Conditions: Upper Facial Lines
Keywords: Glabellar Lines Lateral Canthal Lines Forehead Lines BOTOX Botulinum Toxin Type A OnabotulinumtoxinA Upper Facial Lines Crows Feet Lines Wrinkles Facial Wrinkles Facial Rhytides
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 100
Healthy volunteers: no

Brief summary:
Facial lines that develop from repeated facial expression, such as glabellar lines (GL), lateral canthal lines (LCL), and forehead lines (FHL), are typically treated by selectively weakening specific muscles with small quantities of botulinum toxin. The purpose of this study is to evaluate participant satisfaction and natural outcomes following the administration of BOTOX Cosmetic in adult participants with upper facial lines (GL, LCL, and FHL).

This is an open-label study in which all participants will receive active study treatment. Around 100 adult participants with an assessment of moderate to severe GL, LCL, and FHL, will be enrolled at approximately 10 sites in the United States and Canada.

Participants will receive BOTOX Cosmetic as intramuscular injections to the glabellar lines, lateral canthal lines, and forehead lines at Day 1.

Participants will attend regular visits during the study. The effect of the treatment will be checked by medical assessments for side effects and questionnaires will be completed during regular study visits.

Detailed description:

Arms:
arm 1: Participants will receive injections in the glabellar complex, in each of the lateral canthal area, and in the frontalis muscle on Day 1.

Interventions: intervention 1: BOTOX
Intervention descriptions: intervention 1: Intramuscular Injections

Protocol document:
Prot_000.pdf: 


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Application with the Competent Authority. Additional study contact information can be found in the 
Operations Manual (Appendix F).
TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
6
2.1
BACKGROUND AND RATIONALE
6
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
OBJECTIVES AND ENDPOINTS
7
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
7
3.2
PRIMARY ENDPOINT
8
3.3
SECONDARY ENDPOINT
8
3.4
ADDITIONAL ENDPOINTS
8
3.5
SAFETY ENDPOINTS
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
14
5.3
PROHIBITED MEDICATIONS AND PROCEDURES
15
5.4
PRIOR AND CONCOMITANT PROCEDURES
16
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
18
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
18
5.7
STUDY DRUG
19
5.8
RANDOMIZATION/DRUG ASSIGNMENT
19
5.9
PROTOCOL DEVIATIONS
19
5.10 DATA MONITORING COMMITTEE
20
6
SAFETY CONSIDERATIONS
20
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6.1
COMPLAINTS AND ADVERSE EVENTS
20
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
23
7.1
STATISTICAL AND ANALYTICAL PLANS
23
7.2
DEFINITION FOR ANALYSIS POPULATIONS
24
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND SECONDARY EFFICACY ENDPOINTS
24
7.4
STATISTICAL ANALYSES FOR EFFICACY
24
7.5
STATISTICAL ANALYSES FOR SAFETY
24
7.6
INTERIM ANALYSIS
25
7.7
OVERALL TYPE I ERROR CONTROL
26
7.8
SAMPLE SIZE DETERMINATION
26
8
ETHICS
26
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
26
8.2
ETHICAL CONDUCT OF THE STUDY
26
8.3
SUBJECT CONFIDENTIALITY
27
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
27
10 DATA QUALITY ASSURANCE
27
11 COMPLETION OF THE STUDY
27
12 REFERENCES
27
LIST OF TABLES
TABLE 1.
STUDY DRUG INFORMATION
19
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMA
10
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
29
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APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
31
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
32
APPENDIX D.
ACTIVITY SCHEDULE
33
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
36
APPENDIX F.
OPERATIONS MANUAL
37
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
BOTOX Cosmetic (onabotulinumtoxinA/Botulinum Toxin Type A) is an acetylcholine release inhibitor and 
a neuromuscular blocking agent indicated in adults for the temporary improvement in the appearance 
of moderate to severe glabellar lines (GL) associated with corrugator and/or procerus muscle activity, 
moderate to severe lateral canthal lines (LCL) associated with orbicularis oculi activity, and moderate to 
severe forehead lines (FHL) associated with frontalis muscle activity.1,2
The contraction of these facial muscles serves a role in communicating an emotional state, which 
influences both how an individual presents themselves as well as how they are perceived by others.3  
Over time, the repetitive contraction of facial muscles, along with degenerative changes due to aging, 
can negatively affect social interactions, social perceptions and, ultimately, self-esteem.4
Facial rejuvenation has been rapidly gaining ground to improve subject satisfaction with facial 
appearances, which is often described as achieving a "natural and relaxed" look. It is typical for some 
clinicians to start with less than labeled doses of botulinum toxin to avoid a "frozen" look. As more 
experience has been gained, botulinum toxin dosing, precise placement, and injection techniques have 
become more fine-tuned. As a result of these advances, healthcare professionals have learned that 
proper botulinum toxin procedures can yield a natural look that drives subject satisfaction.5
Although limited, several studies have focused on patient outcomes associated with the improvement in 
signs of aging. The HARMONY study investigated the impact of fillers and onabotulinumtoxinA in a 
pan-facial approach and demonstrated that minimally invasive, multimodal treatment resulted in 
improvements in FACE-Q scores and perceived age, indicating a high degree of patient satisfaction and a 
younger facial appearance.6  In addition, when independent observers were provided with enrolled 
subjects' paired before and after treatment images, the independent observers reported that subjects 
appeared to have a higher social status, look nearly 5 years younger, more healthy, approachable, more 
attractive, and more successful at attracting others after treatment.7
Significant improvements in patient-reported outcomes (PROs) have also been reported in a Phase 3 
study assessing the effectiveness of onabotulinumtoxinA treatment of GL, LCL, and FHL.8  Subjects were 
highly satisfied with onabotulinumtoxinA treatment and reported significant improvement in emotional 
and psychological well-being compared to placebo. Subject satisfaction remained high throughout the 
6 -month double-blind period, and improvements were maintained with repeated onabotulinumtoxinA 
treatment during the following 6 -month open-label period.
The purpose of this study is to evaluate subject satisfaction and natural outcomes following BOTOX 
Cosmetic treatment of upper facial areas (GL, LCL, and FHL).
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2.2 Benefits and Risks to Subjects
The clinical efficacy and safety profile of BOTOX Cosmetic has been demonstrated in multiple clinical 
trials across several indications, with favorable benefit risk profiles. In general, adverse reactions occur 
within the first few days to weeks following injection of BOTOX Cosmetic and, while generally transient, 
may have a duration of several months or, in rare cases, longer.
While Allergan (an AbbVie company) does not consider Coronavirus disease 2019 (COVID-19) to be a 
safety concern for BOTOX Cosmetic due to its mechanism of action and route of administration, the 
sponsor is monitoring COVID-19 events during the pandemic closely. A review of COVID-19 events for 
the period of 01 January 2019 through 31 December 2021 did not identify any new or significant safety 
findings for the subjects receiving BOTOX Cosmetic treatment. Overall, the clinical course and 
presentation of patients with COVID-19 infection coincident with BOTOX Cosmetic is consistent with 
what has been described for the general population. Considering the COVID-19 pandemic and based on 
the limited information to date, no additional risk to study participants is anticipated with the use of 
BOTOX Cosmetic.
For further details, please see findings from completed studies, including safety data in the current
BOTOX Cosmetic investigator's brochure.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Objective
The objective of this study is to evaluate subject satisfaction and natural outcomes following the 
administration of 64 U of BOTOX Cosmetic in subjects with upper facial lines (GL, LCL, and FHL).
Clinical Hypothesis
Single treatment of upper facial lines with BOTOX Cosmetic at 64 U can lead to subject satisfaction and 
natural outcomes.
Estimands
The estimand corresponding to the primary endpoint is as follows: 

The proportion of subjects receiving treatment of BOTOX Cosmetic 64U who achieve the 
responder status of Mostly satisfied or Very satisfied on the Facial Line Satisfaction 
Questionnaire (FLSQ) Item 4 at the Day 30 assessment in the modified intention-to-treat (mITT) 
population. Subjects who have any intercurrent event resulting in not having a Day 30 
assessment will not be included. 
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The estimand corresponding to the secondary endpoint is as follows: 

The mean change from baseline in subject assessment based on Rasch-transformed score of 
FACE-Q Psychological Function at the Day 30 assessment for subjects who receive BOTOX 
Cosmetic 64 U in the mITT population. Subjects who have any intercurrent event resulting in not 
having a Day 30 assessment will not be included.
3.2 Primary Endpoint
The primary endpoint is the responder status of Mostly satisfied or Very satisfied on the Facial Line 
Satisfaction Questionnaire (FLSQ) Follow-up Item 4 at Day 30. 
3.3 Secondary Endpoint
Secondary endpoint is

Change from baseline in subject's assessment based on Rasch-transformed score of FACE-Q 
Psychological Function scale at Day 30
3.4 Additional Endpoints
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3.5 Safety Endpoints
The safety endpoint is the incidence of adverse events (AEs).
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a 6-month, prospective, multicenter, open-label study to evaluate subject satisfaction and natural 
outcomes following the administration of BOTOX Cosmetic 64 U for the treatment of upper facial lines.
The study will enroll approximately 100 subjects with moderate to severe GL, LCL, and FHL as assessed 
by the investigator. Out of the approximately 100 enrolled subjects:

approximately 20% of the study population will be treatment naïve to any botulinum toxin of 
any serotype for any indication, 

approximately 20% of the study population will be self-identified as male,
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
approximately 20% of the study population will be self-identified as Asian, and 

approximately 20% of the study population will have Fitzpatrick skin phototypes of IV, V, or VI.
A review of individual site data will be conducted once a sufficient number of subjects has been
enrolled. The site will be permitted to enroll additional subjects upon sponsor approval. This process 
may be repeated as needed.
On Day 1, after subjects are verified to meet all eligibility criteria and have completed all baseline study 
procedures, they will receive 64 U of BOTOX Cosmetic. Each subject will receive a total of 16 injections 
(0.1 mL or 4 U of BOTOX Cosmetic per injection), with 5 injections in the glabellar complex, 3 injections 
in each of the lateral canthal area (6 total injections), and 5 injections in the frontalis muscle.
There are seven in-clinic visits: screening/baseline/treatment (Day 1), post-treatment follow-up visits 
(Days 30, 60, 90, 120, 150), and study exit (Day 180 or Early Exit). The study schema of the study is 
shown in Figure 1.
Further details on study procedures are located in the Operations Manual (Appendix E).
Figure 1.
Study Schema
4.2 Discussion of Study Design
Choice of Control Group
This is an open-label study. There is no separate control group. 
Appropriateness of Measurements
The primary efficacy measure used in this study (FLSQ) is a validated measure. Allergan has also 
developed and validated upper facial line severity scales (AGLSS, LCLSS, and FHLSS) in accordance with 
the United States Food and Drug Administration requirement. All efficacy-related measurements in this 
study are standard for assessing facial aesthetics correction (for GL, LCL, and FHL). All clinical procedures 
in this study are standard and generally accepted.
Suitability of Subject Population
The study population will include male and female adults with moderate to severe GL, LCL, and FHL at 
maximum contraction as assessed by investigators using the AGLSS, LCLSS, and FHLSS, respectively. To 
avoid confounding the study results, washout from prior facial aesthetic treatments is required as 
described in the eligibility criteria. 
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Selection of Doses in the Study
BOTOX Cosmetic is currently approved for aesthetic treatment of GL, LCL and FHL. The total dose, 
dilution, injection pattern, and route of administration will follow the approved label, and each eligible 
subject will receive a fixed dose of 64 U of BOTOX Cosmetic on Day 1 (20 U to the glabellar complex, 
24 U to the lateral canthal areas, and 20 U to the frontalis muscles). 
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 Eligibility Criterion #8 (listed below). Any 
attempt to rescreen a subject must only occur after agreement with the sponsor. Rescreening can only 
occur once for any given potential subject.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures. 
2. Subjects are willing and able to comply with procedures required in this protocol.
3. Subjects must agree to have photos and videos taken during study visits. Subjects must 
consent to having photographs and videos taken for research/educational purposes but may still 
participate if he/she declines use of the photographs and videos for other purposes.
Demographic and Subject Characteristics
4. Adult male or female, at least 18 years old, at the time of signing the informed consent.
5. Subjects must have sufficient visual acuity without the use of eyeglasses (contact lens use 
acceptable) to accurately assess their facial wrinkles.
6. Subject must be able to follow study instructions and complete study assessment tools 
without any assistance or alterations to the assessment tools and complete all required study 
procedures.
7. Subject must be in good health as determined by medical history, vital signs, and 
investigator's judgement, including no known active pandemic infection.
Condition
8. Subject meets all of the following criteria prior to dosing on Day 1, as determined by the 
investigator:

GL of Moderate (Grade 2) to Severe (Grade 3) on AGLSS at maximum contraction. 
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
LCL of Moderate (Grade 2) to Severe (Grade 3) bilaterally (severity identical on both sides)
on LCLSS at maximum contraction.

FHL of Moderate (Grade 2) to Severe (Grade 3) on FHLSS at maximum contraction.
Subject History
9. No history of known immunization or hypersensitivity to any botulinum toxin serotype.
10. No history of an allergic reaction or significant sensitivity to constituents of the study drug 
(and its excipients) and/or other products in the same class.
11. No history of clinically significant (per investigator's judgment) drug or alcohol abuse within 
the last 6 months.
12. No presence of tattoos, jewelry, or clothing which obscures or interferes with the target area 
of interest and cannot be removed.
14. No history of clinically significant medical conditions or presence of current uncontrolled 
systemic disease or any other reasons, in the investigator's opinion, that may put the subject at 
significant risk, may confound the study results, or may interfere significantly with participation 
in the study.
15. Subjects cannot be directly or indirectly involved in the conduct and administration of this 
study as a principal investigator, sub-investigator, study coordinator, or other study staff 
member; or employee of the sponsor, or a first-degree family member, significant other, or 
relative residing with one of the above persons involved directly or indirectly in the study. 
16. No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If 
a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a 
negative molecular (e.g., polymerase chain reaction [PCR] test result). Note: SARS-CoV-2 
diagnostic tests should be applied following local requirements/recommendations.
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17. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and 
may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria: 

At least 10 days since first positive test result have passed in asymptomatic subjects or at 
least 10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms
20. No history of any botulinum neurotoxin of any serotype for any indication within 6 months
prior to Day 1.
21. No clinically significant abnormal vital signs at Day 1.
Contraception
22. Female subjects of childbearing potential must have a negative urine pregnancy test at Day 1
prior to study treatment. 
23. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from study drug administration (Day 1) through a minimum of
60 days or until last study follow-up visit, whichever is longer. Female subjects of 
nonchildbearing potential do not need to use birth control.
24. Female subject who is not pregnant or breastfeeding and is not considering becoming 
pregnant or donating eggs from study drug administration (Day 1) through a minimum of
60 days after study drug administration or until last study follow-up visit, whichever is longer.
Concomitant Medications or Procedures
25. No anticipated need for treatment with botulinum toxin of any serotype for any indication 
during the study (other than study drug).
26. No anticipated need for surgery or overnight hospitalization during the study.
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27. No plans for an extended absence away from the immediate area of the study site that 
would preclude them from returning for all protocol-specified study visits.
28. In the investigator's opinion, subject is able and willing to maintain his or her standardized 
skin care regimen throughout the study period.
29. Subject must not have been treated with any investigational drug within 30 days or 5 half-
lives of the drug (whichever is longer) prior to the first dose of study drug or is currently enrolled 
in another clinical study or was previously enrolled in this study.
5.2 Contraception Recommendations
Contraception Requirements for Females
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:

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

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy. However, in the absence of 
12 months of amenorrhea, confirmation with more than 1 FSH measurement is 
required.

Females on hormone replacement therapy and whose menopausal status is in 
doubt, as determined by the investigator, will be required to use one of the 
non-hormonal (highly) effective contraception methods if they wish to continue 
their hormone replacement therapy during the study. Otherwise, they must 
discontinue hormone replacement therapy to allow confirmation of 
postmenopausal status before study enrollment.
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
Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy from study drug administration 
(Day 1) through a minimum of 60 days after the last dose or until last study follow-up visit, 
whichever is longer.

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 Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to 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 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.
5.3 Prohibited Medications and Procedures
The decision to administer a prohibited medication/treatment during the study period is done with the 
safety of the subject as the primary consideration. When possible, the sponsor is to be notified before 
the prohibited medication/treatment is administered.
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:
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All other investigational drugs are prohibited. 
5.4 Prior and Concomitant Procedures
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 the study drug administration through the 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 electronic case report form 
(eCRF) at each visit along with the reason the medication is taken, dates of use, and dosing regimen. 
Concomitant medications and concurrent procedures will also be collected at each visit. 
Study site personnel should 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. 
Non-live vaccines may be used during the study, 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.
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Systemic and topical hormones and their derivatives (e.g., sex steroids - androgens, estrogens, 
progesterone) should be maintained throughout the study period to avoid changes in skin, including but 
not limited to:

Oral birth control

IUDs/implants/injections

Oral supplements including testosterone & estrogens and their derivatives, 
dehydroepiandrosterone (DHEA), etc.

Topicals (anywhere on the body) including testosterone & estrogens and their derivatives, 
DHEA, etc.

Androgel, Axiron, Testim, Fortesta, Vogelxo

Emepelle (methyl estradiolpropanoate), Rejuvenate, All Natural Bioidentical Estradiol, Emerita 
Phytoestrogen
Subjects should maintain their skin care regimen throughout the study period.
Any questions regarding concomitant or prior procedures should be raised to the AbbVie non-
emergency contact. Information regarding potential drug interactions with BOTOX Cosmetic can be 
located in the BOTOX Cosmetic Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications as described in the eligibility 
criteria. Subjects must consent to the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
COVID-19 Pandemic-Related Vaccination Guidance
Select non-live vaccines (e.g., messenger ribonucleic acid, non-replicating viral vector, protein subunit, 
etc.) to prevent SARS-CoV-2 infection may be administered during the study, as long as components of 
the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of BOTOX Cosmetic on SARS-CoV-2 vaccination is unknown. Therefore, study drug 
should be administered as follows:

Study drug is preferred to be administered, when possible, at least ± 14 days from the 
SARS-CoV-2 vaccine administration.
Note: The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
vaccination course.
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.
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Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF. Refer to the 
Operations Manual for instructions on reporting any AEs associated with the COVID-19 vaccine.
5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:  

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Subject is significantly noncompliant with study procedures.
This is a single treatment study. Treatment will be administered on Day 1 only. In case of pregnancy or 
AE during the study after study treatment is provided, the subject should continue in the study for 
safety follow-up.
In case the subject has a desire to end his/her participation, or is discontinued for any reason, the Early 
Exit Visit procedures should be completed.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status. At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site. The investigator may 
also stop the study at his/her site if he/she has safety concerns. If AbbVie terminates the study for safety 
reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care. Acceptable mitigation strategies are 
identified and included in the Operations Manual (Appendix E).
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.
5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for efficacy and safety assessments, subjects 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.
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If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Early Exit 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 adverse events (TEAEs)/serious adverse events 
(SAEs) have been resolved.
5.7 Study Drug
Study drugs refer to drugs that are used (or can be used) in this study to assess the safety and the 
efficacy of the Investigational Product. Investigators will assess the relationship of adverse events to the 
use of study drugs. 
Study drug will be provided by AbbVie and administered on Day 1, and subjects will not be retreated 
(Table 1).
Table 1.
Study Drug Information
Product
Mode of 
Administration
Formulation
Total Treatment Dose
Manufacturer
BOTOX Cosmetic
(100 U/vial)
Intramuscular 
Injection
Powder for 
solution
64 U
Allergan
Study drug provided by AbbVie should not be substituted or alternately sourced unless otherwise 
directed by AbbVie. Upon receipt, study drug should be stored as specified on the package insert and 
kept in a secure location. Study drug will only be used for the conduct of this study.
Additional information regarding the study drug and administration is available in the Operations 
Manual (Appendix E).
5.8 Randomization/Drug Assignment
All subjects who provide informed consent will be assigned a unique subject identification number at 
the Day 1 visit. For subjects who rescreen, the subject identification number assigned at the initial Day 1 
visit should be used.
Randomization is not applicable since this is an open-label study.
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 IEC/IRB, regulatory authorities (as applicable), and AbbVie.
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5.10 Data Monitoring Committee
A data monitoring committee is not planned for this study. 
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device. Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
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.
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.
Reporting will be done via electronic data capture (EDC). The date the product complaint details are 
entered into EDC and the form is saved represents the date reported to AbbVie. A back-up paper form 
will be provided for reporting complaints related to unassigned product or in the event of an EDC system 
issue. If a back-up paper form is used, the date the form is emailed to RD_PQC_QA@abbvie.com 
represents the date reported to AbbVie.
All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor. Product complaints associated with AEs will be 
reported in the study summary. All other complaints will be monitored on an ongoing basis. Product 
complaints occurring during the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. 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, regardless of whether the event is considered causally related to the use of 
the product.
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Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not. Any worsening of a pre-existing condition or illness is 
considered an AE. Worsening in severity of a reported AE should be reported as a new AE. Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
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 as a SAE within 24 hours of the site being made aware of 
the SAE (refer to Section 4.2 of the Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken. This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay. This does not include 
an emergency room visit or admission to an outpatient facility.
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).
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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 (e.g., 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 adverse events from the time of study drug administration will be collected for at least 30 days or 
until the last follow-up visit, whichever is longer, whether solicited or spontaneously reported by the 
subject. After 30 days following the last dose of study drug or last follow-up visit, whichever is longer, 
only spontaneously reported SAEs will be collected (nonserious AEs will not be collected). In addition, 
study procedure-related serious and nonserious adverse events 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):
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.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
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:
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Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life threatening.
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 follow-up through study exit but will receive no further treatment with the 
study drug. If a pregnancy occurs in a study subject, information regarding the pregnancy and the 
outcome will be collected. Partner pregnancy information will not 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.
Possible Distant Spread of Toxin
Possible distant spread of toxin (PDSOT) is defined as a possible pharmacologic effect of botulinum toxin 
at sites noncontiguous and distant from the site of injection. Utilizing a standardized methodology to 
assess for PDSOT, MedDRA preferred terms (PTs) that may be associated with botulinum toxin effects 
have been prospectively identified (see the statistical analysis plan [SAP] for a complete list of these 
PTs). Adverse events reporting any of these terms will be medically reviewed on a regular basis 
throughout the study and will be summarized in the clinical study report.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and secondary efficacy
endpoints. Complete and specific details of the statistical analysis will be described in the SAP. 
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7.2 Definition for Analysis Populations
The mITT population includes all enrolled subjects who receive the total dose of 64 U of BOTOX 
Cosmetic, as described in this study protocol. 
The Safety Analysis Set consists of all subjects who receive at least 1 injection of study drug. 
7.3 Handling Potential Intercurrent Events for the Primary and 
Secondary Efficacy Endpoints
Observed data will be used without imputation, so subjects who have an intercurrent event resulting in 
not having a Day 30 assessment for any reason will not be included. Intercurrent events include:

Subjects who are enrolled but do not receive the total dose of 64 U of BOTOX Cosmetic, as 
described in this study protocol

Subjects who are enrolled but prematurely discontinue the study before the Day 30 assessment 

Subjects who die before the Day 30 assessment

Subjects who are lost to follow-up and are missing Day 30 data for the endpoint

Subjects who continue in the study beyond Day 30, but are missing the Day 30 assessment for 
any reason 
7.4 Statistical Analyses for Efficacy
Summary and Analysis of the Primary Endpoint
Analysis of the primary endpoint will be conducted based on mITT population. No formal statistical 
testing will be performed, and descriptive statistics will be tabulated. Observed data will be used 
without imputation.
Summary and Analysis of Secondary and Additional Endpoints
Analysis of the secondary and additional endpoints will be conducted based on mITT population. 
Descriptive statistics will be tabulated and observed data will be used without imputation.
Additional details will be provided in the SAP.
7.5 Statistical Analyses for Safety
The safety analyses will be performed using the safety population. For each safety endpoint evaluating 
change from baseline, the last non-missing safety assessment before study drug administration will be 
used as the baseline for all analyses of that endpoint.
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Treatment-emergent AEs (TEAEs) are defined as any AE with the onset that is after the first dose of 
study drug. Events in which the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless known to have started prior to study drug administration.
An overview of AEs will be presented consisting of the number and percentage of subjects experiencing 
at least one event for each of the following AE categories:

Any TEAE

Any TEAE related to study treatment according to the investigator

Any TEAE related to study drug according to the investigator

Any TEAE related to study procedure according to the investigator

Any mild TEAE

Any mild TEAE related to study treatment according to the investigator

Any moderate TEAE

Any moderate TEAE related to study treatment according to the investigator

Any severe TEAE

Any severe TEAE related to study treatment according to the investigator

Any serious TEAE

Any serious TEAE related to study treatment according to the investigator

Any TEAE leading to death

Any PDSOT TEAE

All deaths
Treatment-emergent adverse events will be summarized by system organ class (SOC) and PT; for TEAEs 
related with reasonable possibility to study treatment (including study drug related and study procedure 
related) as assessed by the investigator by SOC and PT; for maximum severity by SOC and PT; and for
subject numbers by SOC and PT. Specific TEAEs will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same AE occurs multiple times within a subject, 
the highest severity and level of relationship to study treatment will be reported.
Treatment-emergent SAEs (including deaths) will be summarized by SOC and PT. All SAEs will be 
provided in listing format.
Possible distant spread of toxin TEAEs will be identified in the SAP and summarized by PT.
7.6 Interim Analysis
Not applicable for this study.
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7.7 Overall Type I Error Control
Not applicable for this study.
7.8 Sample Size Determination
No formal sample size calculation was performed.
For a conservative expected proportion of 75% for the primary endpoint (proportion of subjects 
reporting Mostly satisfied or Very satisfied on the FLSQ Follow-up Item 4 at Day 30), a sample size of 100 
subjects in the study is required for an adjusted logit-based 95% binomial confidence interval to have a 
width of 16.8% (interval is 75% – 9.1% to 75% + 7.7% with recommended correction of – 1/2).9
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval. Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled. Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study. In 
addition, all changes to the consent form(s) will be IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations, and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki. The 
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), and 
alternative locations for data collection (e.g., use of a local lab instead of a central lab). In all cases, these 
alternative measures must be allowed by local regulations and permitted by IRB/IEC. Investigators 
should notify AbbVie if any urgent safety measures are taken to protect the subjects against any 
immediate hazard.
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8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data. Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s). During the COVID-19 pandemic, remote data review/verification may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results. Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of last visit of the last subject in the study.
12
REFERENCES
1.
BOTOX® (onabotulinumtoxinA) Prescribing Information. (Revised May, 2018): Allergan, Inc;  
[Available from: http://www.allergan.com/assets/pdf/botox_pi.pdf.
2.
BOTOX COSMETIC® Product Monograph. (Revised June, 2020): Allergan, Inc;  [Available from: 
https://allergan-web-cdn-
prod.azureedge.net/allergancanadaspecialty/allergancanadaspecialty/media/actavis-canada-
specialty/en/products/pms/2020-06-29-botox-cosmetic-product-monograph.pdf.
3.
Martinez L, Falvello VB, Aviezer H, et al. Contributions of facial expressions and body language to the 
rapid perception of dynamic emotions. Cogn Emot. 2016;30(5):939-52.
4.
Bale C, Archer J. Self-perceived attractiveness, romantic desirability and self-esteem: a mating 
sociometer perspective. Evol Psychol. 2013;11(1):68-84.
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5.
Molina B, David M, Jain R, et al. Patient Satisfaction and Efficacy of Full-Facial Rejuvenation Using a 
Combination of Botulinum Toxin Type A and Hyaluronic Acid Filler. Dermatol Surg. 2015;41 Suppl 
1:S325-32.
6.
Weinkle SH, Werschler WP, Teller CF, et al. Impact of Comprehensive, Minimally Invasive, 
Multimodal Aesthetic Treatment on Satisfaction With Facial Appearance: The HARMONY Study. 
Aesthet Surg J. 2018;38(5):540-56.
7.
Dayan S, Rivkin A, Sykes JM, et al. Aesthetic Treatment Positively Impacts Social Perception: Analysis 
of Subjects From the HARMONY Study. Aesthet Surg J. 2019;39(12):1380-9.
8.
De Boulle K, Werschler WP, Gold MH, et al. Phase 3 Study of OnabotulinumtoxinA Distributed 
Between Frontalis, Glabellar Complex, and Lateral Canthal Areas for Treatment of Upper Facial 
Lines. Dermatol Surg. 2018;44(11):1437-48.
9.
Edwardes M. The evaluation of confidence sets with application to binomial intervals. Stat Sin. 
1998;8(2):393-409.
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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
DHEA
dehydroepiandrosterone
eCRF
electronic case report form
EDC
electronic data capture
FDA
Food and Drug Administration
FHL
forehead lines
FHLSS
Forehead Line Severity Scale
FLSQ
Facial Line Satisfaction Questionnaire
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GL
glabellar lines
ICH
International Council for Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IUD
intrauterine device
LCL
lateral canthal lines
LCLSS
Lateral Canthal Line Severity Scale
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intention-to-treat
N/A
not applicable
NTEA
Neurotoxin Treatment Experience Assessment
PCR
polymerase chain reaction
PDSOT
possible distant spread of toxin
PRO
patient-reported outcome
PT
preferred term
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
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SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAEs
treatment-emergent adverse events
U
units
UFL
upper facial lines
VDS
verbal descriptor scale
WOCBP
women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M22-974:  A Prospective, Multi-center, Open-label Study to Evaluate Subject Satisfaction and Natural 
Outcomes Following Administration of BOTOX® Cosmetic (Botulinum Toxin Type A) Purified Neurotoxin Complex in 
Subjects with Upper Facial Lines (Glabellar Lines, Lateral Canthal Lines, and Forehead Lines)
Protocol Date:  14 December 2023
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local laws and 
regulations and guidelines governing the study at the site location. In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary 
to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments.
9.
Reporting promptly to AbbVie, the ethics committee/institutional review boards (as required) and other 
appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Clinical Development
Medical Affairs
Statistics
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APPENDIX D. ACTIVITY SCHEDULE
The following tables show the required activities across the study. The individual activities are described in detail in 
the Operations Manual (Appendix E). Allowed modifications due to COVID-19 are detailed in the Operations 
Manual.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
03 June 2022
Version 2.0
26 June 2023
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
1.
Protocol (Title Page) and Operations Manual (Appendix F, Section 1 and Section 4.2) were 
updated to reflect the current Sponsor/emergency medical and non-emergency contacts.
2.
Protocol (Section 3.4) and Operations Manual (Appendix F, Section 3.6) were updated to correct 
measurement of efficacy onset from "Day 1 up to Day 14" to "Day 2 to Day 15."
3.
Protocol (Section 4.1) was updated to allow more flexibility in enrollment and to reflect review 
of site data.
4.
Protocol (Section 5.1, eligibility criterion #3) was updated for consistency with the Operations 
Manual (Appendix F, Section 3.1). Eligibility criterion #8 was updated for clarity.
5.
Protocol (Section 5.2) was updated to provide additional language for females on hormone 
replacement therapy whose menopausal status is in doubt.
6.
Protocol (Section 5.7) and Operations Manual (Appendix F, Section 6.2, Section 6.3, and 
Section 6.6) were updated, as the study drug will be sourced commercially.
7.
Protocol (Section 6.1) was updated to clarify that partner pregnancy information will not be 
collected.
8.
Operations Manual (Appendix F, Section 3.11) was updated to remove a sentence regarding 
images captured on Day 1. A sentence was added to allow for image collection to be repeated 
within 7 days as needed.
Page 36 of 59
 

SAP_001.pdf: 
BOTOX®
M22-974 – Statistical Analysis Plan
Version 2.0 – 17 March 2025
1
Statistical Analysis Plan for Study M22-974
Subject Satisfaction and Natural Outcomes Following 
BOTOX® Cosmetic Treatment in Subjects with Upper 
Facial Lines
Date: 17 March 2025
Version 2.0
NCT06218251


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Table of Contents
1.0
Introduction...........................................................................4
2.0
Study Design and Objectives ................................................4
2.1
Objectives and Hypotheses..................................................................... 4
2.2
Study Design Overview.......................................................................... 4
2.3
Treatment Assignment and Blinding....................................................... 5
2.4
Sample Size Determination .................................................................... 6
3.0
Endpoints...............................................................................6
3.1
Primary Endpoint(s) ............................................................................... 6
3.2
Secondary Endpoint(s) ........................................................................... 6
3.3
Additional Endpoint(s) ........................................................................... 6
3.4
Safety Endpoint(s).................................................................................. 8
4.0
Analysis Populations .............................................................9
5.0
Subject Disposition................................................................9
6.0
Study Drug Duration.............................................................9
7.0
Subject Characteristics .......................................................10
7.1
Demographics and Baseline Characteristics.......................................... 10
7.2
Medical History and Prior and Concomitant Medication....................... 11
7.3
Prior and Concurrent Procedures .......................................................... 11
7.4
Protocol Deviations .............................................................................. 11
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................12
9.0
Efficacy Analyses.................................................................12
9.1
General Considerations......................................................................... 12
9.2
Handling of Missing Data..................................................................... 13
9.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 13
9.3.1
Primary Efficacy Endpoint(s) ............................................................... 13
9.3.2
Main Analysis of Primary Efficacy Endpoint(s).................................... 13
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint(s)........................................................................................... 14
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 14
9.5
Additional Efficacy Analyses ............................................................... 14


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9.6
Effectiveness Subgroup Analyses ......................................................... 16
10.0
Safety Analyses....................................................................16
10.1
General Considerations......................................................................... 16
10.2
Adverse Events..................................................................................... 17
10.2.1
Treatment-Emergent Adverse Events.................................................... 17
10.2.2
Adverse Event Overview...................................................................... 18
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT ...................... 18
10.2.4
SAEs (Including Deaths) ...................................................................... 19
10.2.5
Potential Distant Spread of Toxin Adverse Events................................ 19
10.3
Analysis of Laboratory Data................................................................. 19
10.4
Immunogenicity ................................................................................... 19
10.5
Analysis of Vital Signs......................................................................... 19
10.6
Safety Subgroup Analyses.................................................................... 20
10.7
Other Safety Analyses .......................................................................... 20
11.0
Other Analyses ....................................................................20
11.1
Empirical Cumulative Distribution Function by Treatment Group 
for Change in Clinical Outcome Assessment (COA) Scores ................. 20
12.0
Interim Analyses..................................................................20
13.0
Overall Type-I Error Control.............................................20
14.0
Version History ...................................................................21
15.0
References............................................................................22
List of Figures
Figure 1.
Study Schema......................................................................................... 5
List of Appendices
Appendix A.
List of SAP Signatories ........................................................................ 23
Appendix B.
Definition of Possible Distant Spread of Toxin..................................... 24


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for Study M22-974: 
A Prospective, Multi-center, Open-label Study to Evaluate Subject Satisfaction and 
Natural Outcomes Following Administration of BOTOX® Cosmetic (Botulinum Toxin 
Type A) Purified Neurotoxin Complex in Subjects with Upper Facial Lines 
(Glabellar Lines, Lateral Canthal Lines, and Forehead Lines).
Study M22-974 examines subject satisfaction and natural outcomes following 
simultaneous treatment of multiple upper facial lines (GL, LCL, and FHL) with 64 U of 
BOTOX Cosmetic.
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.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses 
The primary objective of this study is to evaluate subject satisfaction and natural 
outcomes following simultaneous treatment of multiple upper facial lines (GL, LCL, and 
FHL) with 64 U of BOTOX Cosmetic by Facial Line Satisfaction Questionnaire (FLSQ) 
Item 4 at Day 30 based on the modified Intent-to-Treat (mITT) population, which consists 
of all enrolled subjects who receive the total dose of 64U of BOTOX cosmetic.
2.2
Study Design Overview
This is a 6-month, prospective, multicenter, open-label study to evaluate subject 
satisfaction and natural outcomes following the administration of BOTOX Cosmetic 64 U 
for the treatment of upper facial lines.


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The study will enroll approximately 100 subjects with moderate to severe GL, LCL, and 
FHL as assessed by the investigator. Out of the approximately 100 enrolled subjects:
●
approximately 20% of the study population will be treatment naïve to any 
botulinum toxin of any serotype for any indication,
●
approximately 20% of the study population will be self-identified as male,
●
approximately 20% of the study population will be self-identified as Asian, 
and
●
approximately 20% of the study population will have Fitzpatrick skin 
phototypes of IV, V, or VI.
On Day 1, after subjects are verified to meet all eligibility criteria and have completed all 
baseline study procedures, they will receive 64 U of BOTOX Cosmetic. Each subject will 
receive a total of 16 injections (0.1 mL or 4 U of BOTOX Cosmetic per injection), with 5 
injections in the glabellar complex, 3 injections in the lateral canthal area on each side
(6 total injections), and 5 injections in the frontalis muscle.
There are seven in-clinic visits: screening/baseline/treatment (Day 1), post-treatment 
follow-up visits (Days 30, 60, 90, 120, 150), and study exit (Day 180 or Early Exit). The 
study schema of the study is shown in Figure 1.
Figure 1.
Study Schema
2.3
Treatment Assignment and Blinding
This is an open-label study. Hence, there is no subject randomization or blinding for the 
study treatment assignment. 


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2.4
Sample Size Determination
No formal sample size calculation was performed.
For a conservative expected proportion of 75% for the primary endpoint (proportion of 
subjects reporting Mostly satisfied or Very satisfied on the FLSQ Follow-up Item 4 at 
Day 30), a sample size of 100 subjects in the study is required for an adjusted logit-based 
95% binomial confidence interval to have a width of 16.8% (interval is 75% - 9.1% to 
75% + 7.7% with recommended correction of - 1/2).1
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary endpoint is the responder status of Mostly satisfied or Very satisfied on the 
Facial Line Satisfaction Questionnaire (FLSQ) Follow-up Item 4 at Day 30.
3.2
Secondary Endpoint(s)
The secondary endpoint is
●
Change from baseline in subject's assessment based on Rasch-transformed 
score of FACE-Q Psychological Function scale at Day 30
3.3
Additional Endpoint(s)


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3.4
Safety Endpoint(s)
●
The safety endpoint is the incidence of adverse events (AEs).


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4.0
Analysis Populations
The following population sets will be used for the analyses.
The Modified Intent to Treat (mITT) Population includes all enrolled subjects who 
receive the total dose of 64 U of BOTOX Cosmetic, as described in the study protocol.
The mITT Population will be used for all efficacy analyses. The Safety Analysis Set (also 
referred to as the Safety Population) consists of all subjects who receive at least 1 
injection of study drug. The safety analyses will be based on the Safety Population. 
5.0
Subject Disposition
The total number of subjects who were screened, enrolled and treated will be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized:
●
Number of subjects screened 
●
Number of subjects treated
●
Number of subjects completed the study 
●
Number of subjects discontinued from the study 
○
Reasons for discontinuation from the study
The number of subjects in each analysis population will also be summarized.
6.0
Study Drug Duration 
For the Safety Population, study duration will be summarized with descriptive statistics 
(mean and standard deviation, median, Q1, Q3, minimum, and maximum). The number of 
subjects followed for specific periods of time (1-30 days, 31-60 days, 61-90 days, and 91-
120 days, 121-150 days,151 days to 180 days, >180 days ) will also be summarized. 
Study duration will be calculated as date of end of study participation minus date of study 
drug administration +1.


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7.0
Subject Characteristics
Demographics, baseline characteristics, medical history, prior and concomitant 
medications, and prior and concurrent procedure will be summarized for the mITT 
population. 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
Demographic and baseline characteristics will be summarized descriptively for the mITT 
population. Unless otherwise specified, baseline is defined as the last non-missing value 
prior to the first administration of study treatment.
Continuous demographic variables include age, weight, height and BMI.
Categorical demographic variables include:
●
Sex reported at birth
●
Sex
●
Gender identity
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Race
●
Fitzpatrick skin type (I, II, III, IV, V, VI)
●
Prior Botulinum Toxin Treatment
Baseline characteristics include investigator-rated and subject-rated GL severity at 
maximum contraction and at rest using AGLSS, investigator-rated and subject-rated LCL 
at maximum contraction and at rest using LCLSS, investigator-rated and subject-rated 
FHL at maximum contraction and at rest using FHLSS, FLSQ baseline impact domain 
score and FACE-Q baseline Psychological Function score. 


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7.2
Medical History and Prior and Concomitant Medication
Medical history data will be coded using the current Medical Dictionary for Regulatory 
Activities (MedDRA). The actual version of the MedDRA coding dictionary will be noted 
in the statistical tables. The number and percentage of subjects in each medical history 
category (by MedDRA system organ class and preferred term (PT)) will be summarized. 
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 PT).
A prior medication is defined as any medication taken prior to the date of the first study 
drug administration. A concomitant medication is defined as any medication that started 
prior to the date of the first study drug administration and continued to be taken after the 
first study drug administration or any medication that started on or after the date of the 
first study drug administration. Prior and concomitant medications will be summarized 
separately for the mITT Population. The number and percentage of subjects taking prior 
and concomitant medications will be summarized by generic drug name, based on the 
World Health Organization (WHO) Drug Dictionary. The actual version of the WHO 
Drug Dictionary will be noted in the statistical tables.
7.3
Prior and Concurrent Procedures
All procedures undergone prior to the date of the study drug administration will be 
considered as prior procedures. All procedures undergone on or after date of the study 
drug administration through the exit visit will be considered concurrent procedures. Prior 
and concurrent procedures will each be summarized by MedDRA High Level Term 
(HLT) and PT for the mITT Population. The MedDRA HLT will be presented in 
alphabetical order, and the PTs will be presented in alphabetical order within each HLT.
7.4
Protocol Deviations
Protocol deviations are defined in accordance with ICH guidelines and include but are not 
limited to: eligibility criteria violations, receipt of wrong treatment or incorrect dose of 


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study treatment, development of withdrawal criteria without being withdrawn, and the use 
of excluded concomitant medications. A listing of subjects with protocol deviations will 
be provided.
For all protocol deviation categories and across all categories, the number and percentage 
of randomized subjects with at least one protocol deviation will be summarized.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
Observed data will be used without imputation, so subjects who have an intercurrent event 
resulting in not having FLSQ Item 4 at Day 30 for any reason will not be included in the 
primary efficacy endpoint. Intercurrent events include:
●
Subjects who are enrolled but do not receive any study drug;
●
Subjects who are enrolled and treated but prematurely discontinue the study 
before assessment of the primary endpoint;
●
Subjects who die before assessment of primary endpoint;
●
Subjects who are lost to follow-up and are missing assessment of primary 
endpoint;
●
Subjects who are missing assessment of primary endpoint for any other reason 
(including COVID) not mentioned above
○
The same approach will be used for the secondary analysis.
9.0
Efficacy Analyses
9.1
General Considerations
The following considerations apply to all efficacy analyses, unless otherwise specified:
●
All efficacy analyses will be conducted in the mITT population unless 
otherwise specified.
●
Day 1 is defined as the day on which the study treatment is first received. 


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●
Baseline for effectiveness parameters will be the last non-missing assessment 
prior to or on Day 1.
●
Study day is always relative to Day 1.
●
Change from baseline will be computed as postbaseline minus baseline.
●
Continuous variables will be summarized descriptively using number of 
subjects with observed values (n), mean, standard deviation (SD), median, 
minimum (min), and maximum (max). In addition, 95% confidence intervals 
(CIs) will be performed using paired t-tests for change from baseline 
endpoints.
●
Categorical variables will be summarized descriptively using number of 
subjects with observed values or events (n) and the percentage of subjects with 
observed values or events.
●
Analyses based on responder rates will include a 95% CI for the responder rate 
using the exact binominal distribution (Clopper-Pearson approach).
●
All CIs will be 2-sided 95% CIs, unless stated otherwise.
9.2
Handling of Missing Data
No imputation of missing data will be made for the efficacy analyses.
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the responder status of Mostly satisfied or Very satisfied
on the Facial Line Satisfaction Questionnaire (FLSQ) Follow-up Item 4 at Day 30.
9.3.2
Main Analysis of Primary Efficacy Endpoint(s)
Analysis of the primary endpoint will be conducted based on mITT population. No formal 
statistical testing will be performed, and descriptive statistics will be tabulated. Observed 
data will be used without imputation.




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Adverse events (AEs) will be coded using the MedDRA. The actual version of the 
MedDRA coding dictionary will be noted in the statistical outputs and clinical study 
report.
10.2
Adverse Events
AEs will be summarized and presented using primary MedDRA System Organ Classes 
(SOCs) and preferred terms (PTs) according to the current 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 adverse events (TEAEs) are defined as any AE with an onset after 
the first dose of study treatment. Events where the onset date is the same as the study 
treatment start date are assumed to be treatment-emergent, unless the study treatment start 
time and the AE start time are collected and the AE start time is prior to the study 
treatment start time. If an incomplete onset date is collected for an AE, then the AE will 
be assumed to be treatment-emergent unless there is evidence that confirms that the AE 
was not treatment-emergent (e.g., the known portion of the AE onset and/or the AE end 
date was prior to the date of the first dose of study treatment).
All TEAEs will be summarized overall, as well as by primary MedDRA SOC and PT. 
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
The number and percentage of subjects experiencing TEAEs will be summarized.


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An AE will be considered a TESAE if it is a TEAE that additionally meets any serious 
adverse event (SAE) criterion.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study treatment according to the investigator
○
Any TEAE related to study drug according to the investigator
○
Any TEAE related to study procedure according to the investigator
●
Any mild TEAE
○
Any mild TEAE related to study treatment according to the investigator
●
Any moderate TEAE
○
Any moderate TEAE related to study treatment according to the 
investigator
●
Any severe TEAE
○
Any severe TEAE related to study treatment according to the investigator
●
Any serious TEAE
○
Any serious TEAE related to study treatment according to the investigator
●
Any TEAE leading to death
●
Any PDSOT TEAEs
●
Any TEAE of special interest
●
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. 
Furthermore, TEAEs will be summarized by PT and sorted by decreasing frequency.


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Treatment-related TEAEs, study drug related TEAEs, and study procedure related TEAEs 
will also be summarized by SOC and PT.
In addition, for both possible distant spread of toxin (PDSOT) TEAEs and 
treatment-related TEAEs, onset after study drug administration and duration will be 
evaluated. TEAE onset will be reported based on number of days subsequent to the study 
drug administration and will be summarized with descriptive statistics. TEAE duration 
will be defined as (AE end date minus AE start date) + 1 day) and will be summarized 
with descriptive statistics. For ongoing AEs, duration will be estimated based on duration 
at study exit, unless otherwise specified.
10.2.4
SAEs (Including Deaths) 
Serious TEAEs (including deaths) will be summarized by SOC and PT and all SAEs will 
be provided 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 AEs will be listed by subject.
10.3
Analysis of Laboratory Data
Pregnancy test will be performed at Day 1 and may also be performed at any other visit, at 
the investigators' discretion.
10.4
Immunogenicity 
Not applicable.
10.5
Analysis of Vital Signs
Not applicable.


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10.6
Safety Subgroup Analyses
Not applicable.
10.7
Other Safety Analyses
Not applicable.
11.0
Other Analyses
11.1
Empirical Cumulative Distribution Function by Treatment 
Group for Change in Clinical Outcome Assessment (COA) 
Scores
To support the interpretation of meaningful treatment effect as measured by the change in 
FACE-Q Psychological Function Scale, empirical cumulative distribution functions 
(eCDFs) of the change in FACE-Q Psychological Function Scale from baseline to Day 30 
will be plotted by treatment group based on observed data, with change from baseline in 
FACE-Q Psychological Function Scale on the horizontal axis and the cumulative 
percentage of subjects experiencing up to that specific level of change on the vertical axis. 
eCDFs provide a visual display of the cumulative percentage of subjects within each 
group that achieve within-patient change across the entire distribution of change, thereby 
illustrating the percentage of responders across the range of potentially meaningful change 
threshold values.
12.0
Interim Analyses
No interim analysis is planned for this study.
13.0
Overall Type-I Error Control
No statistical test will be performed. All CIs will be 2-sided 95% CIs, unless stated 
otherwise.


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14.0
Version History
SAP Version
Date
Summary
1.0
14 March 2024
Initial version
2.0
17 March 2025
Section 3.3
•
Added 3 additional endpoints:
o
Responder status of Mostly satisfied or Very 
satisfied on the Facial Line Satisfaction 
Questionnaire (FLSQ) Follow-up Item 4 at all 
follow-up visits
o
Change from baseline in subject's assessment 
based on Rasch-transformed score of FACE-Q
Psychological Function scale at all follow-up 
visits
o
Achievement of ≥ 20 points improvement from 
baseline on FLSQ impact domain score at all 
follow-up visits
Section 6.0
•
Updated study drug duration analysis grouping
Section 7.1
•
Added 'prior Botulinum Toxin Treatment' in demographic 
variable list
Section 9.1
•
Stated ‘95% confidence intervals (CIs) will be performed 
using paired t-tests for change from baseline endpoints’ 
and ‘ Analyses based on responder rates will include a 
95% CI for the responder rate using the exact binominal
distribution (Clopper-Pearson approach).’
Section 9.5
•
removed 'Listings of all endpoint values will also be 
provided.' Only listings for primary and secondary 
endpoints will be provided.
•
updated 'Onset of efficacy as measured by subject self-
assessment in a patient electronic diary from Day 1 up to 
Day 14'  to 'Onset of efficacy as measured by subject self-
assessment in a patient electronic diary from Day 2 to Day 
15' per protocol V3.0
•
added Kaplan-Meier language for endpoint 'Onset of 
efficacy as measured by subject self-assessment in a 
patient electronic diary from Day 2 to Day 15.'
•
Added 3 additional endpoints: 


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15.0
References
1.
Edwardes M. The evaluation of confidence sets with application to binomial 
intervals. Stat Sin. 1998;8(2):393-409.
o
Responder status of Mostly satisfied or Very 
satisfied on the Facial Line Satisfaction 
Questionnaire (FLSQ) Follow-up Item 4 at all 
follow-up visits
o
Change from baseline in subject's assessment 
based on Rasch-transformed score of FACE-Q
Psychological Function scale at all follow-up 
visits
o
Achievement of ≥ 20 points improvement from 
baseline on FLSQ impact domain score at all 
follow-up visits
Section 9.6
•
added subgroup analyses for primary and secondary 
endpoint by toxin naïve, sex, race and Fitzpatrick skin 
type


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Appendix A.
List of SAP Signatories
Name
Title
Role/Functional Area
Author
Biostatistics
Statistical Programming
Medical/Scientific Monitor


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Appendix B.
Definition of Possible Distant Spread of Toxin
PDSOT AEs will be identified using the following search criteria for the MedDRA 
version being used for the study:
Area of Safety Interest
Search Criteria
PDSOT
All PTs in the CMQ (company MedDRA query): Botulinum Toxin 
Adverse Events Of Interest Possible Distant Spread Of Toxin (PDSOT) 
(BOTOX Product Specific); identified using CMQ = 12200048