................................... 7
3. 2
Sec o n dar y  E n d p oi nt(s) ........................................................................... 8
3. 3
Ot her Efficac y  E n d p oi nt(s)..................................................................... 8
3. 4
S af et y E n d p o i nt(s)................................................................................ 1 0
4. 0
A n al ysis P o p ul ati o ns ...........................................................1 0
5. 0
S u bject Dis p ositi o n ..............................................................1 1
6. 0
St u d y D ur ati o n a n d Tre at me nt E x p os ure .........................1 1
7. 0
De m o gr a p hics, B aseli ne C h ar acteristics, Me dic al 
Hist or y, a n d Pri or/ C o nc o mit a nt Me dic ati o ns ...................1 1
7. 1
D e m o gra p hics a n d Baseli ne C haracterist ics.......................................... 1 2
7. 2
Me dical Hist or y .................................................................................... 1 2
7. 3
Pri or a n d C o nc o mi ta nt Me dicati ons ...................................................... 1 2
7. 4
C o nc urre nt Pr oce d ure ........................................................................... 1 3
8. 0
H a n dli n g of P ote nti al I nterc urre nt E ve nts f or t he 
Pri m ar y a n d Ke y Sec o n d ar y E n d p oi nts ............................1 3
9. 0
Effic ac y A n al yses .................................................................1 3
9. 1
Ge neral C o nsi derati o ns ......................................................................... 1 3
9. 2
Ha n dli n g of Missi n g Data ..................................................................... 1 4
9. 3
Pri mar y Efficac y  E n d p oi nt(s) a n d A nal yses.......................................... 1 5
9. 3. 1
Pri mar y Efficac y  E n d p oi nt(s) ............................................................... 1 5
9. 3. 2
Mai n A nal ysis of Pri mar y  Efficac y E n d p oi nt(s).................................... 1 5
9. 3. 3
Se nsi tivi t y a nd S u p ple me ntar y  A nal yses of t he Pri mar y Efficac y 
E n d p oi nt(s) ........................................................................................... 1 7
9. 4
Sec o n dar y  Efficac y E n d p oi nts a n d A nal yses ........................................ 1 7
 


O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
3
9. 5
A d dit i onal Efficac y  A nal yses ............................................................... 1 7
9. 6
Efficac y S u b gr o u p A nal yses ................................................................. 1 7
1 0. 0
S afet y A n al yses ....................................................................1 7
1 0. 1
Ge neral C o nsi derati o ns ......................................................................... 1 7
1 0. 2
A d verse E ve nts ..................................................................................... 1 8
1 0. 2. 1
Treat me nt -E m er ge nt A d verse E ve nts.................................................... 1 8
1 0. 2. 2
d verse E ve nt O ver vie w ......................................................................... 1 8
1 0. 2. 3
Treat me nt -E m er ge nt A d verse E ve nts b y S O C a n d/ or P T...................... 1 9
1 0. 2. 4
S A Es (I ncl u di n g Deat hs) a n d A d verse E ve nts Lea di n g t o St u d y 
Dr u g Disc o nt i n uati on ........................................................................... 1 9
1 0. 2. 5
P ote nti al Dista nt S prea d of T o xi n A d verse E ve nts................................ 1 9
1 0. 3
A nal ysis of Vital Si g ns ......................................................................... 2 0
1 0. 4
S af et y S u b gr o u p A nal yses .................................................................... 2 0
1 0. 5
Ot her Safet y A nal yses .......................................................................... 2 1
1 1. 0
Ot her A n al yses ....................................................................2 1
1 2. 0
I nteri m A n al yses..................................................................2 1
1 2. 1
Data M o ni t ori n g C o m mitt e e................................................................. 2 1
1 3. 0
O ver all T y pe -I Err or C o ntr ol.............................................2 2
1 4. 0
Versi o n Hist or y ...................................................................2 2
1 5. 0
Refere nces ............................................................................2 2
Li st of T a bl e s
Ta ble 1.
S u m mar y  of t he Esti ma n d Attri b utes of t he Pri mar y Efficac y 
E n d p oi nt(s) ........................................................................................... 1 6
Ta ble 2.
S A P Versi o n Hist or y  S u m mar y............................................................ 2 2
Li st of Fi g ur e s
Fi g ure 1.
St u d y  Sc he matic..................................................................................... 6
 


O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
4
Li st of A p p e n di c e s
A p pe n di x A.
Pr ot oc ol  De viati ons .............................................................................. 2 3
A p pe n di x B.
Defi nit i on o f P ossi ble Dista nt S prea d of T o xi n ..................................... 2 4
A p pe n di x C.
P ote nti all y Cli nicall y I mp orta nt Cri t eria for S af et y E n d p oi nts .............. 2 5
 


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1. 0
I ntr o d u cti o n
T his Statist ical A nal ysis Pla n ( S A P) descri bes t he statist ical a nal yses f or O na b ot A X 
St u d y  M 2 1 -6 0 6 F ore hea d Li nes: O na b ot uli n u mt o xi n A X i n t he Treat me nt of M o derate t o 
Se vere F ore hea d Li nes ( F H L).
St u d y  M2 1 -6 0 6 e xa mi nes t he safet y a n d efficac y of O na b ot A X i n s u bjects wit h m o derate 
t o se vere f ore hea d li nes.
T he S A P will n ot be u p date d i n case of a d mi nistrati ve c ha n ges or a me n d me nts t o t he 
pr ot oc ol  u nless t he c ha n ges i m pact t he a nal ysis.
U nless n ote d ot her wise, all a nal yses will be perf or me d usi n g S A S Versi o n 9. 4 ( S A S 
I nstitute I nc., Car y , N C 2 7 5 1 3) or later u n der t he Li n u x o perati n g s yste m.
2. 0
St u d y D e si g n a n d O bj e cti v e s
2. 1
O bj e cti v e s, H y p ot h e s e s a n d E sti m a n d s
T he o bj ect i ve of t his st u d y is t o e valuate t he safet y a n d efficac y of 3 d oses of O na b ot A X 
f or t he treat me nt of m o derate t o se vere F H L.
T he n ull a n d alter nate h y p ot heses are t he f o ll owi n g :
H 0: PT = P P ( T he treat me nt res p o nse pr o ba bility bet wee n eac h O na b ot A X treat me nt 
gr o u p a n d t he place b o gr o u p is e q ual)
H A : PT ≠ P P ( T he treat me nt res p o nse pr o ba bility bet wee n eac h O na b ot A X treat me nt 
gr o u p a n d t he place b o gr o u p is n ot e q ual)
Esti ma n d attri b utes of t he pri mar y efficac y e n d p o i nt are detaile d i n Ta ble 1 (see Secti o n
9. 3. 2 ). I n a d ditio n , t he attri b ute of treat me nt is a si n gle d ose of acti ve treat me nt or 
pl ace b o.
Differe nces i n pr o p orti o n of s u bjects w h o w o ul d ac hie ve ≥ 1 -gra de i m pr o ve me nt fr o m 
baseli ne o n t he i n vest i gat or-rate d F W S- F H L at ma xi m u m c o ntracti o n at Da y 3 0 ha d t he y  
 




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Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
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s u bjects will recei ve a fi xe d d ose of 
 O na b ot A X i n t he gla bellar c o m ple x, 
f oll owe d b y i nject i ons i n t he fr o ntalis. Ra n d o mizati o n will be stratifie d b y t he 
i n vestig at or -assesse d baseli ne se verit y of  FH L ( F W S -F H L) at m a xi m u m c o ntractio n  a n d 
i n vestigat or si t e. 
2. 4
S a m pl e Si z e D et er mi n ati o n
A p pr o xi matel y  1 2 0 s u bjects will be ra n d o mize d i nt o t he st u d y in a 1: 1: 1: 1 rati o ( 3 0 i n 
eac h gr o u p) yiel di n g a p pr o xi matel y 9 0 s u bjects recei vi n g O na b ot A X i n t he fr o ntalis 
m uscle f or treat me nt of F H L.  T he sa m ple size of 1 2 0 is c h ose n e m piricall y t o all o w f or 
a n a de q uate safet y data of s u bjects treate d wit h O na b ot A X f or t his i n dicat i on.
T he pri mar y  efficac y e nd p oi nt i s t he ac hie ve me nt of ≥ 1 -gra de i m pr o ve me nt fr o m 
baseli ne o n  t he i n vesti gat or-rate d F W S -F H L at ma xi m u m c o ntractio n at Da y 3 0.   
 
  Ass u mi n g 
 
 t he sa m ple size of N = 3 0 per gr o u p will pr o vi de 9 7 % 
p o wer.
All calculat i ons are base d o n a 2 -side d t y pe I err or rate of 0. 0 5.  
 
 
.
3. 0
E n d p oi nt s
3. 1
Pri m ar y E n d p oi nt ( s)
T he pri mar y  efficac y e nd p oi nt i s t he ac hie ve me nt of ≥ 1 -gra de i m pr o ve me nt fr o m 
baseli ne o n  t he i n vesti gat or-rate d Facial Wri n kle Scale ( F W S -F H L) at ma xi m u m 
c o ntractio n  (als o k n o w n as e ye br o w ele vat i on or s ur prise) at Da y 3 0.
T he F W S -F H L is sc ore d o n a 0-3 ra n ge ( 0 = N o ne, 1 = Mil d, 2 = M o derate, 3 = Se vere). 
 








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5. 0
S u bj e ct Di s p o siti o n
T he t otal  nu m ber of s u bjects w h o were scree ne d, ra n d omize d , a n d treate d will be 
s u m marize d. 
A s u m mar y  of s u bject acc o u nta bility will  be pr o vi de d w here t he n u m ber of s u bjects i n 
eac h of t he f o ll owi n g cate g ori es will be s u m marize d f or o v erall a n d eac h treat me nt gr o u p:
●
S u bjects e nr o lle d (ra n d omize d) i n t he st u d y;
●
S u bjects w h o were treate d ;
●
S u bjects w h o c o m plet e d t he st u d y;
●
S u bjects w h o pre mat urel y disc o nt i n ue d t he st u d y;
●
Reas o ns f or disc o nt i n uati on will be s u m marize d
S u bjects i n eac h a nal ysis p o p ulat i on will als o be s u m marize d.
6. 0
St u d y D ur ati o n a n d Tr e at m e nt E x p o s ur e
F or t he Safet y p o p ul at i on, st u d y durati o n  will be s u m marize d f or eac h treat me nt gr o u p 
a n d o verall. St u d y d uratio n  will be s u m marize d wit h descri pt i ve statistics ( mea n a n d 
sta n dar d de viati on, m e dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m).   T he n u m ber of s u bjects 
e x p ose d f or s pecific peri o d of ti me (
) will als o be s u m marize d.  
7. 0
D e m o gr a p hi c s, B a s eli n e C h ar a ct eri sti c s, M e di c al 
Hi st or y, a n d Pri or/ C o n c o mit a nt M e di c ati o n s
D e m o gra p hics, baseli ne c haracterist ics, me dical hist or y, prior a n d c o nc o mita nt 
me dicat i ons , a n d c o nc urre nt pr oce d ure will be s u m marize d f or t he I T T p o p ulati on o v erall 
a n d b y tr e at me nt gr o u p. Cate g orical varia bles will be s u m marize d wit h t he n u m ber a n d 
perce nta ge of s u bjects; perce nta ges will be calc ulate d base d o n t he n u m ber of n o n -
missi n g o bser vati o ns. C o n tin u o us varia bles will be s u m marize d wit h descri pt i ve statistics 
( n u m ber of n o n-missi n g o bser vat i ons, mea n a n d sta n dar d de viat i on, me dia n, Q 1, Q 3, 
mi ni m u m, a n d ma xi m u m).
 


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7. 1
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s
C o nti n u o us de m o gra p hic varia bles i ncl u de a ge. Cate g orical de m o gra p hic varia bles 
i ncl u de se x, et h nicity, race, a ge gr o u p 
).
Baseli ne c haracteristics i ncl u de wei g ht, hei g h t, b o d y mass i n de x ( B MI), nic oti ne use, 
alc o h o l use, Fi t z p atric k s ki n t y p e, i n vest i gat or-rate d a n d s u bject-rate d F W S -F H L a n d 
F W S -G L se verit y at ma xi m u m c o ntractio n a n d at rest , 
 
 
 
.
7. 2
M e di c al Hi st or y
Me dical hist or y  data will be c o de d usi n g t he Me dical Dicti onar y  for Re g ul at or y Act i vities 
( Me d D R A). T he act ual versi o n of t he Me d D R A c o di n g dict i onar y will be n ote d i n t he 
statistical ta bles a n d cli nical st u d y re p ort. T he n u m ber a n d perce nta ge of s u bjects i n eac h 
me dical hist or y  cate g or y ( b y Me d D R A s yste m or ga n class a n d preferre d t er m) will be 
s u m marize d o verall a n d b y tr e at me nt gr o u p. T he s yste m or ga n class ( S O C) will be 
prese nte d i n al p ha bet ical or der, a n d t he preferre d ter ms will be prese nte d i n al p ha betical 
or der wi t hi n eac h S O C.  S u bjects re p orti n g m ore t ha n o ne c o n diti on/ dia g n osis will be 
c o u nte d o nl y o nce i n eac h r o w ( S O C or preferre d ter m).
7. 3
Pri or a n d C o n c o mit a nt M e di c ati o n s
Pri or a n d c o nc o mita nt me dicat i ons will be s u m marize d b y  g e n eric na me. A pri or 
me dicat i on is defi ne d as a n y me dicati on ta ke n pri or t o t he date of t he st u d y  dr u g
a d mi nistratio n . A c o nc o mita nt me dicat i on is defi ne d as a n y me dicati on t hat starte d pri or 
t o t he st u d y dr u g a d mi nistratio n  a n d c o nt i n ue d t o be ta ke n after t he st u d y dr u g 
a d mi nistratio n  or a n y  me dicat i on t hat starte d after t he st u d y  dr u g a d mi nistratio n . T he 
n u m ber a n d perce nta ge of s u bjects ta ki n g me dicat i o ns will be s u m marize d b y ge neric 
dr u g na me base d o n t he W orl d Healt h Or ga nizat i on ( W H O) Dr u g Dict i onar y  for b ot h 
pri or a n d c o nc o mita nt me dicat i ons.
 


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7. 4
C o n c urr e nt Pr o c e d ur e
All pr oce d ures u n der g o ne o n or after S t u d y Da y 1 visit t hr o u g h t he e xit visit will be 
c o nsi dere d c o nc urre nt pr oce d ures. C o nc urre nt pr oce d ure will be s u m marize d b y 
Me d D R A hi g h le vel ter m a n d pr ef erre d ter m.  T he Me d D R A hi g h le vel ter m
will be 
prese nte d i n al p ha betical or der, a n d t h e preferre d ter ms will be prese nte d i n al p ha betical 
or der wi t hi n eac h hi g h le vel ter m . A listi n g will be ge nerate d f or c o nc urre nt pr oce d ures.  
8. 0
H a n dli n g of P ot e nti al I nt er c urr e nt E v e nt s f or t h e 
Pri m ar y  a n d K e y S e c o n d ar y E n d p oi nt s
T he pri mar y  e n d p oi nt will be a nal yze d base d o n t he I T T p o p ulat i on, a n d t he f o ll owi n g 
met h o ds will be use d t o a d dress p ote ntial i nterc urre nt e ve nts: 

S u bjects w h o di d n ot recei ve a n y d ose of st u d y  dr u g b ut are ra n d o mize d will still 
be i ncl u de d i n t he I T T p o p ulati o n. 

S u bjects w h o a re ra n d o mize d b ut pre mat urel y disc o nti n ue d t he st u d y bef ore 
assess me nt of t he pri mar y e n d p oi nt will be c o nsi dere d as part of t he I T T 
p o p ul at i on. 

S u bjects w h o die bef ore assess me nt of t he pri mar y e n d p o i nt will c o u nt as t h o u g h 
t he y h y p ot heticall y c o nti n ue d i n t he st u d y. 

S u bjects w h o are l ost t o f o ll ow- u p a n d are missi n g data f or t he pri mar y e n d p oi nt 
will c o u nt as t h o u g h t he y  h y p ot heticall y c o nti n ue d i n t he st u d y. 

S u bjects w h o are missi n g data f or a n y  ot her reas o n f or t he pri mar y e n d p oi nt will 
c o u nt as t h o u g h t he y h y p ot heticall y c o nt i n ue d i n t he st u d y.
9. 0
Effi c a c y A n al y s e s
9. 1
G e n er al C o n si d er ati o n s
All efficac y a nal yses will be c o n d ucte d i n t he I T T P o p ul at i on . F or t he efficac y a nal yses, 
s u bjects are s u m marize d base d o n t he ra n d o mize d treat me nt assi g ne d.
T he n u m ber a n d perce nta ge ( or pr o p orti o n) of t he s u bjects w h o are res p o n ders will be 
s u m marize d. C o nti n u o us varia bles will be s u m marize d b y n u m ber of s u bjects wit h 
 


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o b ser ve d val ues ( n), mea n, S D, me dia n, 1st a n d 3r d q uartiles ( Q 1, Q 3), mi ni m u m, a n d 
ma xi m u m . All efficac y  res ults will be s u m marize d b y tr e at me nt gr o u p.
U nless ot her wise s pecifie d, a n y s u bject w h o is ra n d o mize d base d o n a wr o n g strat u m will 
be a nal yze d acc or di n g t o t he act ual strat u m t he s u bject bel o n gs t o.
" Baseli ne" refers t o t he last n o n-mis si n g o bser vati o n bef ore t he first a d mi nistrati o n of 
st u d y dr u g or ra n d o mizati on if n o  st u d y dr u g is gi ve n.
9. 2
H a n dli n g of Mi s si n g D at a
Missi n g data will be i m p ute d usi n g m ult i ple i m p utati o n ( MI) met h o d f or t he pri mar y a n d 
sec o n dar y e n d p oi nts. 
S A S Pr oc MI pr oce d ure will be use d t o ge nerate 5 i m p utati o n data sets. See d f or all Pr oc 
MI pr oce d ure is pre -s pecifie d as 7 2 1 6 0 6 . 
 
 
 
 
 
 
 
 
 
 
 
 


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After i m p utati o n , t he c ha n ges fr om baseli ne val ues will be calc ulate d. T h e res p o n der 
stat us base d o n ra w val ues or c ha n ge fr o m baseli ne val ues will t he n be deri ve d f or eac h 
p ost baseli ne visit. 
Eac h of t he 5 i m p utati o n data sets will be a nal yze d i n di vi d uall y , t he n c o m bi ne d t o 
ge nerate t he fi nal i nfere nces as descri be d i n Sect io n  9. 3. 2 .
9. 3
Pri m ar y Effi c a c y E n d p oi nt( s) a n d A n al y s e s
9. 3. 1
Pri m ar y Effi c a c y E n d p oi nt( s)
T he pri mar y  efficac y e nd p oi nt i s ac hie ve me nt of ≥ 1 -gra de i m pr o ve me nt fr o m baseli ne o n  
t he i n vest i gat or-rated F W S -F H L at ma xi m u m c o ntractio n  at Da y 3 0.
9. 3. 2
M ai n A n al y si s of Pri m ar y Effi c a c y E n d p oi nt( s)
T he attri b utes of t he esti ma n ds c orres p o n di n g t o t he pri mar y efficac y e n d p o i nt are 
s u m marize d i n Ta ble 1 .
 


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T a ble 1.
S u m m ar y of t he Esti m a n d Attri b utes of t he Pri m ar y Effic ac y 
E n d p oi nt(s)
Esti m a n d 
L a bel
Attri b utes of t he Esti m a n d
Tre at me nt
E n d p oi nt
P o p ul ati o n
H a n dli n g of 
I nterc urre nt E ve nts
St atistic al 
S u m m ar y
H y p ot hetical 
esti ma n d f or 
pri mar y  
e n d p oi nt
O na b ot A X 
or  place b o
Ac hie ve me nt 
of ≥ 1 -gra de 
i m pr o ve me nt 
fro m baseli ne 
o n  t he 
i n vesti gat or-
rate d F W S -
F H L at 
ma xi m u m 
c o ntracti on at 
Da y  3 0 
I T T ( All 
ra n d o mize d)
S u bjects w h o 
disc o nti n ue st u d y 
pri or t o Da y 3 0 
assess me nts, or w h o 
d o n ot ha ve F W S -
F H L assess me nts 
will be i ncl u de d i n 
t he a nal ysis as a 
h y p ot hetical sce nari o 
i n w hic h t he y ha d 
n o t misse d t he F W S-
F H L assess me nts
Res p o nse rates 
a n d rate 
differe nces
bet wee n eac h 
acti ve treat me nt 
gr o u p a n d 
place b o, after 
MI usi n g C M H 
test stratifie d b y 
baseli ne 
i n vesti gat or-
rate d F W S -F H L
at ma xi m u m 
c o ntracti on 
F W S -F H L = F acial Wi n kle Scale - F ore hea d Li ne; C M H = C oc hra n -Ma ntel -Hae nszel; I T T = i nte nt -t o-treat; 
MI
= m ulti ple i m p utati o n; O na b ot A X = o na b ot uli n u mt o xi n A X
T he e val uati o n o f t he e q ualit y of  t he pr o p ortio n s of res p o n ders will be base d o n C oc hra n-
Ma ntel -Hae nszel  ( C M H) test stratifie d b y baseli ne i n vest i gat or-rate d F W S -F H L at 
ma xi m u m c o ntracti o n. Wal d c o nfi de nce i nter vals f or pr o p orti o ns of res p o n ders a n d 
differe nce i n t he pr o p orti o n of res p o n ders will be prese nte d.   T he Bresl o w -D a y  
h o m o ge neit y of t he o d ds -rati o test will be perf or me d t o test t he treat me nt-b y -i n vesti gat or-
rate d baseli ne F W S -F H L se verit y at ma xi m u m c o ntractio n  int eractio n .
T o o btai n p o ole d C M H p -val ue, t he Wils o n -Hilfert y  tr a nsfor m at i on will be use d. 1, 2
 
 
 
 


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9. 3. 3
S e n siti vit y a n d S u p pl e m e nt ar y A n al y s e s of t h e Pri m ar y 
Effi c a c y E n d p oi nt( s)
A se nsitivit y a nal ysis will be perf or me d f or t he pri mar y efficac y varia ble usi n g o bser ve d 
data.
9. 4
S e c o n d ar y Effi c a c y E n d p oi nt s a n d A n al y s e s
N o sec o n dar y  e n d p oi nts are ide nt ifie d i n t his st u d y.
 
 
9. 6
Effi c a c y S u b gr o u p A n al y s e s
N ot a p plica ble.
1 0. 0
S af et y A n al y s e s
1 0. 1
G e n er al C o n si d er ati o n s
S af et y data will be s u m marize d f or t he Safet y p o p ul at i on . Safet y s u m maries will be 
prese nte d b y treat me nt gr o u p a n d o verall.  F or t he safet y a nal yses, s u bjects are assi g ne d t o 
a treat me nt gr o u p base d o n t he treat me nt act uall y recei ve d, re gar dless of t he treat me nt 
ra n d omize d .
F or safet y a nal yses " baseli ne" refers t o t he last n o n -missi n g o bser vat i on bef ore t he 
first a d mi nistrati o n of st u d y dr u g u nless ot her wise n ot e d.
 


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1 0. 2
A d v er s e E v e nt s
A d verse e ve nts ( A Es) will be s u m marize d a n d prese nte d usi n g pri mar y Me d D R A S yste m 
Or ga n Classes ( S O Cs) a n d preferre d ter ms ( P Ts) acc or di n g t o t he versi o n of t he Me d D R A 
c o di n g dicti o nar y use d f or t he st u d y at t he ti me of data base l ock. T he act ual versi o n o f 
t he Me d D R A c o di n g dict i onar y  use d will be n ote d i n t he A E ta bles a n d i n t he cli nical 
st u d y re p ort. S pecific a d verse e ve nts will be c o u nte d o nce f or eac h s u bject f or calc ulat i n g 
perce nta ges, u nless state d ot her wise. I n a d ditio n , if t he sa me a d verse e ve nt occ urs 
m ult i ple ti mes withi n a s u bject, t he hi g hest se verit y a n d le vel of relat i ons hi p t o 
i n vestigat i onal pr o d uct will be re p orte d.
1 0. 2. 1
Tr e at m e nt -E m er g e nt A d v er s e E v e nt s
Treat me nt -e mer ge nt A Es are defi ne d as a n y A E wit h t he o nset t hat is after t he st u d y dr u g
a d mi nistratio n . E ve nts w here t he o nset date is t he sa me as t he st u d y dr u g start date are 
ass u me d t o be treat me nt -e mer ge nt , u nless k n o w n t o ha ve starte d pri or t o st u d y dr u g 
a d mi nistratio n . All treat me nt -e mer ge nt A Es will be s u m mar ize d o v erall (i.e., a n y 
preferre d t er m), as well as b y pri mar y Me d D R A S O C a n d Preferre d Ter m. T he S O Cs 
will be prese nte d i n al p ha bet ical or der, a n d t he P Ts will be prese nte d i n alp h a b eti cal or der
wi t hi n eac h S O C.
1 0. 2. 2
d v er s e E v e nt O v er vi e w
A n o ver vie w of A Es will  be prese nte d c o nsist i n g of t he n u m ber a n d perce nta ge of 
s u bjects e x perie nci n g at least o ne e ve nt f or eac h of t he f o ll owi n g A E cate g ories:
●
A n y treat me nt -e mer ge nt A E
●
A n y treat me nt -e mer ge nt A E relate d t o st u d y treat me nt acc or di n g t o t he 
i n vestig at or
○
A n y treat me nt -e mer ge nt A E relate d t o st u d y pr oce d ure acc or din g t o t he 
i n vestig at or
○
A n y treat me nt -e mer ge nt A E relate d t o st u d y dr u g acc or di n g t o t he 
i n vestig at or
 


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M 2 1 -6 0 6 – Statistical A nal ysis Pla n
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A n y se vere treat me nt- e mer ge nt A E
○
A n y severe tr e at me nt -e mer ge nt A E r elate d t o st u d y tr e at me nt acc or di n g t o 
t he i n vest i gat or
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A n y seri o us treat me nt -e mer ge nt A E
○
A n y serio us tr e at m e nt -e mer ge nt A E relate d t o st u d y tr e at me nt acc or di n g t o 
t he i n vest i gat or
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A n y treat me nt -e mer ge nt A E lea di n g t o deat h
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A n y P D S O T T E A Es
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All deat hs
1 0. 2. 3
Tr e at m e nt -E m er g e nt A d v er s e E v e nt s b y S O C a n d/ or P T
Treat me nt - e mer ge nt A Es will be s u m marize d b y S O C a n d P T; b y ma xi m u m se verity b y
S O C a n d P T; a n d b y  s u bject n u m ber a n d S O C a n d P T. S pecific treat me nt -e mer ge nt A Es 
will be c o u nte d o nce f or eac h s u bject f or calc ulat i n g perce nta ges, u nless state d ot her wise. 
I n a d ditio n , if t he sa me A E occ urs m ulti ple ti mes wi t hi n a s u bject, t he hi g hest se verity 
a n d le vel o f r elat i ons hi p t o i n vest i gati onal pr o d uct will be re p orte d.
I n a d ditio n , treat me nt -e mer ge nt a d verse e ve nts will be s u m marize d b y P T a n d s orte d b y  
decreasi n g fre q ue nc y f or t he o verall gr o u p.  S t u d y dr u g relate d treat me nt -e mer ge nt 
a d verse e ve nts a n d st u d y pr oce d ure relate d treat me nt -e mer ge nt a d verse e ve nts will als o be 
s u m marize d b y S O C a n d P T.
1 0. 2. 4
S A E s (I n cl u di n g D e at h s) a n d A d v er s e E v e nt s L e a di n g t o 
St u d y Dr u g Di s c o nti n u ati o n
S A Es (i ncl u di n g deat hs) will be s u m marize d b y S O C a n d P T a n d i n list i n g f or mat.
1 0. 2. 5
P ot e nti al Di st a nt S pr e a d of T o xi n A d v er s e E v e nt s
T o assess P D S O T, Me d D R A preferre d ter ms t hat ma y be ass ociate d wit h b ot uli n u m t o xi n 
effects ha ve bee n i de ntifie d ( A p pe n di x B ). All treat me nt -e mer ge nt A Es ass ociate d wit h 
P D S O T will be ta b ulate d b y  P T; i n a d ditio n , all P D S O T A Es will be liste d b y s u bject.
 


O na b ot A X
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1 0. 3
A n al y si s of Vit al Si g n s
Vi t al si g n meas ure me nts of s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y  
rate, a n d b o d y t e mperat ure will be s u m marize d b y treat me nt gr o u p.
 
 
 
 
 
Vi t al si g n varia bles will be e val uate d base d o n P CI criteria (
).
F or eac h vital si g n P CI criteri o n, t he n u m ber a n d perce nta ge of s u bjects w h o ha ve a vital 
sig n  val ue meet i n g t he criteria will be s u m marize d.
 
 
 
 
 
 
 
 
List i n gs will be pr o vi de d t o s u m marize s u bject-lev el  vit al si g n data f or s u bjects meet i n g 
P CI cri t eria.
1 0. 4
S af et y S u b gr o u p A n al y s e s
N ot a p plica ble.
 


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Ot h er S af et y A n al y s e s
Ne ur ol o gi c Assess me nt : T he ne ur ol ogi c assess me nt, w hic h c o mprises a F oc use d 
S y m pt o m s Q uesti on naire a n d F oc use d Ne ur ol o gic E xa mi nat i on, will be c o n d ucte d 
t hr o u g h o ut t he st u d y. A listi n g of ne ur ol o gic assess me nts will be pr o vi de d.
1 1. 0
Ot h er A n al y s e s
N ot a p plica ble. 
1 2. 0
I nt eri m A n al y s e s
A n i nteri m a nal ysis is pla n ne d t o occ ur w he n t he maj orit y of s u bjects ha ve c om p lete d t he 
 visi t or e xit e d fr o m t he st u d y.
 
 
 
  
T he pri mar y  a n d selecte d ot her efficac y a nal yses will be perf or me d f or eac h i nteri m 
a nal ysis, as well as s u m maries o f all safet y v ari a bles. F urt her details are pr o vi de d i n D M C 
C harter.
1 2. 1
D at a M o nit ori n g C o m mitt e e
A n i n de pe n de nt D M C will be inst itute d t o re vie w i nteri m safet y a n d efficac y data t o 
pr o vi de a d ose rec o m me n dat i on f or f ut ure cli nical st u dies. 
 
 
 
T he D M C will re vie w t he res ults of t he i nteri m a nal yses a n d ma ke a rec o m me n dat i on i n 
acc or da nce wit h t he D M C C harter. 
A se parate D M C c harter pre pare d o utsi de of t he pr ot oc ol de scri bes t he r oles a n d 
res p o nsi bilities of t he D M C me m bers, fre q ue nc y a n d sc o pe of t he data re vie ws, a n d 
e x pectatio n s for bli n de d c o m m u nicat i ons.
 




O na b ot A X
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A p pe n di x A. 
Pr ot oc ol De vi ati o ns
T he n u m ber a n d perce nta ge of u ni q ue s u bjects re p orti n g si g nifica nt pr ot oc ol de viat i ons 
will be s u m marize d i n t otal a n d b y treat me nt gr o u p f or all ra n d o mize d or treate d s u bjects. 
T he n u m ber a n d perce nta ge of u ni q ue s u bjects wit h pr ot oc ol de viat i on cate g ories bel o w 
will als o be s u m marize d i n t otal a n d b y treat me nt gr o u p.
●
S u bject e ntere d i nt o t he st u d y  e ve n t h o u g h s/ he di d n ot satisf y e ntr y criteria.
●
S u bject recei ve d wr o n g treat me nt or i nc orrect d ose of st u d y .
●
S u bject t o o k pr o hi bite d c o nc o mit a nt me d icati on or c o nc urre nt pr oce d ure .
 


O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
2 4
A p pe n di x B.
Defi niti o n of P ossi ble Dist a nt S pre a d of T o xi n
T a ble B -1.
Me d D R A Preferre d Ter ms E v al u ate d
f or P D S O T
Acc o m m o dati o n dis or der
As pirati o n 
B ell's Pals y
B ot ulis m
Br a d ycar dia 
B ul bar pals y
C o nsti pati o n
Cra nial ner ve palsie s m ulti ple
Cra nial ner ve paral ysis
Dia p hra g matic paral ysis
Di pl o pia
Dr y  m o ut h
D y sart hria
D y s p ha gia
D y s p h o nia
D y s p n oea
E yeli d f u ncti o n dis or der
E yeli d pt osis
Facial paral ysis
Facial paresis
H y p orefle xia
H y p ot o nia
Ile us paral ytic
M usc ular wea k ness
O pt hal m o ple gia
Paral y sis
Paresis cra nial ner ve
Pel vic fl o or m uscle wea k ness
Peri p heral ner ve pals y
Peri p heral paral ysis
P ne u m o nia as pirati o n
P u pillar y refle x i m paire d
Res pirat or y  arrest
Res pirat or y  de pressi o n
Res pirat or y  fail ure
S peec h dis or der
Ur i nar y rete nti o n
Visi o n bl urre d
V ocal c or d paral ysis
V ocal c or d paresis
N ote:
Ta ble is base d o n Me d D R A 2 5. 0; t he act ual list use d f or a nal ysis will be base d o n t he Me d D R A versi o n i n use 
at t he ti me of data base l oc k.
 


O na b ot A X
M 2 1 -6 0 6 – Statistical A nal ysis Pla n
Versi o n 2 . 0 – 1 2 Se pte m ber 2 0 2 2
2 5