A Multicenter, Double-Blind, Randomized, Placebo-Controlled Parallel-Group Phase 2 Study Evaluating the Safety and Efficacy of OnabotulinumtoxinA X for the Treatment of Moderate to Severe Glabellar Lines
Phase: PHASE2
Conditions: Glabellar Lines
Sponsor: Allergan



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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
7
3
OBJECTIVES AND ENDPOINTS
8
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
8
3.2
PRIMARY ENDPOINT
8
3.3
SECONDARY ENDPOINTS
9
3.4
ADDITIONAL EFFICACY ENDPOINTS
9
3.5
SAFETY ENDPOINTS
10
3.6
IMMUNOGENICITY AND HYPERSENSITIVITY SAMPLING
11
4
INVESTIGATIONAL PLAN
11
4.1
OVERALL STUDY DESIGN AND PLAN
11
4.2
DISCUSSION OF STUDY DESIGN
12
5
STUDY ACTIVITIES
13
5.1
ELIGIBILITY CRITERIA
13
5.2
CONTRACEPTION RECOMMENDATIONS
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
18
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
19
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
20
5.7
STUDY DRUG
20
5.8
RANDOMIZATION/DRUG ASSIGNMENT
21
5.9
PROTOCOL DEVIATIONS
22
5.10
DATA MONITORING COMMITTEE
22
6
SAFETY CONSIDERATIONS
23
6.1
COMPLAINTS AND ADVERSE EVENTS
23
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
26
7.1
STATISTICAL AND ANALYTICAL PLANS
26
7.2
DEFINITION FOR ANALYSIS POPULATIONS
26
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
27
7.4
STATISTICAL ANALYSES FOR EFFICACY
28
7.5
STATISTICAL ANALYSES FOR SAFETY
28
7.6
INTERIM ANALYSES
29
7.7
OVERALL TYPE I ERROR CONTROL
30
7.8
SAMPLE SIZE DETERMINATION
30
8
ETHICS
30
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
30
8.2
ETHICAL CONDUCT OF THE STUDY
30
8.3
SUBJECT CONFIDENTIALITY
31
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
31
10
DATA QUALITY ASSURANCE
31
11
COMPLETION OF THE STUDY
31
12
REFERENCES
31
LIST OF TABLES
TABLE 1.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY EFFICACY ENDPOINT
9
TABLE 2.
STUDY DRUG IDENTIFICATION
21
TABLE 3.
STUDY ACTIVITIES TABLE (SITE VISITS)
37
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
12
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
33
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
35
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
36
APPENDIX D.
ACTIVITY SCHEDULE
37
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
39
APPENDIX F.
OPERATIONS MANUAL
41
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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 
moderate to severe glabellar lines (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 GL in 2001 and is one of the most 
common nonsurgical procedures in aesthetic medicine.6
 
 
 
 
 
 
 
 
 
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 adverse events (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.
 
 
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More detailed information about the known and expected benefits and risks and reasonably expected 
AEs of OnabotA X may be found in the Investigator's Brochure and the subject's informed consent form 
(ICF).
For further details, please see findings from completed studies, including safety data in the current 
OnabotA X Investigator's Brochure.
Considering the coronavirus disease – 2019 (COVID-19) pandemic, 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. 
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Primary
The primary objectives of this study are:
Efficacy:  To compare the efficacy of OnabotA X and placebo for the treatment of GL in subjects with 
moderate to severe GL.
Safety: To evaluate the safety of OnabotA X for the treatment of GL in subjects with moderate to severe 
GL.
3.2 Primary Endpoint
The primary efficacy endpoint is achievement of ≥ 1-grade improvement from baseline on the Allergan 
Glabellar Line Severity Scale (AGLSS) according to investigator assessments at maximum contraction at 
Day 30.
Estimand attributes of the primary efficacy endpoint are detailed in Table 1.
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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of
Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
primary 
endpoint
OnabotA X 
or 
placebo
Achievement of 
≥1-grade 
improvement from 
baseline on the 
AGLSS according to 
investigator 
assessments at 
maximum 
contraction at 
Day 30
ITT (All 
randomized)
Missing data will be 
imputed using 
multiple 
imputation.
Difference in 
response proportions 
between each active 
treatment group and 
placebo, after MI 
using CMH test 
stratified by baseline 
investigator-rated 
AGLSS at maximum 
contraction
AGLSS = Allergan Glabellar Line Severity Scale; CMH = Cochran-Mantel-Haenszel; ITT = intent-to-treat; MI = multiple imputation; 
OnabotA X = onabotulinumtoxinA X
3.3 Secondary Endpoints
Secondary Endpoints

Achievement of None or Mild on the investigator-rated AGLSS assessments at maximum 
contraction at Day 30

Responses of Very satisfied or Mostly satisfied on satisfaction with treatment per the FLSQ 
follow-up version Item 5 at Day 60

Achievement of ≥ 14-point psychosocial impact improvement from baseline at Day 30 per the 
FLSQ Impact domain, among subjects with baseline scores ≥ 14 points
3.4 Additional Efficacy Endpoints
 
 
 
 
 
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3.5 Safety Endpoints
Safety evaluations include AEs;
 
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3.6 Immunogenicity and Hypersensitivity Sampling
Immunogenicity 
Blood samples for immunogenicity testing will be collected from all subjects according to the Study 
Activities Table (Appendix D).  Collected samples will be processed to yield serum for detection of 
binding and neutralizing antibodies to OnabotulinumtoxinA.
Hypersensitivity 
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 double-blind, randomized, placebo-controlled, Phase 2 study to assess the safety and efficacy of 
OnabotA X for the treatment of moderate to severe GL. To be eligible for enrollment, at baseline 
subjects must have AGLSS scores of moderate or severe GL at maximum contraction (also called frown 
or furrow) by investigator and subject assessments. 
Approximately 280 subjects will be enrolled at approximately 18 sites. Eligible subjects will be 
randomized in a 2:2:2:1 ratio to receive OnabotA X 
 or 
placebo . Randomization 
will be stratified at each investigator site by the investigator-assessed baseline severity of GL (AGLSS 
score) at maximum contraction. Overall study enrollment will be monitored to achieve an 
approximately balanced 
 distribution of subjects with investigator-assessed moderate or 
severe GL at maximum contraction at baseline.
 
Safety parameters
 
will be monitored (see Operations Manual [Appendix F] Section 3). At 
 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 
 
Efficacy will be evaluated based on AGLSS assessed by the investigator and subject, and based on 
subject responses to FLSQ,
 
Standardized facial photography will be collected at all study 
visits from Day 1 through study exit. 
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Suitability of Subject Population
The study population will include male and female adults with moderate to severe GL at maximum 
contraction (also called frown or furrow). To avoid confounding the study results, use of any botulinum 
neurotoxin for any indication within the 6 months prior to Day 1 is excluded, and washout from prior 
facial aesthetic treatments is required as described in the eligibility criteria.
Selection of Doses in the Study
There is growing evidence from clinical practice and within published literature that the use of higher 
doses of onabotulinumtoxinA for facial aesthetic indications, namely treatment of the GL area, provides 
longer durability of therapy benefit with no deleterious change to the overall product safety profile.10-12  
A sustained clinical benefit 
 
 was observed for up to 4 months when the GL area was treated with the approved dose 
 
. Thus, the evaluation of OnabotA X at doses equal to and greater than the approved label dose 
for GL 
 is justifiable to evaluate whether this formulation at equal or higher doses 
might meaningfully extend the time to loss of patient benefit of the aesthetic effect.
 
 
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation. Screen 
failures can occur during the screening period up to the point prior to randomization on Day 1. 
Rescreening is not allowed for individuals who do not meet key safety or efficacy Eligibility 
 
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 independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, at least 18 years old at the time of ICF signature.
3. No clinically significant abnormal values for hematology, chemistry, or urinalysis at screening.
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7. Subject is willing and able to comply with procedures required in this protocol.
Disease/Condition Activity
8. Subject has moderate or severe GL at maximum frown
 
 
Subject History
9. No history of known immunization to any botulinum toxin serotype.
10. No history of known hypersensitivity to any botulinum toxin serotype, 
 
 or any other constituents of the study drug or its excipients, and/or other 
products in the same class.
 
 
13. No presence or history of any medical condition that may place the subject at increased risk 
following exposure to OnabotA X or interfere with the study evaluation, including:

Diagnosed myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis, or 
any other significant disease that might interfere with neuromuscular function

Facial nerve palsy 

Infection or dermatological condition at the site of study drug injection
 
 
 
 
 
 
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·-
D a 
0 
0 
0 
0 
0 
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0 
0 
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Contraception
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D a 
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0 
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0 
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Concomitant Medications
 
 
 
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow 
 contraceptive guidelines 
:

Females, Non-Childbearing Potential
 
 
 
 
 
 
 
 
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Contraception recommendations related to use of concomitant therapies prescribed should be based on 
the local label.
5.3 Prohibited Medications and Therapy
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.
 
 
 
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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.
Non-live vaccines may be used during screening or treatment periods, if not contraindicated or 
medically inappropriate.  When possible, study drug should be given at least ± 7 days from vaccine 
administration.
 
Systemic and topical hormones and their derivatives (i.e., sex steroids - androgens, estrogens, 
progesterone) should be maintained throughout study period to avoid changes in skin, including but not 
limited to:

Oral birth control

IUDs/implants/injections

Oral supplements including testosterone & estrogens and their derivatives, 
dehydroepiandrosterone (DHEA), etc.

Topicals (anywhere on the body) including testosterone & estrogens and their derivatives, 
DHEA, etc.
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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 can be located in the 
OnabotA X Investigator's Brochure.
Subjects must be able to safely discontinue any prohibited medications as described in the eligibility 
criteria.  Subjects must be consented for the study prior to discontinuing any prohibited medications for 
the purpose of meeting study eligibility.
COVID-19 Pandemic-Related Vaccination Guidance
 
  
 
 
 
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 
 
  
 
 
 
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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.
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.
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
(SAE) have been resolved.
5.7 Study Drug
All subjects will receive OnabotA X or Placebo prepared at the investigational site 
 
administered on Day 1 (Baseline).  
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5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who rescreen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule.
Randomization will be stratified by baseline investigator-rated AGLSS at maximum contraction, using 
central by block stratified randomization.  The same block will not be shared across investigative sites or 
by baseline GL severity assessment.
 
 
 
 
 
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Study drug will be labeled with kit numbers in an open-label fashion.  The IRT will provide the IDR with 
the specific kit number for each randomized subject at the time of randomization (Day 1).  The IDR will 
dispense study drug according to the IRT.  The IDR will receive the IRT confirmation notifications for 
each transaction and will maintain these with the other unblinded study source documents with 
restricted access to the blinded site staff. 
 
 
 
 The IDR will then 
provide the filled syringes to the blinded investigator, who will inject the subject according to the study 
treatment administration instructions in the Operations Manual (Appendix F), Section 3.15.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
5.10 Data Monitoring Committee
 
 
 
Study sites and subjects will remain 
blinded for the duration of the study.
The details of the interim analyses are included in Section 7.6.
 
 
 
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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.
 
Medical Complaints/Adverse Events and Serious Adverse Events:  OnabotA X
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not.  Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
 
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
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been pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or Clinical Research Organization (as appropriate) as a 
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):
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 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.  
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In addition, study procedure-related serious and nonserious AEs will be collected from the time the 
subject signs the study-specific informed consent.
 
 
 
 
 
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
 
Possible Distant Spread of Toxin
Possible distant spread of toxin (PDSOT) is defined as a possible pharmacologic effect of botulinum toxin 
at sites noncontiguous and distant from the site of injection.  Utilizing a standardized methodology to 
assess for PDSOT, Medical Dictionary for Regulatory Activities (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).  AEs 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.
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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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.
 
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 key secondary analyses.  
Complete and specific details of the statistical analysis will be described in the SAP.
 
 
7.2 Definition for Analysis Populations
The Intent to Treat (ITT) Population includes all randomized subjects.  The ITT Population will be used for 
all efficacy analyses.
 
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug. The safety 
analyses will be based on the safety population. 
 
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A sensitivity analysis will also be performed for the primary efficacy variable using observed data.
7.4 Statistical Analyses for Efficacy
Summary and Analysis of the Primary Endpoint
Analysis of the primary endpoint will be conducted on the ITT population based on treatment as 
randomized.  Missing data will be imputed using MI method described in Section 7.3. The evaluation of 
the equality of the proportions of responders will be based on Cochran-Mantel-Haenszel (CMH) test 
stratified by baseline investigator-rated AGLSS at maximum contraction. Wald confidence intervals for 
proportions of responders and difference in the proportion of responders will be presented.
The Breslow-Day homogeneity of the odds-ratio test will be performed to test the treatment-by-
investigator-rated baseline GL severity at maximum contraction interaction.
Summary and Analysis of Secondary Endpoints
The proportion of responders will be analyzed using CMH test, stratified by baseline investigator-rated 
AGLSS at maximum contraction. Missing data will be imputed using MI method.
Statistical testing will only be done between each OnabotA X group and the placebo group.
 
 
 
7.5 Statistical Analyses for Safety
The safety analyses will be performed using the safety population. The safety parameters will include
incidence of AEs, change from baseline in vital signs and laboratory (hematology/chemistry)
assessments, and ECG. Safety endpoints will be summarized using descriptive statistics and/or shift 
tables, as applicable. 
 
 
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.
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An overview of AEs will be presented consisting of the number and percentage of subjects experiencing 
at least one event for each of 
 AE categories:

Any treatment-emergent AE

Any treatment-emergent AE related to study treatment according to the investigator

Any PDSOT AEs

All deaths
 
 
 
 
 
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.  
 
Statistical Analyses for Immunogenicity and Hypersensitivity
Immunogenicity results, manifested as the binding antibodies and neutralizing antibodies, will be 
summarized in a table for each sampling timepoint. 
7.6 Interim Analyses
An interim analysis is planned to occur 
 
If a dose recommendation cannot be made at this point, then a second interim 
analysis will be performed, 
 
 
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The primary and secondary efficacy analyses will be performed for each interim analysis, as well as 
summaries of all safety variables.
The SAP will describe the planned interim analyses in detail. No separate SAP will be prepared for the 
interim analyses.
7.7 Overall Type I Error Control
Analyses will be conducted using a gated hierarchical testing procedure to preserve a familywise Type I 
error rate of α=0.05 for each OnabotA X group.  
 
 
 
7.8 Sample Size Determination
The sample size was chosen empirically. The primary efficacy parameter is the proportion of subjects 
with a ≥ 1-grade improvement from baseline according to investigator-rated AGLSS at maximum 
contraction at Day 30. Based on previous BOTOX studies, the responder rate of ≥ 1-grade improvement 
from baseline on the GL severity scale 
 Assuming 
 
responder rate for OnabotA X and placebo, respectively, at least 28 OnabotA X and 14 placebo subjects 
will be required to detect the above intervention difference with a power of 90% or greater at the 2 
sided 5% significance level for the primary endpoint. 
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.  Responsibilities of 
the investigator are specified in Appendix B.
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In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab) and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC.  Investigators 
should notify AbbVie if any urgent safety measures are taken to protect the subjects against any 
immediate hazard.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH 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 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.
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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.
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.
13. Joseph JH, Eaton LL, Robinson J, et al. Does increasing the dose of Abobotulinumtoxina impact the 
duration of effectiveness for the treatment of moderate to severe glabellar lines? J Drugs Dermatol. 
2016;15(12):1544-9.
14. EB W, MM H. The distribution of chi-squared. Proceedings of the National Academy of Sciences, 
Washington. 1931;17(12):684-8.
15. O'Kelly M, Ratitch B. Clinical trials with missing data: a guide for practitioners. First ed: John Wiley & 
Sons, Ltd; 2014.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AGLSS
Allergan Glabellar Line Severity Scale
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease – 2019
CRF
case report form
CS
clinically significant
DHEA
dehydroepiandrosterone
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
ePRO
electronic patient-reported outcome device
GCP
Good clinical practice
GL
glabellar lines
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IDR 
Independent Drug Reconstitutor 
IEC
Independent ethics committee
IM
intramuscular
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
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Abbreviation
Definition
ITT
intent-to-treat
IUD
intrauterine device
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
N/A
not applicable
NCS
not clinically significant
OnabotA X
onabotulinumtoxinA X
PCR
polymerase chain reaction
PDSOT
possible distant spread of toxin
PRO
patient-reported outcomes
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
QTcF
QT interval corrected for heart rate using Fridericia's formula
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
units
VDS
verbal descriptor scale
WOCBP
woman of child-bearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol 2042-201-008:  A Multicenter, Double-Blind, Randomized, Placebo-Controlled Parallel-Group 
Phase 2 Study Evaluating the Safety and Efficacy of OnabotulinumtoxinA X for the Treatment of 
Moderate to Severe Glabellar Lines
Protocol Date:  07 February 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, 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, 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 Program Development
Clinical Study Leadership
Medical Writing 
 Head of Clinical Development, 
Aesthetic Medicine
Therapeutic Area
 Biostatistics
Statistics
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the study.  The individual activities are described 
in detail in the Operations Manual.  Allowed modifications due to COVID-19 are detailed in the 
Operations Manual (Appendix F) in Section 2 and Section 3.  
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 2.0
07 September 2021
Version 1.0
14 June 2021
Version 3.0
The purpose of the version update to 3.0 is to change the number of estimated sites from approximately 
15 to 18.
Version 2.0
 
Additional edits were made, as follows:
 
 
Added the following eligibility criterion to Section 5.1 Eligibility Criteria: "If the subject has received a 
  
 
 
 
 
 
 
 
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