Conditions: Glabellar Lines
Keywords: Glabellar Lines OnabotulinumtoxinA X BOTOX
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 92
Healthy volunteers: no

Brief summary:
Hyperfunctional facial lines that develop from repeated facial expression, such as glabellar lines (GL), are typically treated by selectively weakening specific muscles with small quantities of botulinum toxin. BOTOX (onabotulinumtoxinA) was first approved for aesthetic treatment of glabellar lines in 2001 and is one of the most common nonsurgical procedures in aesthetic medicine. This is a proof-of-concept study to evaluate how safe this new OnabotA X formulation is in treating adult participants with GL .

OnabotA X is an onabotulinumtoxinA investigational product being developed for the treatment of moderate to severe glabellar lines (GL). This is a 180-day, open-label study to assess the safety of a single dose of 3 different formulations of OnabotA X (A, B \& C; each with varying amounts of the standard excipients in the formulation) in adult subjects with moderate to severe GL. Around 90 participants will be enrolled in the study in approximately 5 sites in the United States.

Participants will receive one dose of OnabotA X administered as 5 injections on Day 1.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular weekly visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Detailed description:

Arms:
arm 1: Participants will receive one dose of OnabotA X administered as 5 injections to the corrugator and procerus muscles on Day 1. arm 2: Participants will receive one dose of OnabotA X administered as 5 injections to the corrugator and procerus muscles on Day 1. arm 3: Participants will receive one dose of OnabotA X administered as 5 injections to the corrugator and procerus muscles on Day 1.

Interventions: intervention 1: Formulation A: OnabotulinumtoxinA intervention 2: Formulation B: OnabotulinumtoxinA intervention 3: Formulation C: OnabotulinumtoxinA
Intervention descriptions: intervention 1: Intramuscular Injection intervention 2: Intramuscular Injection intervention 3: Intramuscular Injection

Protocol document:
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
6
3
OBJECTIVES AND ENDPOINTS
7
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
7
3.2
PRIMARY ENDPOINTS
7
3.3
SECONDARY ENDPOINTS
7
3.4
ADDITIONAL EFFICACY ENDPOINTS
7
3.5
SAFETY ENDPOINTS
8
3.6
IMMUNOGENICITY AND HYPERSENSITIVITY SAMPLING
9
4
INVESTIGATIONAL PLAN
9
4.1
OVERALL STUDY DESIGN AND PLAN
9
4.2
DISCUSSION OF STUDY DESIGN
10
5
STUDY ACTIVITIES
11
5.1
ELIGIBILITY CRITERIA
11
5.2
CONTRACEPTION RECOMMENDATIONS
13
5.3
PROHIBITED MEDICATIONS AND THERAPY
15
5.4
PRIOR AND CONCOMITANT THERAPY
15
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
17
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
17
5.7
STUDY DRUG
18
5.8
RANDOMIZATION/STUDY DRUG ASSIGNMENT
18
5.9
PROTOCOL DEVIATIONS
19
6
SAFETY CONSIDERATIONS
19
6.1
COMPLAINTS AND ADVERSE EVENTS
19
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
23
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7.1
STATISTICAL AND ANALYTICAL PLANS
23
7.2
DEFINITION FOR ANALYSIS POPULATIONS
23
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
23
7.4
STATISTICAL ANALYSES FOR EFFICACY
24
7.5
STATISTICAL ANALYSES FOR SAFETY
24
7.6
OVERALL TYPE I ERROR CONTROL
25
7.7
SAMPLE SIZE DETERMINATION
25
8
ETHICS
25
8.1
INSTITUTIONAL REVIEW BOARD (IRB)
25
8.2
ETHICAL CONDUCT OF THE STUDY
26
8.3
SUBJECT CONFIDENTIALITY
26
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
26
10 DATA QUALITY ASSURANCE
26
11 COMPLETION OF THE STUDY
27
12 REFERENCES
27
LIST OF TABLES
TABLE 1.
STUDY DRUG IDENTIFICATION
18
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
10
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
29
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
31
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
32
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APPENDIX D.
ACTIVITY SCHEDULE
33
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
35
APPENDIX F.
OPERATIONS MANUAL
37
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
OnabotA X is an onabotulinumtoxinA investigational product being developed for the treatment of GL.  
Hyperfunctional facial lines that develop from repeated facial expression, such as GL, are typically 
treated by selectively weakening specific muscles with small quantities of botulinum toxin.1-5  Botulinum 
toxins act selectively at the neuromuscular or neuroglandular junction to reversibly block presynaptic 
acetylcholine release.  BOTOX (onabotulinumtoxinA) was first approved for aesthetic treatment of 
glabellar lines in 2001 and is one of the most common nonsurgical procedures in aesthetic medicine.6
A key factor contributing to patient satisfaction with aesthetic treatments is the durability of therapeutic
benefit.7,8  An enhanced duration could increase patient satisfaction and require fewer clinician visits
and injections to maintain the therapeutic benefit.  With the intent of developing a formulation of 
onabotulinumtoxinA that would potentially meet this clinical need, several prototype formulations were 
screened and lead candidate formulations of OnabotA X were identified. 
 
  OnabotA X formulations may offer an improved treatment option to 
patients based on their durability profile.  This is a proof-of-concept study to evaluate the safety and 
exploratory efficacy of 3 different formulations of OnabotA X (A, B, and C; 
 
).
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 this 
first-in-human study of OnabotA X.  
The clinical efficacy and safety 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.  
In a meta-analysis conducted by Brin et al, the most frequently reported AEs among subjects treated for 
GL with BOTOX 
 were headache, nasopharyngitis, eyelid sensory disorder, eyelid ptosis, 
injection site pain, and nausea.9  All of these events were mild or moderate in severity, and the 
incidence decreased with increasing number of treatment cycles.  The safety profile for the 
 dose of 
OnabotA X selected for evaluation in this study is expected to fall within that of BOTOX for the 
treatment of GL.  
 
 
 
 
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.
Considering the coronavirus disease – 2019 (COVID-19) pandemic, the benefit and risk to subjects 
participating in this study have been re-evaluated.  Based on the limited information to date, no 
additional risk to study subjects is anticipated with the use of OnabotA X.  
For further details, please see findings from completed studies, including safety data in the current 
OnabotA X Investigator's Brochure.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objective of the study is to evaluate the safety of OnabotulinumtoxinA X injection in the 
glabellar region of subjects with severe GL.
The clinical hypothesis is that OnabotulinumtoxinA X has an acceptable safety profile when administered 
to the corrugator and procerus muscles in subjects with severe GL.
No estimands are defined for the safety evaluations.
3.2 Primary Endpoints
No primary efficacy endpoint is defined for this study.  The primary objective of the study is an 
evaluation of safety.
3.3 Secondary Endpoints
No secondary efficacy endpoints are defined for this study.
3.4 Additional Efficacy Endpoints
Additional efficacy endpoints are:

Number and proportion of subjects who achieve the following at maximum frown, based upon 
the FWS-GL – Investigator: 

1-grade improvement from baseline, by visit

2-grade improvement from baseline, by visit

Achievement of None or Mild, by visit 
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
Number and proportion of subjects who achieve the following at maximum frown, based upon 
the FWS-GL – Subject: 

1-grade improvement from baseline, by visit

2-grade improvement from baseline, by visit

Achievement of None or Mild, by visit 

Number and proportion of subjects who achieve a 2-grade improvement from baseline based 
upon both the FWS-GL Investigator and the FWS-GL – Subject (composite endpoint), at 
maximum frown, by visit

Number and proportion of subjects who achieve the following at maximum frown, based upon 
the Allergan Glabellar Line Severity Scale (AGLSS) (assessed by an independent evaluating 
investigator): 

1-grade improvement from baseline, at Day 30 (among subjects who are rated at least Mild 
at baseline)

2-grade improvement from baseline, at Day 30 (among subjects who are rated at least 
Moderate at baseline)

Achievement of None or Mild, at Day 30 (among subjects who are rated at least Moderate 
at baseline)

Number and proportion of subjects who achieve the following at rest (among subjects who are 
rated at least Mild at baseline, at rest):

1-grade improvement from baseline, by visit, based upon the FWS-GL Investigator

1-grade improvement from baseline, by visit, based upon the FWS-GL Subject

1-grade improvement from baseline, at Day 30, based upon the AGLSS
3.5 Safety Endpoints
Safety assessments include the following:

Adverse Events

Abbreviated Physical Examination (general appearance, head, ears, eyes, nose, throat, and neck)

Neurologic Assessment

Vital Sign Measurements (body temperature, pulse rate, respiration rate, and blood pressure 
[systolic and diastolic])

Clinical Laboratory Tests (hematology, chemistry, urinalysis)

ECG
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3.6 Immunogenicity and Hypersensitivity Sampling
Immunogenicity 
Blood samples for immunogenicity testing will be collected from all subjects treated with OnabotA X 
according to the Study Activities Table (Appendix D) at Day 1 (Baseline), Day 30, Day 90, and End-of-
Study (Day 180 or Premature Discontinuation) visits.  Collected samples will be processed to yield serum 
for detection of binding and neutralizing antibodies to OnabotulinumtoxinA.
Hypersensitivity Assessments 
In suspected cases of anaphylaxis, blood samples should be collected within 2 hours after dosing or as 
soon as possible.  See Appendix F Operations Manual, Section 3.5 and Section 7.2.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 180-day, Phase 2a, open-label, proof-of-concept study to assess the safety and efficacy of a 
single
 dose of 3 different formulations of OnabotA X (A, B, and C; 
 
). The study will enroll approximately 90 adult female subjects 
(≥18 years old) with severe GL based on FWS-GL ratings.  Approximately 5 sites in the United States will 
enroll subjects.
The study will include up to a 7-day Screening period, occurring from Day -14 to -7.  On Day 1, eligible 
subjects will be randomized (1:1:1) to receive one 
 dose of Formulation A, B, or C of OnabotA X.  
The single treatment of study drug will be administered in an open-label manner as
 
to the corrugator and procerus muscles.  Following treatment administration for each 
subject, the investigator will complete the Injector Experience Survey. 
Each subject will be in the study for up to 180 days and have 9 visits after screening.  Follow-up visits will 
be on Days 3, 7, 14, 30, 60, 90, 120, and 180 (exit).  The visit at Day 3 will be permitted a window of 
± 1 day, the visits at Days 7 and 14 will be permitted a window of ± 3 days, and the visits at Days 30, 60, 
90, 120, and 180 (exit) will be permitted a window of ± 7 days.  Safety parameters such as clinical 
laboratory test results, neurologic assessment, abbreviated physical examination, ECG, and vital signs 
will be monitored (see Operations Manual [Appendix F] Section 3).  At Screening, Baseline (Day 1) prior 
to treatment, and study exit, females of childbearing potential will undergo pregnancy testing.  For all 
subjects, AEs will be collected, whether solicited or spontaneously reported by the subject.  Blood 
samples for immunogenicity testing will be collected at Days 1, 30, 90, and 180 (exit).  
Additional efficacy will be evaluated based on FWS-GL-Investigator (assessed by an independent 
evaluating investigator), the FWS-GL-Subject, and the AGLSS.  
Subjects who discontinue should complete the procedures outlined for the Premature Discontinuation 
visit as soon as possible, preferably within 2 weeks (see Appendix D Study Activities Table).  
Further details regarding study procedures are in the Operations Manual (Appendix F) Section 3.
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expected, based on the literature10-12
 
 
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.  Rescreening 
is not allowed for individuals who do not meet key safety and efficacy Eligibility Criteria: numbers 4, 5, 6, 
7, or 9. Any attempt to rescreen a subject must only occur after agreement with the sponsor.
Consent
1. Subject 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.
Demographic and Laboratory Assessments
2. Adult female, at least 18 years old.
3. Subject has sufficient visual acuity without the use of eyeglasses (contact lens use is 
acceptable) to accurately assess their facial lines
 
8. Subject is willing and able to comply with procedures required in this protocol.
Disease Activity/Condition
9. Subject has severe GL at maximum frown as assessed by both the investigator and subject 
using the FWS-GL at Baseline.
Subject History
10. No history of known immunization to any botulinum toxin serotype
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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

History of facial nerve palsy 

Infection or dermatological condition at the site of study drug injection

Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick 
sebaceous skin, excessively photodamaged skin, or the inability to substantially lessen facial 
lines even by physically spreading them apart

Any eyebrow or eyelid ptosis at baseline or Day 1 as determined by the investigator
14. No history of clinically significant medical conditions or any other reason that the 
investigator determines would interfere with the subject's participation in this study or would 
make the subject an unsuitable candidate to receive study drug.
15. No clinically relevant or significant ECG abnormalities, 
 
 
 
 
17. If the subject has received a SARS-CoV-2 vaccination, the subject must have completed their 
final dose at least 7 days prior to Day 1.  Unvaccinated subjects may enroll in the study.  
18. No reported use of any botulinum neurotoxin of any serotype for any indication within the 6 
months prior to Day 1
19. No history of the following procedures or treatments in the specified period before 
enrollment (Day 1):

3 months: any mid-or upper-facial cosmetic procedures with superficial 
resurfacing/planning (e.g., microdermabrasion, dermaplaning), superficial chemical peels 
(e.g., glycolic acid), or nonablative energy-based facial treatments (e.g., radiofrequency, 
ultrasound, electromagnetic, laser, light).  
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
6 months: any mid- or upper-facial aesthetic treatments targeting deeper tissue layers 
including, but not limited to, any ablative or non-ablative laser resurfacing, fractionated 
laser resurfacing, radiofrequency, ultrasound treatment, medium-depth or deep chemical 
peels (eg, trichloroacetic acid [TCA] above 35% and phenol), or permanent make-up.  

18 months: any periorbital, mid-facial, or upper-facial treatment with HA soft tissue/dermal 
fillers
20. No history of prior treatments to the mid- or upper face such as radiation, surgical treatment 
(including but not limited to cosmetic procedures such as brow lift, eyelid surgery, facelift, 
rhinoplasty, or other reconstructive surgery), cosmetic/surgical suspension threads, non-HA soft 
tissue/dermal fillers, synthetic implantation, and/or autologous fat transplantation
Contraception
21. For all females of child-bearing potential, a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at Day 1 prior to the first dose of study drug.
22. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Study Day 1 through study exit.  Female subjects of non-
childbearing potential do not need to use birth control.  
23. Female who is not pregnant or breastfeeding, and is not considering becoming pregnant or 
donating eggs during the study.
Concomitant Therapy
24. Subject must not have been treated with any investigational drug within 30 days prior to the 
first dose of study drug or is currently enrolled in another clinical study or was previously 
enrolled in this study.
25. Subject must not have received any live vaccine within 4 weeks prior to the first dose of 
study drug, or expected need of live vaccination during study participation including at least 4 
weeks after the last dose of study drug.
5.2 Contraception Recommendations
Contraception Requirements 
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:
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
Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.
2.
Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone level > 30 International Unit/L.

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy throughout the duration of the 
study

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation-initiated at 
least 30 days prior to study Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system.

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence, defined as:  Refraining from heterosexual intercourse when 
this is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable).

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, initiated at least 30 days prior to Study Day 1.

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier method).
Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
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5.3 Prohibited Medications and Therapy
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.  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 drug)

Medium depth to deep facial chemical peels (i.e., TCA above 35% and phenol) to the face

Energy-based treatments (e.g., intense pulsed light, Clear + Brilliant®, monopolar 
radiofrequency, microfocused ultrasound) to the face

Microneedling to the face

Facial lift (partial or full face) or cosmetic/surgical suspension threads

Rhinoplasty

Blepharoplasty

Synthetic implantation (e.g., Gore-Tex) to the mid or upper face

Autologous fat transplantation to the mid or upper face

non-HA soft tissue/dermal fillers to the mid or upper face

HA soft tissue/dermal fillers to the mid or upper face

Permanent make-up to the mid or upper face
During the study, all other investigational drugs are prohibited.
5.4 Prior and Concomitant 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 
be discontinued at the discretion of the investigator or sponsor. Concomitant medications and 
concurrent procedures will be tabulated and listed.
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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.
Co-administration of aminoglycosides or agents that could interfere with neuromuscular transmission 
(e.g., curare-like agents) or muscle relaxants are to be used with caution as the effects of the toxin, 
theoretically, could be potentiated.
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 and estrogens and their derivatives,
dehydroepiandrosterone (DHEA), etc.

Topicals (anywhere on the body) including testosterone & estrogens and their derivatives, 
DHEA, etc.

Androgel, Axiron, Testim, Fortesta, Vogelxo

Emepelle (methyl estradiolpropanoate), Rejuvenate, All Natural Bioidentical Estradiol, Emerita 
Phytoestrogen
Subjects must maintain their standardized skin care regimen throughout the study period.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie non-emergency 
contact.  Information regarding potential drug interactions with OnabotA X may be found in the 
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.
COVID-19 Pandemic-Related Vaccination Guidance
The potential impact of OnabotA X on SARS-CoV-2 vaccination is unknown.  If the subject has received a 
SARS-CoV-2 vaccination, the subject must have completed their final dose at least 7 days prior to Day 1.  
Following Day 1, 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.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines and as more data are collected in real-world scenarios and clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any AEs associated with the COVID-19 vaccine.
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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:  

Clinically significant abnormal laboratory results or AEs, as determined by the investigator or 
sponsor.

The investigator believes it is in the best interest of the subject.

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.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

Subject is significantly noncompliant with study procedures.
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, in Section 2 and Section 3.
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.
Refer to the Operations Manual in Appendix F, Section 2 and Section 3, for details on how to handle 
study activities/procedures.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for efficacy and safety 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.
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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/serious adverse events 
(SAEs) have been resolved.
5.7 Study Drug 
 
  
Table 1.
Study Drug Identification
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
 
 
 
 
 
 
 
N/A = not applicable; U = unit(s)
 
  
 
 
 
Immediately before dispensing the study drug, the investigator (or appropriately trained designee) will 
write the subject's identification number and the date on the label.  Further details are provided in the 
pharmacy manual.
5.8 Randomization/Study Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
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used. The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule (1:1:1).
Randomization will be central by block randomization.  The same block will not be shared across 
investigative sites.
All subjects will be treated with OnabotA X (Formulation A, B, or C) in an unblinded, open-label manner.  
Study drug will be labeled with study kit numbers.  The IRT system will provide the designated site 
personnel with the specific study kit number for each subject after eligibility is confirmed on Day 1.  The 
designated site personnel will receive and maintain the IRT confirmation notifications for each 
transaction.  The designated, qualified site personnel will prepare the study drug per the instructions in 
the pharmacy manual and per subject randomization, and will draw up the required administration 
volume into an appropriately sized syringe(s) and label the syringe(s) with the subject's assigned 
identification number (and other information as specified in the pharmacy manual for a given 
formulation).  At the time of study drug administration, the designated site personnel will provide the 
labeled dosing syringe(s) to the trained qualified physician who will inject the subject according to the 
study drug administration instructions.
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 the IRB, regulatory authorities (as applicable), and AbbVie.
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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Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
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 drug, and/or if the investigator considers them to be 
AEs.
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.
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 contract research organization (as appropriate) as a 
SAE within 24 hours of the site being made aware of the SAE (refer to Section 4.2 of the Operations 
Manual [Appendix F] for reporting details and contact information):
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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.  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 until 30 days after the last dose of study 
drug or until completion of the study or the last follow-up visit, whichever is longer, will be collected, 
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.
The following definitions will be used for Serious Adverse Reactions (SAR) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR):
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SAR
Defined as all noxious and unintended responses to an investigational medicinal 
product (IMP) related to any dose administered that result in an SAE as defined 
above.
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable Reference Safety 
Information), and meets one of the above serious criteria.
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local
requirements.
AEs will be monitored throughout the study to identify any of special interest that may indicate a trend 
or risk to subjects.
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.  To assess possible local and distant spread 
of toxin, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) that may be 
associated with botulinum toxin effects have been identified, and the final terms will be listed in the 
statistical analysis plan.  All AEs will be medically reviewed by the Sponsor on a regular basis throughout 
the duration of the study to identify PDSOT events, which will be assessed for severity, frequency, and 
trending and will be summarized in study clinical study report.
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE as mild, moderate, or severe.
The investigator will use the following definitions to rate the severity of each AE:
Mild
The AE is transient and easily tolerated by the subject.
Moderate
The AE causes the subject discomfort and interrupts the subject's usual 
activities.
Severe
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life threatening.
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The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study will be encouraged 
to remain in the study for safety follow-up.  If a pregnancy occurs in a study subject, information 
regarding the pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose of study drug.  
The FAS will be used for all efficacy and baseline analyses. Subjects in this population will be analyzed 
per randomization, regardless of actual treatment received.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  The Safety 
Analysis Set will be used for all safety analyses. Subjects in this population will be analyzed according to 
the actual treatment received.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
Not applicable.
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7.4 Statistical Analyses for Efficacy
Summary and Analysis of the Primary Endpoint
Not applicable.
Summary and Analysis of Secondary Endpoints
Not applicable.
Summary and Analysis of Additional Efficacy Endpoints
The number and percentage (or proportion) of the subjects who are responders will be summarized, 
95% confidence interval will be calculated with an exact method based on the binomial distribution for 
percentage (or proportion) of the subjects.  Observed data without imputation will be used.
For efficacy endpoints using AGLSS, subsets of subjects will be used as follows:

1-grade improvement from baseline at maximum frown or at rest: only subjects with 
corresponding baseline score being at least mild are included

2-grade improvement from baseline at maximum frown: only subjects with corresponding 
baseline score being at least moderate are included

Achieving none or mild at maximum frown: only subjects with corresponding baseline score 
being at least moderate are included
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, laboratory assessments, and ECG.  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
o
Any treatment-emergent AE related to study procedure according to the investigator
o
Any treatment-emergent AE related to study drug according to the investigator

Any severe treatment-emergent AE
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
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 level of 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 and laboratory measurements will be summarized for changes from baseline at each 
assessment timepoint.
Analyses for ECGs and other safety endpoints will be addressed in the SAP.
Statistical Analyses for Immunogenicity and Hypersensitivity
Samples from subjects treated with OnabotA X will be analyzed for anti-drug antibodies using validated 
assays.  Immunogenicity results, manifested as the binding antibodies and neutralizing antibodies, will 
be summarized in a table for each sampling timepoint.
Results from hypersensitivity evaluations, if any are conducted, will be listed.
7.6 Overall Type I Error Control
Not applicable.
7.7 Sample Size Determination
This is a proof-of-concept study with a primary objective of evaluating safety.  A sample size of 90 (30 
per treatment group) subjects will provide sufficient data for safety evaluations of OnabotA X to support 
future placebo-controlled studies in larger sample sizes, powered for efficacy evaluations.
8 ETHICS
8.1 Institutional Review Board (IRB)
The protocol, investigator brochure, informed consent form(s), recruitment materials, and all subject 
materials will be submitted to the IRB for review and approval.  Approval of both the protocol and the 
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informed consent form(s) must be obtained before any subject is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study.  
In addition, all changes to the consent form(s) will be IRB approved.
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.
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.  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, 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 
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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 the last subject's last visit.
12
REFERENCES
1.
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.
2.
Carruthers A, Carruthers J. Botulinum toxin type A for the treatment of glabellar rhytides. 
Dermatol Clin. 2004;22(2):137-44.
3.
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.
4.
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.
5.
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.
6.
ASAPS. American Society of Aesthetic Plastic Surgery: Cosmetic surgery national data bank: 
statistics. New York: ASAPS; 2017.
7.
Glogau R, Kane M, Beddingfield F, et al. OnabotulinumtoxinA: a meta-analysis of duration of 
effect in the treatment of glabellar lines. Dermatol Surg. 2012;38(11):1794-803.
8.
Prager W, Bee EK, Havermann I, et al. Onset, longevity, and patient satisfaction with 
incobotulinumtoxinA for the treatment of glabellar frown lines: a single-arm, prospective clinical 
study. Clin Interv Aging. 2013;8:449-56.
9.
Brin MF, Boodhoo TI, Pogoda JM, et al. Safety and tolerability of onabotulinumtoxinA in the 
treatment of facial lines: a meta-analysis of individual patient data from global clinical 
registration studies in 1678 participants. J Am Acad Dermatol. 2009;61(6):961-70.e1-11.
10.
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.
11.
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.
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12.
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.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AGLSS
Allergan Glabellar Line Severity Scale
COVID-19
Coronavirus Disease – 2019
CRF
case report form
DAS
Digit Abduction Score
DHEA
dehydroepiandrosterone
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
FAS
full analysis set
FWS-GL
Facial Wrinkle Scale – Glabellar Lines
GCP
Good clinical practice
GL
glabellar lines
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IM
intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional review board
IRT
interactive response technology
IUD
intrauterine device
MedDRA
Medical Dictionary for Regulatory Activities
N/A
not applicable
OnabotA X
onabotulinumtoxinA X 
PCR
polymerase chain reaction
PDSOT
possible distant spread of toxin 
POC
proof-of-concept
PT
preferred term
QT
time from the start of the Q wave to the end of the T wave
QTc
QT interval corrected for heart rate
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Abbreviation
Definition
QTcF
QT interval corrected for heart rate using Fridericia's formula
RSI
reference safety information
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
U
unit(s)
WOCBP
woman of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-324:  A Phase 2a Multicenter Open-label Study to Evaluate the Safety and Efficacy of 
OnabotulinumtoxinA X in Subjects with Glabellar Lines
Protocol Date:  07 September 2021
Clinical research studies sponsored by AbbVie are subject to the ICH 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), 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., 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, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, 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
Director, Clinical Program Development
Clinical Study Leadership
Principal Medical Writer
Medical Writing 
Vice President, Head of Clinical Development, 
Aesthetic Medicine
Therapeutic Area
Vice President, Non-Clinical and Translational 
Science
Therapeutic Area
Executive Director, Biostatistics
Statistics 
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 2.0
07 June 2021
Version 1.0
19 March 2021
Version 3.0
The primary purpose of the version update to 3.0 is to incorporate ECGs into the study design, per FDA 
feedback. Edits were made in Section 1. Synopsis; Section 4.1 Overall Study Design and Plan; Section 5.1
Eligibility Criteria; Section 7.5 Statistical Analyses for Safety; Appendix D, Activity Schedule; Appendix F, 
Operations Manual.
Additional edits were made, as follows:
Instructions to collect concomitant medications and concurrent procedures at each visit were added to 
Section 5.4 Prior and Concomitant Therapy.
For the definition of PDSOT, the word "potential" was corrected to "possible" (Section 6.1 Complaints 
and Adverse Events). 
The following verbiage in Section 6.1 Complaints and Adverse Events was copied verbatim into 
Appendix F, Operations Manual (Section 4.1): "All AEs reported from the time of study drug 
administration until 30 days after the last dose of study drug or until completion of the study or the last 
follow-up visit, whichever is longer, will be collected, 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."
Categories of study drug-related AEs and study procedure-related AEs were added to the overview of 
AEs analysis described in Section 7.5 Statistical Analyses of Safety.
Protocol signatories were updated to be current (Appendix C List of Protocol Signatories).
In Appendix F, Operations Manual, the Fitzpatrick Skin Phototype scale was added, COVID-19-related 
acceptable protocol modifications were deleted for standardized facial photography, paper forms were 
removed from the procedures for SAE reporting, and height and weight were added to the Baseline 
collection of vital signs.
Version 2.0
 
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STUDY M21-324  |  Version 3.0  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Edits to align with these study design updates were made in the following sections of the protocol:  
Section 1. Synopsis; Section 2.1 Background and Rationale; Section 3.1 Objectives, Hypotheses, and 
Estimands; Section 4.1 Overall Study Design and Plan; Section 4.2 Discussion of Study Design; Section 5.1
Eligibility Criteria; Section 5.8 Randomization/Study Drug Assignment; Section 7.2 Definition for Analysis 
Populations; Section 7.7 Sample Size Determination; Appendix D, Activity Schedule; Appendix F,
Operations Manual.
Additional edits were made, as follows:
The non-emergency medical contact was changed (Cover page and Appendix F, Operations Manual).
The AGLSS endpoints were edited to specify which subjects were included in each analysis, based on 
baseline AGLSS grades (Section 3.4 Additional Efficacy Endpoints)
A study schematic was added to Section 4.1 Overall Study Design and Plan.
An Injector Experience Survey was added to the study, to be completed by the Investigator following 
study drug administration on Day 1 (Section 4.1 Overall Study Design and Plan; Appendix D, Activity 
Schedule; Appendix F, Operations Manual).
Eligibility criteria that, if failed, would preclude a subject from being permitted to rescreen for the study, 
were identified at the beginning of Section 5.1 Eligibility Criteria.
Diluent was added to the list of Investigational Products in Section 5.7 Study Drug and Appendix F,
Operations Manual. Allergan (rather than Allergan Pharmaceuticals Ireland) was listed as the 
manufacturer in Section 5.7 Study Drug. The verbiage "Formulations A, B, or C" was included in 
Section 5.7 Study Drug, Section 5.8 Randomization/Study Drug Assignment, and Appendix F, Operations 
Manual.  
Updated verbiage was incorporated to align with other aesthetic toxin protocols, in Section 5.4 Prior and 
Concomitant Therapy and Section 5.5 Withdrawal of Subjects and Discontinuation of Study. 
The FWS-GL Investigator assessment was changed to be completed at all timepoints by an independent 
evaluating sub-investigator; the AGLSS will now be completed by the principal investigator (Appendix D,
Activity Schedule; Appendix F, Operations Manual).
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STUDY M21-324  |  Version 3.0  
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Medical 
Contact
Allergan Aesthetics, an AbbVie company
2525 Dupont Drive
Irvine, CA 92612
EMERGENCY 24-hour Number:  
+1 (973) 784-6402
Mobile:
Email:
Sponsor/Non-
Emergency 
Medical 
Contact:
Allergan Aesthetics, an AbbVie Company
2525 Dupont Drive
Irvine, CA 92612
Mobile:
Email:
Safety 
Concerns
Aesthetics Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Phone:
+1 (833) 942-2226
Email: 
SafetyManagement_Aesthetics_Devices@
abbvie.com
SAE Reporting 
outside of EDC
Email:
IR-Clinical-SAE@allergan.com
Fax:
+1 (714) 796-9504
Backup fax:
+1 (714) 246-5295
Certified 
Central Clinical 
Lab
LabCorp Drug Development
8211 SciCor Drive
Indianapolis, IN 46214
Phone:
+1 (317) 271-1200
Toll free:
+1 (800) 462-8885
Fax:
+1 (317) 273-4030
ECG vendor
ERT
1818 Market Street 10th floor 
Philadelphia, PA 19103
Phone:
+1 (215) 282-5583
Mobile:
+1 (215) 960-5834
Immunogenicity 
Sample Labs
BAB: 
BioAgilytix Labs
2300 Englert Dr
Durham, NC 27713
NAB:
Battelle Memorial Institute
1425 Plain City-Georgesville Road
(FedEx/UPS Only S.R.  142 NE)
West Jefferson, OH 43162
Phone: +1 (919) 381-6097
Fax:
+1 (919) 381-6099
Phone: +1 (800) 201-2011; +1 (614) 424-5833
Fax:
+1 (614) 458-5833
Photography
Canfield Scientific, Inc.
4 Wood Hollow Road
Parsippany, NJ 07054
Phone: +1 (973) 434-1200
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
2.2
INDIVIDUAL POST-TREATMENT PERIOD VISIT ACTIVITIES
7
3
STUDY PROCEDURES
11
3.1
STUDY SUBJECT INFORMATION AND INFORMED CONSENT
11
3.2
MEDICAL/SURGICAL HISTORY
11
3.3
SUBJECT TRAINING ON FWS-GL
12
3.4
ADVERSE EVENT ASSESSMENT
12
3.5
IMMUNOGENICITY AND HYPERSENSITIVITY SAMPLING
12
3.6
VITAL SIGNS
13
3.7
ABBREVIATED PHYSICAL EXAMINATION
13
3.8
CLINICAL LABORATORY TESTS
13
3.9
NEUROLOGIC ASSESSMENT
15
3.10
12-LEAD ELECTROCARDIOGRAM
16
3.11
FACIAL WRINKLE SCALE – GLABELLAR LINES (FWS-GL)
17
3.12
ALLERGAN GLABELLAR LINE SEVERITY SCALE (AGLSS)
17
3.13
STANDARDIZED FACIAL PHOTOGRAPHY
18
3.14
STUDY DRUG ADMINSTRATION
19
3.15
INJECTOR EXPERIENCE SURVEY
20
3.16
SUBJECT WITHDRAWAL FROM STUDY
20
3.17
UNSCHEDULED VISITS
20
4
SAFETY MANUAL
20
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
20
4.2
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
20
5
COUNTRY-SPECIFIC REQUIREMENTS
22
5.1
SAMPLE RETENTION REQUIREMENTS
22
5.2
SUSAR REPORTING
22
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6
STUDY DRUG
23
6.1
TREATMENTS ADMINISTERED
23
6.2
PACKAGING AND LABELING
23
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
23
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
24
6.5
PREPARATION/RECONSITUTION OF DOSAGE FORM
24
7
APPENDICES
25
7.1
FOCUSED NEUROLOGICAL EXAMINATION SHEET
25
7.2
ANAPHYLAXIS AND SYSTEMIC HYPERSENSITIVITY
28
8
REFERENCES
29
LIST OF TABLES
TABLE 1.
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE AND FOOD ALLERGY AND 
ANAPHYLAXIS NETWORK CRITERIA FOR ANAPHYLAXIS
28
LIST OF FIGURES
FIGURE 1.
GLABELLAR LINE INJECTION PARADIGM
19
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to the COVID-19 pandemic.  This may include changes such as phone 
or virtual visits, visits at alternative locations, or changes in the visit frequency and timing of study 
procedures, among others.  Additional details are provided in the subsequent sections.  Every effort 
should be made to ensure the safety of subjects and site staff, while maintaining the integrity of the 
study.  If visits cannot be conducted onsite due to travel restrictions or other pandemic-related reasons, 
follow the updates below on how to proceed.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study procedures to be performed as specified 
due to travel restrictions or other reasons, the following modifications are allowed with agreement from 
the sponsor:

If permitted by local regulations, the IRB, and the subject, postbaseline visits may be conducted 
virtually, including only prior/concomitant therapy, AE assessment, and partial neurologic 
assessment. 

During a virtual visit, the following activities do not need to be performed: abbreviated physical 
examination, vital signs, FWS-GL assessments by investigator and subject, AGLSS (independent 
evaluating investigator assessment), standardized facial photography, immunogenicity blood 
sampling, urine pregnancy testing.

Clinical laboratory assessments and ECGs may be skipped, unless the investigator has a 
significant concern and it is possible to arrange for the subject to have laboratory work and/or 
ECG done at an appropriate local facility.  The local laboratory draw and/or ECG should be 
scheduled within 7 days of the missed scheduled visit, if possible.

Study Visits should be performed as scheduled whenever possible.  If it is not possible to do so 
due to the pandemic, the following modification is allowed with sponsor approval:

If the Day 1 visit cannot occur within 30 days of Screening, then the subject will be 
considered a screen failure and must be rescreened to participate in the study.
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit.  The dot pattern 
on the upper right indicates the place of the visit in the overall Activity Schedule.
Activities are grouped by category (Interview, Examinations, etc.).  Further information about each 
activity is provided in Section 3.
All Screening and Baseline visit procedures must be performed onsite.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3 STUDY PROCEDURES
3.1 Study Subject Information and Informed Consent
The investigator or his/her representative will explain the nature of the study to the subject, the 
benefits and risks anticipated from participation in the study and will answer all questions regarding this 
study.  Prior to any study-related screening procedures being performed on the subject or any 
medications being discontinued by the subject in order to participate in this study, the informed consent 
statement will be reviewed, signed, and dated by the subject or their legally authorized representative, 
the person who administered the informed consent, and any other signatories according to local 
requirements.  A copy of the signed informed consent will be given to the subject and the original will be 
placed in the subject's medical record.  An entry must also be made in the subject's dated source
documents to confirm that informed consent was obtained prior to any study-related procedures and 
that the subject received a signed copy.
Photographs will be taken for research purposes, and may also be used for education, commercial, 
and/or marketing purposes.  To participate in this study, the subject must consent to having 
photographs taken for research but may still participate if he/she declines use of the photographs for 
other purposes.  The sponsor shall have full ownership rights to any photographs derived from the 
study.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed because of participation in the study can be found in the 
informed consent form.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not outlined in this 
protocol may become necessary.  If this situation arises, in addition to the study informed consent, 
additional temporary verbal consent may be obtained prior to these adaptations or substantial changes 
in study conduct in accordance with local regulations.  An appropriately signed and dated informed
consent form should be obtained from the subject afterwards, as soon as possible.
3.2 Medical/Surgical History
A complete medical history including demographics; history of tobacco, alcohol, and drug use; and 
Fitzpatrick skin phototype will be taken at screening. 
Fitzpatrick skin phototypes are defined as follows1:
I = Always burns, never tans
II = Always burns easily, tans minimally
III = Burns moderately, tans uniformly
IV = Burns minimally, always tans well
V= Rarely burns, tans profusely
VI = Never burns
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The subject's medical history will be updated at the Study Day 1 visit.  This updated medical history will 
serve as the baseline for clinical assessment. Any abnormal findings from screening assessments (e.g.,
laboratory assessments, ECG, neurologic assessment) should be captured as medical history.
3.3 Subject Training on FWS-GL
At the Screening and Day 1 visits, subjects will view a training video on how to assess their GL severity 
using the FWS-GL-Subject. At any time during the study, subjects may view the training video again, if 
the site considers it to be necessary or helpful.
3.4 Adverse Event Assessment
Please refer to Section 4.1.
3.5 Immunogenicity and Hypersensitivity Sampling
Immunogenicity Sampling
Blood samples for immunogenicity testing will be collected from all subjects according to the Study 
Activities Table (Protocol, Appendix D) at Day 1 (Baseline), Day 30, Day 90, and End-of-Study (Day 180 or 
Premature Discontinuation) visits.  Instructions regarding the collection, processing, and shipping of 
these samples will be provided by the central laboratory.  Collected samples will be processed to yield 
serum for analysis.  
A 2-tier assay approach will be used for the detection of binding and neutralizing antibodies to 
OnabotulinumtoxinA in human serum.  In Tier 1, serum samples will be screened using a validated 
enzyme-linked immunosorbent assay (ELISA).  The positive samples will subsequently be 
immunodepleted to confirm that the antibodies were specifically binding to OnabotulinumtoxinA and 
then titered to assess the magnitude of antibodies present.  In Tier 2, only samples that are confirmed
positive in the ELISA will be tested for neutralizing antibodies to OnabotulinumtoxinA using a validated 
assay.
Samples collected will also be used for investigative purpose in characterizing the assay.
There are no pandemic or natural disaster-related protocol modifications for immunogenicity samples.  
If a site visit is missed at which immunogenicity samples were planned to be collected, this assessment 
will be skipped for that timepoint.
Hypersensitivity Assessments 
In suspected cases of anaphylaxis or systemic hypersensitivity reactions (see Appendix 7.2), blood 
samples for testing of biomarkers (i.e., tryptase) should be collected within 2 hours after dosing or as 
soon as possible after the event.  The sponsor may require additional testing be conducted.  Instructions 
regarding the collection, processing, and shipping of these samples will be provided by the central 
laboratory.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Subjects who experience anaphylaxis (regardless of seriousness) or serious systemic hypersensitivity will 
be managed per standard of care and referred to an allergist/immunologist for further assessment.  
Subjects who experience systemic hypersensitivity reactions will be followed until stabilization or 
resolution of the event.  
3.6 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature will be obtained at visits as specified in Section 2; height and weight will also be collected, 
at the baseline visit.  Blood pressure and pulse rate should be measured after the subject has been 
sitting for at least 5 minutes.  
Measurements should be assessed consistently throughout the study.  Vital signs measurements 
determined prior to dosing on Day 1 will serve as baseline.
There are no pandemic or natural disaster-related protocol modifications for vital signs.  If a site visit is 
missed at which vital signs were planned to be collected, this assessment will be skipped for that 
timepoint.
3.7 Abbreviated Physical Examination
An abbreviated physical examination, including general appearance, head, ears, eyes, nose, throat, and 
neck, will be performed at the designated study visits as specified in Section 2.  The physical examination 
performed on Study Day 1 will serve as the baseline physical examination for the entire study.  Physical 
examination abnormalities noted at the Baseline Visit prior to the first dose of study drug should be 
recorded in the subject's medical history.  Any significant physical examination findings after the first 
dose will be recorded as AEs.  All findings, whether related to an AE or part of each subject's medical 
history, will be captured on the appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed necessary by the 
investigator.
There are no pandemic or natural disaster-related protocol modifications for physical examinations.  If a 
site visit is missed at which a physical examination was planned, this assessment will be skipped for that 
timepoint.
3.8 Clinical Laboratory Tests
The blood samples for serum chemistry tests will be collected nonfasting.  The baseline laboratory test 
results for clinical assessment for a particular test will be defined as the last measurement prior to the 
initial dose of study drug.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained prior to the initiation of the study.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Instructions regarding the collection, processing, and shipping of these samples will be provided by the 
central laboratory.
If a laboratory test value at Screening is outside the reference range and the investigator considers the 
laboratory result to be clinically significant, the subject will be a screen failure and will be referred for 
follow-up with their physician. Laboratory abnormalities at Screening will be captured as medical 
history for enrolled subjects.
If a post-baseline laboratory test value is outside the reference range and the investigator considers the 
laboratory result to be clinically significant, the investigator will record the result as an AE, repeat the 
test to verify the value, and:

follow the out-of-range value to a satisfactory clinical resolution; or

discontinue the subject from the study or require the subject to receive treatment
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands 
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not acceptable)
International normalized ratio (INR)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Direct and indirect bilirubin
Gamma-glutamyl transferase (GGT)
Albumin
Alanine transaminase (SGPT/ALT) 
Aspartate transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Pregnancy Tests
Serum pregnancy tests will be performed at Screening and urine pregnancy tests will be performed at 
Day 1 prior to treatment, for all female subjects of childbearing potential.  Females of child-bearing 
potential must have a negative pregnancy test result at Day 1 prior to administration of study drug.
Additional urine pregnancy tests will be performed at the exit visit, and may be conducted at any visit, if 
deemed necessary by the investigator.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
There are no pandemic or natural disaster-related protocol modifications for urine pregnancy testing.  If 
a site visit is missed at which a urine pregnancy test was planned, this assessment will be skipped for 
that timepoint.  (Screening and Day 1 visits are mandatory to occur onsite.)
Urinalysis
Dipstick urinalysis will be completed by the central laboratory at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater than negative, 
or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations due to a pandemic or natural disaster prevent 
the subject from having blood drawn for laboratory testing at the study site, it may be skipped unless 
the investigator has a significant concern and it is possible to arrange for the subject to have laboratory 
work done at a local laboratory, hospital, or other facility.  The local laboratory draw should be 
scheduled within 7 days of the missed scheduled visit, if possible.  Local laboratory results should be 
obtained along with reference ranges and kept within the subjects' source documentation.  The 
investigator should review local laboratory results as soon as possible.
3.9 Neurologic Assessment
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations due to a pandemic or natural disaster prevent 
the subject from completing an in-person visit, a partial neurologic assessment could be conducted 
remotely, to the best of ability by observing the subject via video call, if subject is in good health and a 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
video call is possible to arrange.  In this case, the missing components of the neurologic assessment 
must be documented as not performed.
3.10 12-Lead Electrocardiogram
12-Lead Electrocardiogram (ECG)
All subjects will undergo conventional 12-lead ECG using standardized equipment and electrode 
placement at the visits outlined in the study activities table (Protocol Appendix D). Subjects are to be in 
a semirecumbent position for at least 10 minutes prior to starting the tracing. Single, legible/readable
ECG tracings will be taken at all timepoints. When an ECG is scheduled at the same time as a blood 
collection, the ECG will be obtained prior to the blood collection.  
A qualified third-party vendor will read the ECGs and report the findings as normal, abnormal, or unable 
to evaluate.
For screening ECGs, prespecified significant abnormal findings will be flagged as exclusion alerts, and a 
third-party vendor will generate an exclusion alert for the site and the sponsor. For all subsequent ECGs, 
a qualified third-party vendor will also report the appearance of any new, prespecified significant 
abnormal findings and generate a protocol alert for the site and the sponsor.
The cardiologists will be blinded to participant study intervention assignments. If the ECG finding is 
abnormal, they will specify the abnormality or give a diagnosis, whenever it is possible. ECG reports will 
be provided to the investigator and the sponsor via a secure portal within 24 hours of screening and 
within 72 hours for all other visits.
Before study intervention, if the ECG finding is clinically significant, the investigator must capture the 
finding in the medical history eCRF. After study intervention, if the pre-existing finding becomes worse 
and is clinically significant or the new ECG finding is clinically significant, the investigator must capture 
the AE in the AE eCRF. Hard copies of the ECG tracings will be kept in the study files at the investigator's 
site.
The ECG will be assessed for the following measures: heart rate, QRS duration, QT interval, QTcB 
interval, QTcF interval, ST segment, RR interval, PR interval, and qualitative results.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
In the event the ECG may not be performed due to study modifications related to the COVID-19 
pandemic, it may be skipped for that timepoint unless the investigator has a significant concern and an 
arrangement can be safely made to have an alternative acceptable local facility perform the ECG. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.11 Facial Wrinkle Scale – Glabellar Lines (FWS-GL)
Investigators' and subjects' assessments of the severity of GL at rest and maximum contraction using the 
FWS-GL are based on the following scale:
0 = None
1 = Mild
2 = Moderate
3 = Severe
The FWS-GL scales will be provided by the sponsor to each study site.  Both versions of the scale provide 
photographic examples of GL severity at rest and at maximum contraction.  Prior to enrolling subjects, 
physician investigators will be trained in grading GL severity using the FWS-GL to ensure that severity is 
graded consistently at each site and across all sites.  For this training, the same set of images will be 
used for all raters and all sites.  
The FWS-GL must be evaluated by a qualified, trained, physician sub-investigator other than the 
principal investigator who administers the study drug and who completes all other assessments
(described in Section 2 as an "independent evaluating investigator"). The FWS-GL is the only assessment 
in the study that this sub-investigator will complete.  The FWS-GL assessment is to be performed by the 
same sub-investigator throughout the study whenever possible.  If it is not possible to use the same 
assessor to follow the subject, it is recommended that the FWS-GL assessments overlap (assess the 
subject together and discuss findings) for at least 1 visit for a given subject.  The sub-investigator who 
performs the FWS-GL assessment must do so independent of the investigator who completes the AGLSS, 
and the results of the FWS-GL and AGLSS assessments must not be discussed.
Subjects will also be provided standardized training in grading GL severity using the FWS-GL to ensure 
that severity is scored consistently.  Instructions on using the FWS-GL will be provided prior to 
performing the assessment.  Standard mirrors (non-magnifying mirrors) will be used by the subject to 
aid in self-assessments.
Investigators and subjects will assess GL severity using the FWS-GL at the same time.  However, 
assessments must be independent of each other, and the results of the assessments must not be 
discussed.  The investigator and subject must grade the severity of GL first at rest and then at maximum 
contraction, using the FWS-GL.
There are no pandemic or natural disaster-related protocol modifications for the FWS-GL scale.  If a site 
visit is missed at which this assessment was planned, the assessment will be skipped for that timepoint.
3.12 Allergan Glabellar Line Severity Scale (AGLSS)
Similar to the FWS-GL, the AGLSS assessments are to be conducted at rest and maximum contraction. 
The scale provides photographic examples of GL severity at rest and at maximum contraction; it uses a 
different set of photographs than the FWS-GL scales.
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The AGLSS uses the following scale:
0 = None
1 = Mild
2 = Moderate
3 = Severe
The AGLSS will be provided by the sponsor to each study site.  Prior to enrolling subjects, physician 
investigators will be trained in grading GL severity using the AGLSS to ensure that severity is graded 
consistently across all sites.  For this training, the same set of images will be used for all raters and all 
sites.  The AGLSS assessment is to be performed by the principal investigator; it must not be conducted 
by the sub-investigator who conducts the FWS-GL assessments (see Section 3.10).  These 2 investigators
must perform the assessments independently of each other, and the results of the assessments must 
not be discussed.  
The investigator must grade the severity of GL first at rest and then at maximum contraction, using the 
AGLSS.  
There are no pandemic or natural disaster-related protocol modifications for the AGLSS.  If a site visit is 
missed at which this assessment was planned, the assessment will be skipped for that timepoint.
3.13 Standardized Facial Photography 
Standardized digital facial photography will be performed prior to injection of study drug for all subjects 
at the times described in Section 2.  Images will be taken by study site staff of each subject's face from 
the front at rest and at maximum contraction.  Each site will receive documented training and 
instructions on taking photographs.  
Conditions of photography will be standardized across all photographs, including camera equipment,
exposure, background, lighting, and focal length.  Ideally, the same photographer will take all required 
photographs.  A qualified third-party vendor will provide instructions for taking photographs and 
processing digital photographs.  All digital images will be transferred to the sponsor at the end of the 
study.  
Photographs may be used for education, commercial, and/or marketing purposes.  To participate in this 
study, the subject must consent to having photographs taken for research but may still participate if 
he/she declines use of the photographs for other purposes.  The sponsor shall have full ownership rights 
to any photographs derived from the study.
There are no pandemic or natural disaster-related protocol modifications for standardized facial 
photography.  If a site visit is missed at which photography was planned, it will be skipped for that 
timepoint.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.14 Study Drug Adminstration
Study drug will be dispensed to site personnel at Baseline (Day 1), as specified in Section 2.1, and will be 
administered after all other baseline (Day 1) procedures are completed.  
Only the principal investigator as a trained and medically qualified physician is authorized to administer 
the study drug.  Study-specific training for GL injections is provided to investigators via a video with 
injection demonstration, and review of injection techniques as outlined in the protocol.  The video is 
available on the training portal for injectors to access at any time as a refresher course.  
The study intervention will be administered as intramuscular (IM) injections at 5 different injection sites 
in the glabellar complex (Figure 1).
Glabellar Line (GL) Injection Technique
Prior to injection, the skin at the injection sites and surrounding areas will be cleansed with 
antimicrobial solution.  Injections will be given using a sterile needle.  Each injection will contain 0.1 mL.  
Injections must be given with the bevel oriented superiorly and laterally.  The first injection will be made 
to the midline at the base of the procerus muscle.  The next 4 injections will be made bilaterally (i.e., 2 
injections per side) into each corrugator muscle (Figure 1).  The corrugators will be injected 
inferomedially near the origin of the supratrochlear nerve and superolaterally to the superior middle 
aspect ≥ 1 cm above the bony orbital rim.  
Figure 1.
Glabellar Line Injection Paradigm
m = muscle
Subjects must remain in the investigator's office for a minimum of 2 hours following the injection and be 
observed clinically during this time for any AEs.  The subject should be instructed to avoid rubbing or 
massaging the injection area for the next 24 hours.
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Procerus m. 
/Front n rn. 
corrugator 
supercilli m. 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3.15 Injector Experience Survey
Following study drug administration on Day 1, the investigator will complete the Injector Experience 
Survey, which collects information about the investigator's experiences with administering the 
treatment (e.g., ease of injection).
3.16 Subject Withdrawal from Study
All attempts must be made to determine the primary reason for discontinuation of study drug or study 
participation.  The information will be recorded on the appropriate eCRF page.  However, these 
procedures should not interfere with the initiation of any new treatments or therapeutic modalities that 
the investigator feels are necessary to treat the subject's condition.  Following discontinuation of study 
drug, the subject will be treated in accordance with the investigator's best clinical judgment, irrespective 
of whether the subject decides to continue participation in the study.
3.17 Unscheduled Visits
An Unscheduled Visit should be performed when the subject comes in for a medical visit for evaluation 
and assessment.  During Unscheduled Visits, blood and urine samples may be obtained for the 
laboratory tests listed in Section 3, or for other tests, at the investigator's discretion.
Visits to only retest a lab will not be considered an Unscheduled Visit.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All AEs reported from the time of study drug administration until 30 days after the last dose of study 
drug or until completion of the study or the last follow-up visit, whichever is longer, will be collected, 
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.  
4.2 Reporting Adverse Events and Intercurrent Illnesses
In the event of an SAE, whether associated with study drug or not, the investigator will notify Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the SAE by entering the SAE data 
into the electronic data capture (EDC) system (RAVE) within 24 hours of the site being made aware of 
the SAE.  SAEs that occur prior to the site having access to the RAVE® system, or if RAVE is not operable, 
should be documented on the SAE nonCRF form and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the SAE and entered into RAVE 
system as soon as it becomes available.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
For non-emergencies, please contact:
Allergan Aesthetics, an AbbVie Company
2525 Dupont Drive
Irvine, CA 92612
Contact Information:
Mobile:
Email:
COVID-19 Pandemic-Related Acceptable Protocol Modifications
If travel restrictions or other changes in local regulations due to a pandemic or natural disaster prevent 
the subject from in-person visits, AEs may be collected via phone or video conference.
Supplemental study CRFs should be completed in the event of COVID-19 related missed/virtual visits, or 
AEs (including capture of specific signs/symptoms of infection and testing results).
SARS-CoV-2 infections should be captured as AEs.  If the event meets the criteria for an SAE, then follow 
the SAE reporting directions per the protocol and above.  The following COVID-19 related supplemental 
eCRFs should be completed (for both serious and non-serious events):

COVID -19 Supplemental Signs/ Symptoms

COVID-19 Status Form
Reactions known to be associated with the SARS-CoV-2 vaccine should be reported as AEs.  If the event 
meets the criteria for an SAE, then follow the SAE reporting directions.  All AEs associated with the SARS-
CoV-2 vaccine will be linked to the vaccine on the COVID-19 Vaccine eCRF.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 Sample Retention Requirements
Samples for immunogenicity and hypersensitivity (as needed) testing may be stored for a maximum of 5 
years from application approval or 5 years from study completion (if not approved) at a facility selected 
by the sponsor to enable further characterization if necessary.
5.2 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local guidelines and the Investigator Brochure will serve as the Reference 
Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting period serves as the RSI 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
during the reporting period.  For follow-up reports, the RSI in place at the time of occurrence of the 
'suspected' Serious Adverse Reaction will be used to assess expectedness.
6 STUDY DRUG
6.1 Treatments Administered
The study drug (OnabotA X Formulations A, B, and C) will be dispensed, prepared, and administered as 
an IM injection at the Baseline/Day 1 visit as described in Section 5.7 of the study protocol.
Study drug must not be dispensed without contacting the IRT system.  Study drug may only be 
dispensed to subjects enrolled in the study through the IRT system.  
6.2 Packaging and Labeling
 
 
 
 
The investigational products are for investigational use only and are to be used only within the context 
of this study.  The study drug supplied for this study must be maintained under adequate security and 
stored under the conditions specified on the label until dispensed for subject use or destroyed on site as 
appropriate.
6.3 Method of Assigning Subjects to Treatment Groups
This is a randomized, open-label study.  All eligible subjects will receive the same 
 dosage of 
OnabotA X; however, 1 of 3 different formulations (A, B, or C) will be administered to subjects based on 
randomization.
At the screening visit, all subjects will be assigned a unique subject number through the use of the IRT.  
For subjects who do not meet the study selection criteria, the site personnel must contact the IRT 
system and identify the subject as a screen failure.
Subjects who are enrolled will retain their subject number assigned at the screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
  Subjects must remain at the site for observation for at least 2 hours following 
administration.
6.5 Preparation/Reconsitution of Dosage Form
Written instructions for the preparation of OnabotA X Formulations A, B, and C for injection will be 
provided in the pharmacy manual.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7 Appendices
7.1 Focused Neurological Examination Sheet
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.2
Anaphylaxis and Systemic Hypersensitivity
The National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
(NIAID/FAAN) diagnostic criteria serve as a rapid and simplified method to make an accurate clinical 
diagnosis of anaphylaxis.2  Investigators should utilize these criteria to recognize any early signs and 
symptoms of anaphylaxis and practice clinical judgement for acute treatment and referral to emergency 
care.  The NIAID/FAAN diagnostic criteria for anaphylaxis are outlined below.  
Table 1.
National Institute of Allergy and Infectious Disease and Food Allergy and 
Anaphylaxis Network Criteria for Anaphylaxis
National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network 
Criteria for Anaphylaxis
Anaphylaxis is likely when any one of these 3 criteria is fulfilled:
Acute onset of illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both 
(e.g., generalized hives, pruritus or flushing, swollen lips, tongue, or uvula) and at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze or bronchospasm, stridor, reduced peak expiratory 
flow, hypoxemia)
b.
Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence)
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to 
several hours):
a.
Involvement of the skin or mucosal tissue (e.g., generalized hives, itch or flush, swollen lips, tongue, or 
uvula)
b.
Respiratory compromise (e.g., dyspnea, wheeze or bronchospasm, stridor, reduced peak expiratory 
flow, hypoxemia)
c.
Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
d.
Persistent gastrointestinal tract symptoms (e.g., crampy abdominal pain, vomiting)
Reduced blood pressure after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic blood pressure (age-specific) or > 30% decrease in systolic blood 
pressurea
b.
Adults: systolic blood pressure < 90 mm Hg or > 30% decrease from that person's baseline
a.
Low systolic blood pressure for children is defined as < 70 mm Hg from 1 month to 1 year, < (70 mm Hg + [2 x age]) 
from 1 to 10 years, and < 90 mm Hg from 11 to 17 years.
Source: 2
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-324 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
8 References
1.
ARPANSA. Fitzpatrick Skin Phototype  [Available from: 
https://www.arpansa.gov.au/sites/default/files/legacy/pubs/RadiationProtection/FitzpatrickSki
nType.pdf.
2.
Manivannan V, Decker WW, Stead LG, et al. Visual representation of National Institute of Allergy 
and Infectious Disease and Food Allergy and Anaphylaxis Network criteria for anaphylaxis. Int J 
Emerg Med. 2009;2(1):3-5.
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SAP_001.pdf: 
OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
1
Statistical Analysis Plan for Study M21-324
Glabellar Lines: Safety and Efficacy and 
OnabotulinumtoxinA X in Subjects with Glabellar 
Lines
Date:  02 August 2022
Version 3.0
 
NCT05013424


OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
2
Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 5
2.3
Treatment Assignment and Blinding....................................................... 6
2.4
Sample Size Determination .................................................................... 6
3.0
Endpoints...............................................................................6
3.1
Primary Endpoint(s) ............................................................................... 6
3.2
Secondary Endpoint(s) ........................................................................... 7
3.3
Other Efficacy Endpoint(s)..................................................................... 7
3.4
Safety Endpoint(s).................................................................................. 8
3.5
Additional Endpoint(s) ........................................................................... 8
4.0
Analysis Populations .............................................................9
5.0
Subject Disposition................................................................9
6.0
Study Drug Duration and Compliance ..............................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................10
7.1
Demographics and Baseline Characteristics.......................................... 10
7.2
Medical History.................................................................................... 11
7.3
Prior and Concomitant Medications...................................................... 11
7.4
Concurrent Procedure........................................................................... 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..................................................................... 12
9.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 12
9.3.1
Primary Efficacy Endpoint(s) ............................................................... 12
9.3.2
Main Analysis of Primary Efficacy Endpoint(s).................................... 12
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint(s)........................................................................................... 13


OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
3
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 13
9.4.1
Key Secondary Efficacy Endpoints....................................................... 13
9.4.2
Main Analyses of Key Secondary Efficacy Endpoints .......................... 13
9.4.3
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoints ............................................................................... 13
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 13
9.5
Additional Efficacy Analyses ............................................................... 13
9.6
Efficacy Subgroup Analyses................................................................. 14
10.0
Safety Analyses....................................................................14
10.1
General Considerations......................................................................... 14
10.2
Adverse Events..................................................................................... 15
10.2.1
Treatment-Emergent Adverse Events.................................................... 15
10.2.2
Adverse Event Overview...................................................................... 15
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 16
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 16
10.2.5
Potential Distant Spread of Toxin Adverse Events................................ 16
10.3
Analysis of Laboratory Data................................................................. 17
10.4
Analysis of Vital Signs......................................................................... 18
10.5
Safety Subgroup Analyses.................................................................... 19
10.6
Other Safety Analyses .......................................................................... 19
11.0
Other Analyses ....................................................................19
12.0
Interim Analyses..................................................................20
12.1
Data Monitoring Committee................................................................. 20
13.0
Overall Type-I Error Control.............................................20
14.0
Version History ...................................................................20
15.0
References............................................................................21
List of Tables
Table 1.
SAP Version History Summary ............................................................ 20


OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
4
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 22
Appendix B.
Definition of Possible Distant Spread of Toxin..................................... 23
Appendix C.
Potentially Clinically Important Criteria for Safety Endpoints .............. 24


OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for OnabotA X 
Study M21-324 Glabellar Lines: Safety and Efficacy of OnabotulinumtoxinA X in 
Subjects with Glabellar Lines.
Study M21-324 examines the efficacy and safety of OnabotA X in female subjects with
severe glabellar lines.
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 primary objective of the study is to evaluate the safety of OnabotA X injection in the 
glabellar region of female subjects with severe GL.
The clinical hypothesis is that OnabotA X has an acceptable safety profile when 
administered to the corrugator and procerus muscles in subjects with severe GL.
No estimand is defined for the safety evaluations.
2.2
Study Design Overview
The schematic of the study is shown in Figure 1.




OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
7
3.2
Secondary Endpoint(s)
Not applicable.
3.3
Other Efficacy Endpoint(s)
All efficacy endpoints will utilize the Facial Wrinkle Scale for Glabellar Lines (FWS-GL) 
and/or the Allergan Glabellar Line Severity Scale (AGLSS), each of which are scored on 
a 0-3 range, where 0 = None, 1 = Mild, 2 = Moderate, and 3 = Severe. 
The efficacy endpoints for the investigator-rated and subject-rated FWS-GL at maximum 
frown include:
●
Number and proportion of subjects who achieve 1-grade improvement from 
baseline;
●
Number and proportion of subjects who achieve 2-grade improvement from 
baseline;
●
Number and proportion of subjects who achieve 2-grade improvement from 
baseline in both Investigator and Subject ratings;
●
Number and proportion of subjects who achieve a "None" or "Mild" rating
With the exception of the endpoint above that is based on both the Investigator and 
Subject ratings, the other endpoints listed above are calculated separately for Investigator-
rated and subject-rated FWS-GL.
The efficacy endpoints for the Allergan Glabellar Line Severity Scale (AGLSS) at 
maximum frown evaluated by independent investigator (separate from the investigator 
evaluating FWS-GL) include: 
●
Number and proportion of subjects rated at least "Mild" at baseline who 
achieve 1-grade improvement from baseline;
●
Number and proportion of subjects rated at least "Moderate" at baseline who 
achieve 2-grade improvement from baseline;


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M21-324 – Statistical Analysis Plan
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8
●
Number and proportion of subjects at least "Moderate" at baseline who achieve 
a "None" or "Mild" rating
The efficacy endpoints for the subjects whose glabellar lines were rated at least "Mild" at 
baseline at rest include: 
●
Number and proportion of subjects with 1-grade improvement from baseline in 
investigator-rated FWS-GL;
●
Number and proportion of subjects with 1-grade improvement from baseline in 
FWS- subject-rated GL;
●
Number and proportion of subjects who achieve a 1-grade improvement from 
baseline in AGLSS
The FWS-GL endpoints will be assessed at screening, baseline, and at each follow-up 
visit, while the AGLSS endpoints will only be assessed at baseline and Day 30.
3.4
Safety Endpoint(s)
The safety endpoints for this study include:
●
Adverse Events
●
Abbreviated Physical Examination (general appearance, head, ears, eyes, nose, 
throat, and neck)
●
Clinical Laboratory Test (hematology, chemistry, and urinalysis)
●
Vital Sign Measurements (body temperature, pulse rate, respiration rate, 
systolic and diastolic blood pressure)
●
Electrocardiogram (heart rate, QRS duration, QT interval, QTcB interval, 
QTcF interval, ST segment, RR interval, PR interval)
●
Neurologic Assessment
3.5
Additional Endpoint(s)
The following additional endpoints will also be assessed:


OnabotA X
M21-324 – Statistical Analysis Plan
Version 3.0 – 02 August 2022
9
Immunogenicity: Blood samples for immunogenicity testing will be collected 
from all subjects treated with OnabotA X at Day 1 (Baseline), Day 30, Day 90, 
and End-of-Study (Day 180). Collected samples will be processed to yield serum 
for detection of binding and neutralizing antibodies to OnabotulinumtoxinA.
Hypersensitivity: Blood samples are to be collected within 2 hours of suspected 
anaphylaxis or systemic hypersensitivity reaction.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose 
of study drug. The FAS will be used for all efficacy and baseline analyses. Subjects in 
this population will be analyzed per randomization, regardless of actual treatment 
received.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug. 
The Safety Analysis Set will be used for all safety analyses. Due to the difficulty of 
determining the actual treatment received if wrong kits are given or reconstitution is not 
done correctly, subjects in this population will be analyzed per randomization.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled, and treated will be 
summarized.  Reasons for exclusion, including screen failure, will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group:
●
Subjects enrolled (randomized) in the study;
●
Subjects who were treated;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued (all reasons and primary reason);


OnabotA X
M21-324 – Statistical Analysis Plan
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10
●
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 (or did not with associated reasons) will be summarized 
overall and by treatment group.
6.0
Study Drug Duration and Compliance
Duration of exposure will be summarized with descriptive statistics (mean and standard 
deviation, median, Q1, Q3, minimum, and maximum).  The number of subjects exposed 
for specific period of time (1-30 days, 31-60 days, 61-90 days, 91-120 days, 121-150 
days, 151-180 days, and >180 days) will also be summarized.  Duration of exposure will 
be calculated as date of study exit minus date of study drug administration +1.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline characteristics, medical history, prior and concomitant 
medications, and concurrent procedure will be summarized overall and by treatment 
group for the FAS.  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. Categorical demographic variables 
include sex, ethnicity, race, age group (18-25, 26-40, 41-55, 56-64, or ≥65 years).
Baseline characteristics include weight, height, body mass index (BMI), Fitzpatrick skin 
type, baseline Investigator-rated and subject-rated FWS-GL severity at maximum frown 
and rest, and baseline AGLSS severity at maximum frown and at rest.


OnabotA X
M21-324 – Statistical Analysis Plan
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11
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group. 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).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
drug.  A concomitant medication is defined as any medication that started prior to the date 
of study drug administration and continued to be taken after the first dose of study drug or 
any medication that started on or after the date of the first dose of study drug.  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.
7.4
Concurrent Procedure
All procedures undergone on or after Study Day 1 visit through the exit visit will be 
considered concurrent procedures. Concurrent procedure will be summarized by 
MedDRA high-level term and preferred term.  The MedDRA high level term will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each high-level term. A listing will be generated for concurrent procedures.  
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
Not applicable.


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M21-324 – Statistical Analysis Plan
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9.0
Efficacy Analyses
9.1
General Considerations
Data will be summarized for subjects for the FAS Population.  For the efficacy analyses, 
subjects are summarized based on the randomized treatment assigned.
The number and percentage (or proportion) of the subjects who are responders will be 
summarized.  Calculation of a 95% CI with an exact method based on the binomial 
distribution will be utilized alongside the summary data. 
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
9.2
Handling of Missing Data
Missing data will not be imputed.  Instead, the following method will be used for the 
efficacy summary data:
●
As Observed (AO): The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit (within the applicable visit window) will be excluded from the AO 
analysis for that visit.  AO will include all values collected in the study.
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
Not applicable.
9.3.2
Main Analysis of Primary Efficacy Endpoint(s)
Not applicable.


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9.3.3
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint(s)
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
Additional Efficacy Analyses
Additional Efficacy Endpoints are:
●
Achievement of ≥1-grade improvement from baseline on the investigator-rated
FWS-GL at maximum frown by visit
●
Achievement of ≥1-grade improvement from baseline on the subject-rated
FWS-GL at maximum frown by visit
●
Achievement of ≥2-grade improvement from baseline on the investigator-rated
FWS-GL at maximum frown by visit
●
Achievement of ≥2-grade improvement from baseline on the subject-rated
FWS-GL at maximum frown by visit


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●
Achievement of None or Mild on the investigator-rated FWS-GL at maximum 
frown by visit
●
Achievement of None or Mild on the subject-rated FWS-GL at maximum 
frown by visit
●
Achievement of ≥2-grade improvement from baseline on both the investigator-
rated and subject-rated FWS-GL at maximum frown by visit
●
Achievement of ≥1-grade improvement from baseline on the AGLSS at 
maximum frown for those who were rated at least Mild at baseline
●
Achievement of ≥2-grade improvement from baseline on the AGLSS at 
maximum frown for those who were rated at least Moderate at baseline
●
Achievement of None or Mild on the AGLSS at maximum frown for those 
who were rated at least Moderate at baseline
●
Achievement of ≥1-grade improvement from baseline on the investigator-rated
FWS-GL at rest by visit for those who were rated at least Mild at baseline
●
Achievement of ≥1-grade improvement from baseline on the subject-rated
FWS-GL at rest by visit for those who were rated at least Mild at baseline
●
Achievement of ≥1-grade improvement from baseline on the AGLSS at rest
for those who were rated at least Mild at baseline
Listings of all endpoint values for each subject will also be provided.
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 analyses, 
subjects are summarized based on the treatment as randomized.
For safety analyses, "Baseline" refers to the last non-missing observation before the 
first administration of study drug unless otherwise noted.


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10.2
Adverse Events
Adverse events (AEs) will be summarized overall and by treatment group 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 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 are defined as any AE with the onset that is after the study drug
administration. Events where the onset date is the same as the study drug start date are 
assumed to be treatment-emergent.  All treatment-emergent AEs will be summarized 
overall, as well as by primary MedDRA SOC and Preferred Term.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in alphabetical order within 
each SOC.
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 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


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o
Any severe treatment-emergent AE related to study treatment according to 
the investigator
●
Any serious treatment-emergent AE
o
Any serious treatment-emergent AE related to study treatment according to 
the investigator
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent PDSOT AEs
●
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 
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 overall group.  Treatment-related treatment-emergent 
adverse events, study drug related treatment-emergent adverse events, and study 
procedure related treatment-emergent adverse events will also be summarized by SOC 
and PT.
10.2.4
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) will be summarized by SOC and PT and in listing format.
10.2.5
Potential Distant Spread of Toxin Adverse Events
To assess PDSOT, MedDRA preferred terms that may be associated with botulinum toxin 
effects have been identified (Appendix B).  All TEAEs associated with PDSOT will be 
tabulated by PT; in addition, all PDSOT TEAEs will be listed by subject.


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10.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments before the first dose of study drug will be excluded. The clinical 
laboratory tests defined in the protocol operations manual (e.g., hematology, clinical 
chemistry, and urinalysis) will be summarized by treatment group.
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group.
Changes in laboratory parameters will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample. A 
shift table from baseline to the minimum post-baseline value, to the maximum post-
baseline value, and to the final post-baseline value will be created.
Laboratory abnormalities will be evaluated based on Potentially Clinically Important 
(PCI) criteria (Table C-1 in Appendix C). For each laboratory PCI criterion, the number 
and percentage of subjects who have a post-baseline laboratory value meeting the criteria 
will be summarized. The percentages will be calculated relative to the number of 
participants with at least 1 postbaseline assessment.  The numerator will be the total 
number of participants with at least 1 PCI postbaseline value during the study that is more 
extreme than baseline (if present).
Listings will be provided to summarize subject-level laboratory data for subjects meeting 
PCI criteria.


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A listing of possible Hy's Law cases, defined as those who meet all of the following 
conditions simultaneously, will be provided: ALT > 3 × ULN or AST > 3 × ULN that is 
associated with an increase in bilirubin ≥ 2 × ULN and alkaline phosphatase < 2 × ULN.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature will be summarized by treatment group.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum. Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign variable, with the number of observations, 
baseline mean, and visit mean.  The change from baseline mean, standard error, and 95% 
confidence interval will be presented for the mean change from baseline within each 
treatment group.
Vital sign variables will be evaluated based on PCI criteria (Table C-2 in Appendix C).  
For each vital sign PCI criterion, the number and percentage of subjects who have a vital 
sign value meeting the criteria will be summarized.  Except for temperature, the 
percentages will be calculated relative to the number of participants with an available 
baseline value and at least 1 post-baseline assessment; the numerator will be the total 
number of participants with at least 1 PCI post-baseline value during the study that is 
more extreme than baseline. For temperature, the percentages will be calculated based on
the number of participants with at least 1 post-baseline assessment. The numerator will be 
the total number of participants with at least 1 PCI post-baseline value during the study;
no baseline is required, however if a baseline value is present the observed value must 
also be more extreme than baseline to be considered PCI.
Listings will be provided to summarize subject-level vital sign data for subjects meeting 
PCI criteria.


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10.5
Safety Subgroup Analyses
Not applicable.
10.6
Other Safety Analyses
Electrocardiogram (ECG): Descriptive statistics for quantitative ECG parameters 
(i.e., heart rate, QRS duration, QT interval, QTc interval, QTcB interval, QTcF interval, 
RR interval and PR interval) at baseline, postbaseline, and changes from baseline values 
at each postbaseline timepoint will be presented.
ECG parameter values are considered PCI if ECG values meet either the actual value or 
change from baseline PCI high criteria listed in Table C-3 of Appendix C.  The number 
and percentage of participants with PCI post-baseline values will be tabulated.  The 
percentages will be calculated relative to the number of participants with at least 1 post-
baseline assessment.  The numerator will be the total number of participants with at least 
1 PCI post-baseline value during the study that is more extreme than baseline (if present).
A supportive listing of participants with PCI post-baseline values will be provided.  
 
 
11.0
Other Analyses
Immunogenicity: Immunogenicity results, manifested as the binding antibodies and
neutralizing antibodies, will be summarized overall and by treatment group for each 
sampling timepoint.  A listing of each subject's results by visit will also be produced.
Hypersensitivity: Blood sample results from hypersensitivity evaluations, if any are 
conducted, will also be listed.


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12.0
Interim Analyses
Not applicable.
12.1
Data Monitoring Committee
Not applicable.
13.0
Overall Type-I Error Control
Not applicable.
14.0
Version History
Table 1.
SAP Version History Summary
Version
Date of Approval
Summary
1.0
05 August 2021
Initial version
2.0
10 October 2021
In Section 10.6, added text about ECG because the protocol was 
amended (v3.0) to include collection of ECG.  Includes ECG 
parameters, ECG PCI table, and text stating how the ECG 
parameters will be summarized and listed.
Updated Section 10.2.2 and Section 10.2.3 regarding AE 
overview table, and added treatment-related adverse events 
tables.
Updated Section 10.3 to add lab PCI.
Updated Section 10.4 to revise the vital PCI language.
3.0
Section 4.0, changed the safety analysis set to be analyzed per
randomization due to the difficulty of determine the actual 
treatment
Section 7.1, changed age group from <65, or ≥65 years to 18-
25, 26-40, 41-55, 56-64, or ≥65 years
Table B-1: MedDRA preferred terms evaluated for PDSOT, 
removed the term “Extraocular muscles paresis”, added the term 
“Opthalmoplegia”
Updated Table C-1 Criteria for Potentially Clinically Important 
Clinical Laboratory Values: updated the value corresponding to 
Cholesterol, Glucose, and Triglycerides.  Changed “Inorganic 
phosphorus” to “Phosphate”


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15.0
References


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Appendix A.
Protocol Deviations
The number and percentage of unique subjects reporting significant protocol deviations 
will be summarized in total and by treatment group for all randomized or treated subjects.  
The number and percentage of unique subjects with protocol deviation categories below 
will also be summarized in total and by treatment group.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication or concurrent procedure.


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Appendix B.
Definition of Possible Distant Spread of Toxin 
Table B-1.
MedDRA Preferred Terms Evaluated for PDSOT 
Accommodation disorder
Aspiration 
Bell's Palsy
Botulism
Bradycardia 
Bulbar palsy
Constipation
Cranial nerve palsies multiple
Cranial nerve paralysis
Diaphragmatic paralysis
Diplopia
Dry mouth
Dysarthria
Dysphagia
Dysphonia
Dyspnoea
Eyelid function disorder
Eyelid ptosis
Facial paralysis
Facial paresis
Hyporeflexia
Hypotonia
Ileus paralytic
Muscular weakness
Opthalmoplegia
Paralysis
Paresis cranial nerve
Pelvic floor muscle weakness
Peripheral nerve palsy
Peripheral paralysis
Pneumonia aspiration
Pupillary reflex impaired
Respiratory arrest
Respiratory depression
Respiratory failure
Speech disorder
Urinary retention
Vision blurred
Vocal cord paralysis
Vocal cord paresis
Note:
Table is based on MedDRA 25.0; the actual list used for analysis will be based on the MedDRA version in use 
at the time of database lock.




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Table C-1.
Criteria for Potentially Clinically Important Clinical Laboratory
Values (Continued)
Parameter
Flag
Criteriaa
Observed Value
Total Bilirubin (umol/L)
High
>1.5 x ULN
Low
-
Calcium (mmol/L)
High
Corrected serum calcium >2.9@; 
Ionized calcium >1.5
Low
Corrected serum calcium <2.0@; 
Ionized calcium <1.0
Cholesterol (mmol/L)
High
>10.34
Low
-
Creatinine (umol/L)
High
>1.5 x ULN
Low
-
Gamma Glutamyl Transferase (U/L)
High
>2.5 x ULN
Low
-
Glucose (mmol/L)
High
>13.9
Low
<2.2
Potassium (mmol/L)
High
>5.5
Low
<LLN 
Sodium (mmol/L)
High
>150
Low
<130
Triglycerides (mmol/L)
High
>5.70
Low
-
Phosphate (mmol/L)
High
-
Low
<0.8
a.
A post-baseline value must be more extreme than baseline (if present) to be considered a potentially clinically 
important finding.
@
Calcium corrected for Albumin (can be used if it is confirmed with the lab that the result has been corrected for 
Albumin and not a different protein).
Note:
LLN = Lower Limit of Normal; ULN = Upper Limit of Normal


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The criteria for PCI criteria for vital sign findings are described in Table C-2.
Table C-2.
Criteria for Potentially Clinically Important Vital Sign Values
Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Sitting systolic blood 
pressure, mm Hg
High
≥ 160
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Sitting diastolic blood 
pressure, mm Hg
High
≥ 100
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, bpm
High
≥ 110
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Temperature, degrees C
High
≥38.3
-
Low
-
-
bpm = beats per minute; C = Celsius
a.
Except for temperature, a post-baseline value is considered potentially clinically important if it meets both the 
observed-value and the change-from-baseline criteria; for temperature, only the observed-value criterion is needed 
to be potentially clinically important (but must be more extreme than baseline if baseline is present).
The criteria for PCI criteria for ECG findings are described in Table C-3.
Table C-3.
Criteria for Potentially Clinically Important ECG Values
Parameter
Unit
Criteriaa
Observed Value
Change from Baseline
QRS interval
msec
≥ 150
-
PR interval
msec
≥ 250
-
QTcB
msec
> 500
Increase of > 60
QTcF
msec
> 500
Increase of > 60
QTcB = QT interval corrected for heart rate using the Bazett formula.
QTcF = QT interval corrected for heart rate using the Friderica formula.
a.
A post-baseline value is considered potentially clinically important if it meets either the observed-value or the 
change-from-baseline criteria (but must be more extreme than baseline if baseline is present).