A Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of AGN-151586 for the Treatment of Glabellar Lines in Toxin-Naïve Subjects
Phase: PHASE3
Conditions: Glabellar Lines
Sponsor: AbbVie



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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
9
3.2
PRIMARY ENDPOINTS
14
3.3
SECONDARY ENDPOINTS
15
3.4
3.5
SAFETY ENDPOINTS
17
3.6
IMMUNOGENICITY ASSESSMENT
17
4
INVESTIGATIONAL PLAN
17
4.1
OVERALL STUDY DESIGN AND PLAN
17
4.2
DISCUSSION OF STUDY DESIGN
19
5
STUDY ACTIVITIES
20
5.1
ELIGIBILITY CRITERIA
20
5.2
RETREATMENT CRITERIA
23
5.3
CONTRACEPTION RECOMMENDATIONS
24
5.4
PROHIBITED MEDICATIONS AND THERAPY
25
5.5
PRIOR AND CONCOMITANT THERAPY
26
5.6
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
27
5.7
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
29
5.8
STUDY DRUG
29
5.9
RANDOMIZATION/DRUG ASSIGNMENT
30
5.10 PROTOCOL DEVIATIONS
31
5.11 DATA MONITORING COMMITTEE
31
6
SAFETY CONSIDERATIONS
31
6.1
COMPLAINTS AND ADVERSE EVENTS
31
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6.2
OTHER SAFETY DATA COLLECTION
34
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
35
7.1
STATISTICAL AND ANALYTICAL PLANS
35
7.2
DEFINITION FOR ANALYSIS POPULATIONS
35
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
35
7.4
STATISTICAL ANALYSES FOR EFFICACY
36
7.5
STATISTICAL ANALYSES FOR SAFETY
39
7.6
OVERALL TYPE I ERROR CONTROL
40
7.7
SAMPLE SIZE DETERMINATION
42
8
ETHICS
43
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
43
8.2
ETHICAL CONDUCT OF THE STUDY
43
8.3
SUBJECT CONFIDENTIALITY
43
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
43
10 DATA QUALITY ASSURANCE
43
11 COMPLETION OF THE STUDY
44
12 REFERENCES
44
LIST OF TABLES
TABLE 1.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY EFFICACY ENDPOINTS
10
TABLE 2.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE SECONDARY EFFICACY ENDPOINTS
11
TABLE 3.
IDENTITY OF INVESTIGATIONAL MEDICINAL PRODUCT
30
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
19
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
45
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
47
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
48
APPENDIX D.
ACTIVITY SCHEDULE
49
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
54
APPENDIX F.
OPERATIONS MANUAL
57
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Item 4 (natural look) for GL at Day 7
For EU Regulatory Agencies:
a.
Key secondary endpoint: ≥20-point improvement from 
baseline in 11-item Facial Line Outcomes (FLO-11©) total 
scores for GL at Day 7
b.
≥2-grade improvement from baseline on the FWS according 
to subject assessment of GL severity at maximum frown at 
Hour 24 
c.
≥2-grade improvement from baseline on the FWS according 
to investigator assessment of GL severity at maximum frown 
at Hour 24 
d.
≥1-grade improvement from baseline on the FWS according
to subject assessment of GL severity at maximum frown at 
Hour 24 
e.
≥1-grade improvement from baseline on the FWS according 
to investigator assessment of GL severity at maximum frown 
at Hour 24 
f.
Mostly satisfied or Very satisfied on the FLSQ follow-up version 
Item 5 (overall satisfaction) for GL at Hour 24
g.
Mostly satisfied or Very satisfied on the FLSQ follow-up version 
Item 4 (natural look) for GL at Day 7
h.
Time to the first ≥ 1-grade improvement from baseline on the 
FWS according to subject assessments of GL severity at 
maximum frown (double-blind period)*
i.
Time to the first ≥ 1-grade improvement from baseline on the 
FWS according to investigator assessments of GL severity at 
maximum frown (double-blind period)*
j.
≥ 2-grade improvement from baseline on the FWS according 
to subject assessments of GL severity at maximum frown over 
time (double-blind period)*
k.
≥ 2-grade improvement from baseline on the FWS according 
to investigator assessments of GL severity at maximum frown 
over time (double-blind period)*
l.
Time to return to baseline FWS according to subject 
assessments of FWS at maximum frown (double-blind 
period)* 
m. Time to return to baseline FWS according to investigator 
assessments of FWS at maximum frown (double-blind 
period)*
n.
Mostly satisfied or Very satisfied on the FLSQ follow-up version 
Item 5 (overall satisfaction) for GL over time*
o.
≥4-point improvement from baseline in FLO-11 Item 10 (look 
angry) for GL at Day 7
p.
≥4-point improvement from baseline in FLO-11 Item 5 (look 
less attractive) for GL at Day 7
q.
Subject-reported global assessment of change in GL based on 
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2 INTRODUCTION
2.1
Background and Rationale
Why Is This Study Being Conducted?
AGN-151586 is an investigational product being developed for the treatment of glabellar lines (GL).  
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 reversibly 
block presynaptic acetylcholine release at the neuromuscular or neuroglandular junction.  
There are 8 antigenically-distinct botulinum neurotoxin serotypes (A, B, C1, D, E, F, G, and H) that are 
similar in structure and action and produced by different strains of the anaerobic bacterium Clostridium 
botulinum.  Botulinum Neurotoxin Serotype A (BoNT/A) is popular as a cosmetic treatment of GL in 
adults due to its proven efficacy for reducing moderate to severe facial lines,6 well documented safety 
profile,7 and positive impact on psychological well-being and the resulting psychosocial benefits.8  
Botulinum Neurotoxin Serotype E is the active ingredient of AGN-151586.  The rationale for the use of 
AGN-151586 to treat GL is the same as that for BoNT/A in that by inhibiting the release of the 
neurotransmitter acetylcholine at peripheral cholinergic nerve endings,9,10 the overactivity of the 
muscles responsible for these lines can be reduced, thus eliminating or diminishing the appearance of 
GL.  AGN-151586 offers the potential for faster onset of efficacy compared with the BoNT/A products.9  
The purpose of this study is to evaluate the safety and efficacy of AGN-151586 for the treatment of GL in 
toxin-naïve subjects with moderate to severe GL.
2.2
Benefits and Risks to Subjects
Allergan (an AbbVie company) completed 1 dose ranging study (Study 2034-201-008) to explore the 
safety and efficacy of single cycle treatments at doses ranging from 
 AGN-151586-specific 
units for the treatment of GL in adults.  Units of biological activity of AGN-151586 cannot be converted 
to those of other neurotoxin products.
In this Phase 2b Study, a clinical dose response was observed, demonstrating that the proportion of 
responders (i.e., subjects having ≥ 2-grade improvement from baseline as assessed by investigator 
through Day 7) increased with increasing AGN-151586 dose.  The responder rate was approximately 
95% for the cohort dosed with 
.  The overall incidence of study drug-related treatment-emergent 
adverse event (TEAEs) was similar between the placebo group (18.0%) compared with the AGN-151586 
group (20.9%).  There were no safety trends or patterns identified with increasing dose of AGN-151586.  
Overall, AGN-151586 had a favorable safety profile with 
 showing the most robust benefit and 
thus, 
 was selected for Phase 3 pivotal studies. 
For further details, please see findings from completed studies, including safety data in the current 
AGN-151586 Investigator's Brochure.
Based on the Phase 2b Study results, there are no known adverse drug reactions (ADRs) for 
AGN-151586.  Since AGN-151586 is given as an intramuscular injection, injection site reactions 
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(e.g., pain, bruising, swelling, etc.) are anticipated.  In addition, the mechanism of action of AGN-151586 
is similar to BOTOX and thus, adverse reactions associated with BOTOX, when injected into the glabellar 
region, may also occur with AGN-151586.  These ADRs include facial pain, facial paresis, eyelid ptosis, 
and muscular weakness.
The overall benefit:risk profile is anticipated to be favorable.
For further details, please see findings from completed studies, including safety data in the current 
AGN-151586 Investigator's Brochure.
Considering the coronavirus disease – 2019 (COVID-19) pandemic, and based on the limited information 
to date, no additional risk to study participants is anticipated with the use of AGN-151586.  While 
AbbVie does not consider COVID-19 to be a safety concern for AGN-151586 or BOTOX due to their 
mechanism of action and route of administration, the marketing authorization holder is monitoring 
COVID-19 events during the pandemic closely. A recent review of COVID-19 events for the period of 01 
January 2019 through 31 December 2021 did not identify any new or significant safety findings for the 
patients receiving BOTOX treatment with onabotulinumtoxinA-branded products (BOTOX, BOTOX 
Cosmetic, VISTABEL®, VISTABEX®, and BOTOX Vista 50®) or botulinum toxin type A products (in which 
the manufacturer was not identified).  Overall, the clinical course and presentation of patients with 
COVID-19 infection coincident with onabotulinumtoxinA-branded products and botulinum toxin type A 
products is consistent with what has been described for the general population. The same results are 
expected with AGN-151586 since onabotulinumtoxinA-branded products, botulinum toxin type A 
products, and AGN-151586 have a similar mechanism of action.  
3 OBJECTIVES AND ENDPOINTS
3.1
Objectives, Hypotheses, and Estimands
Overall Objective
The objective of this pivotal study is to evaluate the safety and efficacy of AGN-151586 for the 
treatment of GL in toxin-naïve subjects with moderate to severe GL.
The clinical hypotheses are:

AGN-151586 is more effective than placebo in treating GL, as measured by both investigator
and subject assessments of GL severity at maximum frown using the Facial Wrinkle Scale (FWS). 

AGN-151586 has an acceptable safety profile after single and repeat treatments.
Estimands: Primary Endpoints
The attributes of the estimands corresponding to the coprimary efficacy endpoints are summarized in 
Table 1.  In addition, the attribute of treatment is a single dose of AGN-151586 or placebo.
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Table 1.
Summary of the Estimand Attributes of the Primary Efficacy Endpoints
Attributes of the Estimand
Estimand 
Label
Variable (Endpoint)
Population
Handling of 
Intercurrent Events
Statistical Summary
Hypothetical 
estimand for 
composite 
primary 
endpoint (US 
FDA)
Achievement of at least a 
2-grade improvement 
from baseline on the FWS 
according to both the 
investigator and subject 
assessments (composite) 
of GL severity at 
maximum frown on Day 7 
ITT (all 
randomized)
Subjects who 
discontinue study 
prior to Day 7 
assessments, or who 
do not have FWS 
assessments will be 
included in the 
analysis as a 
hypothetical scenario 
in which the 
assessments were 
conducted as per 
protocol
Response rates and 
rate differences 
between 
AGN-151586 and 
placebo treatment 
groups; Cochran-
Mantel-Haenszel
(CMH) test
 
 
 
Hypothetical 
estimand for 
coprimary 
endpoints (EU)

Achievement of at 
least a 2-grade 
improvement from 
baseline on the FWS 
according to subject's 
assessment of GL 
severity at maximum 
frown at Day 7, and

Achievement of at 
least a 2-grade 
improvement from 
baseline on the FWS 
according to 
investigator's 
assessment of GL 
severity at maximum 
frown at Day 7
ITT 
Subjects who 
discontinue study 
prior to Day 7 
assessments, or who 
do not have FWS 
assessments will be 
included in the 
analysis as a 
hypothetical scenario 
in which the 
assessments were 
conducted as per 
protocol
Response rates and 
rate differences 
between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
 
CMH = Cochran-Mantel-Haenszel; Estimands = Secondary Endpoints; EU = European Union; FDA = Food and Drug 
Administration; FWS = Facial Wrinkle Scale; GL = glabellar lines; ITT = intent-to-treat; US = United States
Estimands: Secondary Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are summarized in 
Table 2.  Treatment is the same as for the primary efficacy endpoints.  For the US Food and Drug 
Administration (FDA) variables/endpoints, the population is the intent-to-treat (ITT) population (all 
randomized); for the European Union (EU) variables/endpoints, the population is also the ITT 
population.  For the EU, subgroup analyses will be performed for the primary and key secondary 
endpoints for the ITT population that also has baseline 11 item Facial Line Outcomes (FLO-11) total 
scores ≤ 50.  The variables/endpoints listed have the same handling of intercurrent events and statistical 
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summary (including population-level summary and analysis methods) within their respective analysis 
populations for the US FDA and EU, per estimand label.
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy Endpoints
Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (US FDA 
and EU)
Key (US FDA): Achievement of 
at least a 2-grade improvement 
from baseline on the FWS 
according to investigator 
assessment of GL severity at 
maximum frown over time 
(double-blind period)*
Subjects who discontinue 
study in the double-blind 
period, or who do not 
have FWS assessments 
will be included in the 
analysis as a hypothetical 
scenario in which the 
assessments were 
conducted as per protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups at each time 
point; CMH test 
 
 
.  Endpoints 
will be evaluated outside 
of the gated hierarchical 
testing. 
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (US FDA 
and EU)
Key (US FDA): Achievement of 
at least a 2-grade improvement 
from baseline on the FWS 
according to subject 
assessment of GL severity at 
maximum frown over time 
(double-blind period)*
Subjects who discontinue 
study in the double-blind 
period, or who do not 
have FWS assessments 
will be included in the 
analysis as a hypothetical 
scenario in which the 
assessments were 
conducted as per protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups at each time 
point; CMH test 
 
 
.  Endpoints
will be evaluated outside 
of the gated hierarchical 
testing.
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (EU only)

Achievement of at least a 
2-grade improvement from 
baseline in GL severity at 
maximum frown based on 
subject assessment using 
FWS at Hour 24 

Achievement of at least a 
2-grade improvement from 
baseline in GL severity at 
maximum frown based on 
investigator assessment 
using FWS Hour 24 
Subjects who discontinue 
study prior to Hour 24 
assessments, or who do 
not have FWS 
assessments will be 
included in the analysis as 
a hypothetical scenario in 
which the assessments 
were conducted as per 
protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
 
.  Gated 
hierarchical testing will 
be conducted.
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (EU only)

Achievement of at least a 
1-grade improvement from 
baseline in GL severity at 
maximum frown based on 
subject assessment using 
FWS at Hour 24 
Achievement of at least a 
1-grade improvement from 
baseline in GL severity at 
maximum frown based on 
investigator assessment 
using FWS at Hour 24
Subjects who discontinue 
study prior to Hour 24 
assessments, or who do 
not have FWS 
assessments will be 
included in the analysis as 
a hypothetical scenario in 
which the assessments 
were conducted as per 
protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
 
.  Gated 
hierarchical testing will 
be conducted.
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (US FDA 
only)

Mostly satisfied or Very 
satisfied on the FLSQ 
follow-up version Item 5 
(overall satisfaction) for GL 
at Day 7
Subjects who discontinue 
study prior to Day 7 for 
the FLSQ follow-up 
assessments will be 
included in the analysis as 
a hypothetical scenario in 
which the assessments 
were conducted per 
protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
.  Gated 
hierarchical testing will 
be conducted.
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (US FDA; 
EU)

Mostly satisfied or Very 
satisfied on the FLSQ 
follow-up version Item 5 
(overall satisfaction) for GL 
at Hour 24

Mostly satisfied or Very 
satisfied on the FLSQ 
follow-up version Item 4 
(natural look) for GL at 
Day 7
Subjects who discontinue 
study prior to Hour 24 or 
Day 7 respective 
assessments for the FLSQ 
follow-up assessments 
will be included in the 
analysis as a hypothetical 
scenario in which the 
assessments were 
conducted as per protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
 
.  Gated 
hierarchical testing will 
be conducted.
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (EU)
Mostly satisfied or Very 
satisfied on the FLSQ follow-up 
version Item 5 (overall 
satisfaction) for GL over time*
Subjects who discontinue 
study or who do not have 
FLSQ follow-up version 
Item 5 will be included in 
the analysis as a 
hypothetical scenario in 
which the assessments 
were conducted as per 
protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups at each time 
point; CMH test 
 
 
.  Endpoints 
will be evaluated outside 
of the gated hierarchical 
testing.
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (EU only)

Key: Achievement of at 
least a 20-point 
improvement from 
baseline in FLO-11 total 
scores for GL at Day 7

Achievement of at least a 
4-point improvement from 
baseline in FLO-11 Item 10 
(look angry) for GL at Day 7

Achievement of at least a 
4-point improvement from 
baseline in FLO-11 Item 5 
(look less attractive) for GL 
at Day 7
Subjects who discontinue 
study prior to Day 7 
assessments or who do 
not have FLO-11 Day 7 
assessments will be 
included in the analysis as 
a hypothetical scenario in 
which the assessments 
were conducted as per 
protocol
Response rates and rate 
differences between 
AGN-151586 and 
placebo treatment 
groups; CMH test 
 
 
  Gated 
hierarchical testing will 
be conducted.
Hypothetical 
estimand for 
secondary 
categorical 
endpoints (EU only)

Subject-reported global 
assessment of change in 
GL based on the GAC-GL 
over time*
Subjects who discontinue 
study or who do not have 
the GAC-GL assessments 
will be included in the 
analysis as a hypothetical 
scenario in which the 
assessments were 
conducted as per protocol
Responses and mean and 
their differences 
between AGN-151586 
and placebo treatment 
groups at each time 
point; CMH test and 
analysis of variance 
(ANOVA) models 
 
 
  Endpoints 
will be evaluated outside 
of the gated hierarchical 
testing.
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Estimand Label
Attributes of the Estimand
Variables (Endpoints)
Handling of Intercurrent 
Events
Statistical Summary
Hypothetical 
estimand for 
secondary 
continuous 
endpoints (EU only)

Time to the first ≥1-grade 
improvement from 
baseline on the FWS 
according to subject 
assessment*

Time to the first ≥1-grade 
improvement from 
baseline on the FWS 
according to investigator 
assessment*

Time to return to baseline 
FWS according to subject 
assessment of FWS 
(double-blind period)*

Time to return to baseline 
FWS according to 
investigator assessment of 
FWS (double-blind 
period)*
Subjects who discontinue 
study or do not have FWS 
assessments will be 
included in the analysis as 
a hypothetical scenario in 
which the assessments 
were conducted as per 
protocol
Number of days until 
response and differences 
between AGN-151586 
and placebo treatment 
groups; log-rank tests 
 
 
  Endpoints 
will be evaluated outside 
of the gated hierarchical 
testing.
ANOVA = analysis of variance; CMH = Cochran-Mantel-Haenszel; EU = European Union; FDA = Food and Drug Administration; 
FLO-11 = 11 item Facial Line Outcomes; FLSQ = Facial Line Satisfaction Questionnaire; FWS = Facial Wrinkle Scale; 
GAC-GL = Global Assessment of Change in Glabellar Lines; GL = Glabellar lines; US = United States
*
Endpoints will be excluded from hierarchical testing.
3.2
Primary Endpoints
For US FDA, the primary composite endpoint is:

≥2-grade improvement from baseline on the FWS according to both investigator and subject 
assessments of GL severity at maximum frown at Day 7 
For EU regulatory agencies, the coprimary endpoints are:

≥ 2-grade improvement from baseline on the FWS according to subject assessment of GL 
severity at maximum frown at Day 7 

≥ 2-grade improvement from baseline on the FWS according to investigator assessment of GL 
severity at maximum frown at Day 7
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3.3
Secondary Endpoints
For US FDA, the secondary endpoints are:  
a.
Key secondary endpoint: ≥ 2-grade improvement from baseline on the FWS according to 
investigator assessment of GL severity at maximum frown over time (double-blind period)*
b.
Key secondary endpoint: ≥ 2-grade improvement from baseline on the FWS according to subject 
assessment of GL severity at maximum frown over time (double-blind period)*
c.
Mostly satisfied or Very satisfied on the Facial Lines Satisfaction Questionnaire (FLSQ) follow-up 
version Item 5 (overall satisfaction) for GL at Day 7
d.
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall satisfaction) for 
GL at Hour 24
e.
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 4 (natural look) for GL at 
Day 7
For EU Regulatory Agencies, the secondary endpoints are:
a.
Key secondary endpoint: ≥ 20-point improvement from baseline in FLO-11 total scores for GL at 
Day 7
b.
≥2-grade improvement from baseline on the FWS according to subject assessment of GL 
severity at maximum frown at Hour 24 
c.
≥2-grade improvement from baseline on the FWS according to investigator assessment of GL 
severity at maximum frown at Hour 24 
d.
≥1-grade improvement from baseline on FWS according to subject assessment of GL severity at 
maximum frown at Hour 24 
e.
≥1-grade improvement from baseline on FWS according to investigator assessment of GL 
severity at maximum frown at Hour 24
f.
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall satisfaction) for 
GL at Hour 24
g.
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 4 (natural look) for GL at 
Day 7
h.
Time to the first ≥ 1-grade improvement from baseline on the FWS according to subject 
assessment of GL severity at maximum frown (double-blind period)*
i.
Time to the first ≥ 1-grade improvement from baseline on the FWS according to investigator 
assessment of GL severity at maximum frown (double-blind period)*
j.
≥ 2-grade improvement from baseline on the FWS according to subject assessment of GL 
severity at maximum frown over time (double-blind period)*
k.
≥ 2-grade improvement from baseline on the FWS according to investigator assessment of GL 
severity at maximum frown over time (double-blind period)*
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3.5
Safety Endpoints
Safety evaluations include adverse event (AE) monitoring, vital sign measurements, 12-lead 
electrocardiogram (ECG) collection, laboratory evaluations (hematology and chemistry), neurological 
assessment (examination to consist of assessment of cranial nerves II through VII), and physical 
examinations as measures of safety.  The safety endpoints are:

Incidence of AEs (including any abnormality found during neurological assessment and physical 
examination)

Change from baseline in vital sign parameters 

Change from baseline in ECG parameters

Change from baseline in laboratory evaluations (hematology and chemistry)

Presence of binding and neutralizing antidrug antibodies (see Section 3.6 for more details)
3.6
Immunogenicity Assessment
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 AGN-151586 and may also be used for additional characterization 
of antibody response to other neurotoxin subtypes.
4 INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a 12-week, multicenter, Phase 3 study designed to evaluate the safety and efficacy of 
AGN-151586 in treating GL in subjects who have not had any prior botulinum toxin treatment of any 
serotype, for any indication.  Subjects are adults (≥ 18 years of age) with moderate to severe GL at 
maximum frown as assessed independently by both the investigator and subject using the FWS.  The 
investigator and subject ratings for GL will be done at the Screening Visit and at the Baseline Day 1 Visit.  
The investigator and subject ratings must match within a visit but do not have to match between 
Screening and Baseline Day 1.  Each eligible subject may receive up to 2 study treatments with 
AGN-151586. The time of study treatment administration defines Hour 0 for the treatment period (on 
Day 1 for double-blind period and on Day 43 for open-label period).
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Eligible subjects will be enrolled into the study containing 2 treatment periods: 
Double-blind Period: 
Screening will occur up to 14 days prior to Baseline Day 1.  Randomization and treatment will occur on 
Baseline Day 1 after all other study procedures have been completed.  A single treatment of 
AGN-151586 
 or placebo will be administered on Baseline Day 1, based on randomization (3:1 ratio 
of AGN151586:placebo).  Randomization will be stratified by investigator site and baseline GL severity at 
maximum frown.  All enrolled subjects will receive treatment on Baseline Day 1 and attend in-clinic site 
visits 
 to fully characterize the onset of treatment effect.  Thereafter, 
 in-clinic site visits 
 will be completed to characterize the peak and 
duration of effect.
The double-blind period will end on Day 43.  The Day 43 visit will occur 42 ± 2 days following the Day 1 
visit.  The study assessments conducted during the Day 43 visit serve as the final assessment for the 
double-blind period and as the baseline assessment for the open-label period. 
Open-label Period: 
For subjects meeting all the retreatment criteria on Day 43, a single open-label treatment with 
AGN-151586 
 will be administered on the same day.  The subject will then be followed for 
approximately 6 weeks (through Day 84).  The schedule of the follow-up visits in the open-label period is 
the same as that in the double-blind period.  After each study treatment administration, subjects must 
remain in the clinic for at least 30 minutes for observation of any AEs. 
Retreatment is only permitted on the Day 43 visit.  
If the subject does not meet the GL severity criterion at Day 43 visit for retreatment, the subject will be 
followed weekly as per the Activity Schedule (Appendix D) until the FWS grades assessed by both 
investigator and subject have returned to moderate or severe (investigator and subject grades do not 
need to match) before being discontinued from the study after completing either the Early Exit or Study 
Exit Visit.  If the subject becomes pregnant, then study drug may not be administered, and the subject 
can either be discontinued from the study after Early Exit Visit procedures are completed or remain in 
the study for all safety follow-up assessments.  If the subject declines retreatment despite meeting the 
retreatment criteria at Day 43 visit, the subject may be discontinued from the study after Early Exit Visit 
procedures are completed.
The efficacy measures include investigator FWS, subject FWS, FLO-11, FLSQ, GAC-GL, SPA, 
 
. 
To assess the safety of AGN-151586 for the treatment of GL, the safety measures are collected in the 
study are AEs, vital sign measurements, ECG, laboratory evaluations (hematology and chemistry), 
neurological assessment 
 physical 
examinations, and immunogenicity.
Prior to commencing any assessment, all makeup must be removed and care must be taken so that hair 
does not obscure the upper face.  All assessments must be completed before administration of study 
treatment.  
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The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual (Appendix F).
See Section 5 for information regarding eligibility criteria.
Figure 1.
Study Schematic
4.2
Discussion of Study Design
Choice of Control Group
A placebo-control group is the gold standard for comparative evaluations of safety and efficacy in clinical 
trials and will be used for the double-blind period of the study.  No control group will be used for the 
open-label period.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy and 
safety-related measurements in this study are standard for assessing subjects with GL.  All clinical and 
laboratory procedures in this study are standard and generally accepted.
Suitability of Subject Population
The study population will be toxin-naïve adult subjects with moderate or severe GL at maximum frown 
as assessed by both the investigator and subject using the FWS.  Eligibility criteria will be assessed at 
Screening Visit and Baseline Day 1 Visit to ensure subject safety. 
Selection of Doses in the Study
In the previous Phase 2b Study 2034-201-008, a clinical dose response was observed, demonstrating 
that the proportion of responders (i.e., subjects having ≥ 2-grade improvement from baseline as 
assessed by investigator through Day 7) increased with increasing AGN-151586 dose.  The responder 
rate was approximately 95% for the cohort dosed with 
. The overall incidence of study drug-
related TEAEs was similar between the placebo group (18.0%) compared with the AGN-151586 group 
(20.9%).  There were no safety trends or patterns identified with increasing the dose of AGN-151586.  
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Overall, AGN-151586 had a favorable safety profile and 
 AGN-151586 showed the most robust 
benefit and thus, 
 AGN-151586 was selected for the Phase 3 pivotal studies.
The dose selected is expected to be efficacious with an acceptable safety profile.
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.  Subjects 
who do not meet the eligibility criteria for participation in this study (screen failures) may be allowed to 
be rescreened.  Rescreening of subjects must only occur after discussion with the sponsor.  Rescreening 
can only occur once for any given potential subject; however, if the original screen failure was due to 
ineligible FWS grade(s), the subject will not be permitted to rescreen.
4. Subjects must be able to accurately assess their facial lines without the use of eyeglasses 
(contact lens use is acceptable).
Disease/Condition Activity
6. Subjects must have moderate or severe GL at maximum frown as assessed by both the 
investigator and subject using the FWS at Screening and Baseline Day 1 Visit. 
Subject History
7. Subjects must not have uncontrolled systemic disease.
8. Subjects must not have a history of any use of botulinum neurotoxin of any serotype for any 
indication (including any investigational botulinum neurotoxin product).
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9. Subjects do not present with or have a history of any medical condition that may place the 
subject at increased risk following exposure to AGN-151586 or interfere with the study 
evaluation.
10. Subjects must not have a diagnosis of myasthenia gravis, Lambert-Eaton syndrome, 
amyotrophic lateral sclerosis, or any other significant disease that might interfere with 
neuromuscular function.
11. Subjects must not have a history of facial nerve palsy.
12. Subjects must not have infection or dermatological condition at the treatment injection sites.
13. Subjects must not have marked facial asymmetry, dermatochalasis, deep dermal scarring, 
excessively thick sebaceous skin, excessively photodamaged skin, or the inability to substantially 
lessen facial lines even by physically spreading them apart.
14. Subjects must not have any eyebrow or eyelid ptosis at screening or Baseline Day 1 visit as 
determined by the investigator.
18. Subjects must not have tattoos, jewelry, or clothing which obscure the glabellar area and 
cannot be removed.
19. Subjects do not have known immunization to any botulinum neurotoxin serotype.
20. Subjects do not have anticipated need for surgery or overnight hospitalization during the 
study.
21. Subjects do not have history of surgical procedures on forehead and/or periorbital areas or 
affecting these areas including any lifting procedure (e.g., rhinoplasty, facial lift, suture lift, 
thread lift, brow lift, eyelid and/or eyebrow surgery).
22. Subjects do not have history of periorbital, mid-facial, or upper-facial treatment with semi-
permanent or permanent soft tissue fillers (e.g., poly-L-lactic acid, polyalkylimide, 
polymethylmethacrylate, polytetrafluoroethylene, and silicone), synthetic implantation and/or 
autologous fat transplantation.
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5.3
Contraception Recommendations
Contraception Requirements for Females
Female 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.

Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt, as determined by the investigator, will be required to use one of the non-
hormonal effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 

Females, of Childbearing Potential

Review and document pregnancy avoidance recommendations with females of childbearing 
potential. 

Females of childbearing potential must avoid pregnancy during the study and for at least 30 
days after the last dose of study drug or until the end of study, whichever is longer.

Among the birth control methods given below, females enrolled in sites located in the EU 
must choose from one of the methods 1 through 7 and subjects enrolled in sites located 
outside of EU must choose from one of the methods 1 through 10.
1.
Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to study Baseline Day 1.
2.
Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.
3.
Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure).
4.
Intrauterine device (IUD).
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5.
Intrauterine hormone-releasing system.
6.
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).
7.
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).
8.
Male or female condom with or without spermicide.
9.
Cap, diaphragm, or sponge with spermicide.
10. 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.
5.4
Prohibited Medications and Therapy
 
 
 
 
 
During the study, all other investigational drugs are prohibited.
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5.5
Prior and Concomitant Therapy
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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5.6
Withdrawal of Subjects and Discontinuation of Study
A subject can voluntarily withdraw at any time or will be withdrawn from the study for reasons 
including, but not limited to, the following:  

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the study 
drug, as determined by the investigator or the Sponsor.  However, when possible, the subject is 
encouraged to remain in the study for all safety follow-up assessments, even if the subject does 
not meet retreatment criteria. 

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.
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
Subject is significantly noncompliant with study procedures.

If the subject does not meet the GL severity criterion at Day 43 visit for retreatment, the subject 
will be followed weekly per the visit schedule (Appendix D) until the FWS grades assessed by 
both investigator and subject have returned to moderate or severe (investigator and subject 
grades do not need to match) before being discontinued from the study by completing either 
the Early Exit or Study Exit Visit.

If the subject becomes pregnant, then study drug will not be administered, and the subject can 
either be discontinued from the study after Early Exit Visit procedures are completed or remain 
in the study for all safety follow-up assessments.  If a pregnancy occurs in a study subject, 
information regarding the pregnancy and the outcome will be collected.

If the subject declines retreatment despite meeting the retreatment criteria at Day 43 visit, the 
subject will be discontinued from the study after Early Exit Visit procedures are completed
unless the investigator determines the subject should remain in the study for safety follow-up.
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.
The following events, if applicable, will also cause premature termination of the clinical study:

Unjustifiable risk and/or toxicity in risk-benefit analysis (decision taken by sponsor 
representative), e.g., when AEs occur, unknown to date in respect of their nature, severity, 
duration or frequency in relation to the current established safety profile (substantial changes in 
risk-benefit considerations), and therefore medical and/or ethical reasons affect the continued 
performance of the study.

New scientific evidence becomes available during the study that could affect the patient's safety 
(benefit-risk analysis no longer positive), e.g., new insights from other clinical trials.

Request of the sponsor or regulatory agency, e.g., as a consequence of inspection; favorable
opinion withdrawn by ethics commission.

In case of difficulties in the recruitment of the planned number of subjects in the indicated time 
(insufficient recruitment rate).

Withdrawal of the license to manufacture or of the permission to import.
AbbVie can terminate this study prematurely, either in its entirety or at any site.  The investigator can
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 and appropriate Health Authority.
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 F), Section 2 and Section 3.
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The investigator should contact the sponsor 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.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the study drug dosing period, a subject with confirmed (viral test positive) or suspected 
COVID-19 infection can only be dosed with study drug if the following COVID-19 viral clearance criteria 
are met:

At least 10 days since first positive test result have passed in asymptomatic patients or at least 
10 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms.
Delays in study drug dosing due to the above COVID-19 testing guidance for subjects must be discussed 
with the AbbVie medical contact, along with the possibility of early exit from the study drug dosing 
period.  Follow subsequent protocol Section 5.7 for subjects who discontinued study drug.
5.7
Follow-Up After Subject Discontinuation of Study Drug or from 
Study
For subjects who 

are ineligible for retreatment because of not meeting GL severity criterion on Day 43, the 
subjects will be followed weekly per the visit schedule (Appendix D) until the FWS grades 
assessed by both investigator and subject have returned to moderate or severe (investigator 
and subject grades do not need to match) before being discontinued by completing either the 
Early Exit or Study Exit Visit.

are ineligible for retreatment because of pregnancy, the subjects will not receive study drug.  
They can either be discontinued from the study after Early Exit Visit procedures are completed 
or remain in the study for all safety follow-up assessments. 

prematurely discontinue study treatment, or who prematurely discontinue study participation 
(due to withdrawal of informed consent or if the protocol-specified discontinuation criteria are 
met), the procedures outlined for the Early Exit visit (in Appendix D) should be completed as 
soon as possible, preferably within 2 weeks, but no sooner than 30 days since last treatment. 
5.8
Study Drug 
All subjects will receive AGN-151586 or matching placebo, which will be prepared at the investigator site 
as an injectable solution and administered on Baseline Day 1.  Based on meeting the retreatment 
criteria, the subject may be retreated at Day 43.  See Operations Manual (Section 3.15) for information 
about study drug administration.
AGN-151586 / matching placebo will be supplied in vials in quantities sufficient to accommodate study 
design.  
  
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  Study 
drug will only be used for the conduct of this study.
Detailed study drug preparation instructions will be provided to sites in the Pharmacy Manual.
Table 3.
Identity of Investigational Medicinal Product
AbbVie will provide study drug for AGN-151586 1500 U/vial and matching placebo.  AbbVie provided 
study drug should not be substituted or alternately sourced unless otherwise directed by AbbVie.  
5.9
Randomization/Drug Assignment
At the Screening Visit, all subjects will be assigned a unique identification number using the IRT.  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 (3:1 ratio AGN-151586:placebo).
Randomization will be stratified by investigator site and baseline GL severity at maximum frown.  
 
  
 
 To support this, the site will 
manually enter the subject's Baseline Day 1 FWS score (moderate or severe; per eligibility criteria, the 
investigator and subject FWS assessments must be identical) and the Baseline Day 1 FLO-11 total score 
(as calculated by the electronic data capture [EDC] after the subject completes the questionnaire) in to 
the IRT.  
All AbbVie personnel with direct oversight of the conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment throughout the study.  To maintain the blind, the 
AGN-151586 / matching placebo provided for the study will be identical in appearance.  The IRT will 
provide access to unblinded subject treatment information in the case of a medical emergency.
Investigational Medicinal 
Product
AGN-151586
Placebo for AGN-151586
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5.10 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.
5.11 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 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.
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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 or vital sign measurement), 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.
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 serious adverse event (SAE) within 24 hours of the 
site being made aware of the SAE (refer to Section 4.2 of the Operations Manual [Appendix 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.
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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. 
All AEs reported from the time of study drug administration will be collected for at least 30 days after 
last dose or until the last follow-up visit, whichever is longer, whether solicited or spontaneously 
reported by the subject.  In addition, study procedure-related serious and nonserious AEs will be 
collected from the time the subject signs the study-specific informed consent.
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 Events of Special Interest
There are no AEs of special interest in this study.
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 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.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug and to the injection procedure:
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 can either be discontinued from the 
study after Early Exit Visit procedures or 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 an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2
Other Safety Data Collection
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 (the statistical analysis 
plan [SAP] will include a complete list of these PTs).  Adverse events reporting any of these terms will be 
medically reviewed on a regular basis throughout the duration of the study and will be summarized in 
the study clinical study report (CSR). 
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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 analyses.  
Complete and specific details of the statistical analysis will be described in the SAP.
The primary analysis will be conducted after all subjects have completed their end of study visit for the 
purpose of submission.
7.2
Definition for Analysis Populations
The following population sets will be used for the analyses.
The ITT Population includes all randomized subjects.  For double-blind period analyses, subjects will be 
included in the analysis according to the treatment groups to which they were randomized.  For open-
label period analyses, data will be analyzed according to the treatments randomized in the double-blind 
period and received in the open-label period (i.e., AGN-151586/AGN-151586, AGN-151586/None, 
Placebo/AGN-151586, Placebo/None).
Baseline analyses and efficacy analyses for US FDA and EU Regulatory agencies will be performed on the 
ITT population, consisting of all randomized subjects.  Subjects will be included in the double-blind 
period analysis according to the treatment groups to which they were randomized.  For open-label 
period analyses, data will be analyzed according to the treatments randomized in the double-blind 
period and received in the open-label period (i.e., AGN-151586/AGN-151586, AGN-151586/None, 
Placebo/AGN-151586, Placebo/None).
Additionally, for EU regulatory agencies only, subgroup analyses will be performed on the ITT 
population, that also has a baseline FLO-11 total score ≤ 50.  Analyses will consist of the EU primary and 
key secondary endpoints.
The Safety Analysis Set consists of all subjects who were treated with at least 1 dose of study drug (i.e., 
AGN-151586 or placebo).  All safety analyses will be performed with subjects analyzed by their actual 
treatment received in double-blind period/open-label period (i.e., AGN-151586/AGN-151586, 
AGN-151586/None, Placebo/AGN-151586, Placebo/None), and will be presented with overall safety 
data for the study (i.e., either period), for double-blind period, and for open-label period.  The Safety 
Analysis Set will be used for all safety analyses.
7.3
Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The primary efficacy endpoint of the composite endpoints for the US FDA and the coprimary endpoints 
for the EU regulatory agencies (defined in Section 3.2), respectively, will be analyzed based on the ITT 
population and the following methods will be used to address potential intercurrent events:
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
Subjects who did not receive any dose of study drug but are randomized will still be included in 
the ITT population.  For the EU, those who also had baseline FLO-11 total score of ≤ 50 will be 
included in subgroup analyses of the coprimary and key secondary endpoints.

Subjects who are randomized but prematurely discontinued the study before assessment of the 
primary endpoints will be considered as part of the ITT population.

Subjects who die before assessment of the primary endpoints will count as though they 
hypothetically continued in the study.

Subjects who are lost to follow-up and are missing data for the primary endpoints will count as 
though they hypothetically continued in the study.

Subjects who are missing assessments or data due to the COVID-19 pandemic and are missing 
data for the primary endpoints will count as though they hypothetically continued the study.

Subjects who are missing data for any other reason for the primary endpoints will count as 
though they hypothetically continued in the study.
The efficacy analysis of secondary endpoints (defined in Section 3.3) will be analyzed based on the same 
populations as above with similar methods for addressing potential intercurrent events.
7.4
Statistical Analyses for Efficacy
Demographics, baseline or disease characteristics, medical history, and prior and concomitant 
medications will be summarized for the ITT population.  Medical history data will be reported and 
summarized separately from prior procedures data for the ITT population. Medical history data and
prior procedure data will be coded using the MedDRA. Prior and concurrent procedures will be 
summarized by MedDRA high level term and PT.
Summary and Analysis of the Primary Endpoints
Analysis of the respective primary endpoints will be conducted on the ITT Population for the US and for 
the EU regulatory agencies based on treatment as randomized. 
The assessments of the severity of GL at maximum frown using the validated FWS is based on the 
following scale:

0 = None

1 = Mild

2 = Moderate

3 = Severe
The composite primary endpoint for FDA is the following:

≥ 2-grade improvement from baseline on the FWS according to both investigator and subject 
assessments of GL severity at maximum frown at Day 7 
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The coprimary endpoints for EU regulatory agencies consist of the following:

≥ 2-grade improvement from baseline on the FWS according to subject assessment of GL 
severity at maximum frown at Day 7, and

≥ 2-grade improvement from baseline on the FWS according to investigator assessment of GL 
severity at maximum frown at Day 7.
The attributes of the estimands corresponding to the primary efficacy endpoints for the US FDA and EU 
regulatory agencies are summarized in Section 3.1.
US FDA: The composite primary responder endpoint for at least a 2-grade improvement will be analyzed 
using the Cochran-Mantel-Haenszel (CMH) method 
 
.  The primary endpoint must meet p ≤ 0.05 to be 
considered successful.
European Union regulatory agencies:  The coprimary responder endpoints for ≥ 2-grade improvement 
from baseline in the FWS will be analyzed separately using the CMH method 
 
.  Both coprimary endpoints 
must meet p ≤ 0.05 to be considered successful.
The evaluation of the equality of the proportions of responders for the primary endpoints at Day 7 will 
be based on the CMH test stratified by baseline FWS and by investigator site.  (Sites may be pooled for 
stratification purposes if there are too few subjects in a site.) A p-value ≤ 0.05 (2-sided testing) will be 
claimed as statistically significant.  
 
For primary and secondary endpoints, missing data will first be imputed at the visit level using multiple 
imputation, and then the responder definitions will be applied.  Details are provided in the SAP for 
missing data handling.
Sensitivity analyses of the primary efficacy variables will be performed to establish their consistency and 
robustness as well as to further characterize the extent of subjects' responses. As-observed data 
analysis, as well as missing as non-responder (using non-responder imputation [NRI]) analysis, stratified 
by baseline FWS and by investigator site are planned for sensitivity analyses.
 
 
 
 
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Summary and Analysis of Secondary Endpoints
Secondary efficacy endpoints for the US FDA and EU regulatory agencies are listed in Section 3.3, and 
include other response definitions for the FWS by investigator and subject, as well as for the FLO-11, 
FLSQ, and GAC-GL. 
The attributes of the estimands corresponding to the secondary efficacy endpoints are summarized in 
Section 3.1.  Analysis of the secondary endpoints will be conducted on the ITT population based on 
treatment as randomized for the US FDA and the EU regulatory agencies.
For the secondary endpoints, the proportion of responders will be analyzed using the CMH test 
 
.  The continuous variables will be analyzed using analysis of 
covariance with treatment as the main effect, 
.
 
 
 
 
 
 
 
 
 
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7.5
Statistical Analyses for Safety
The safety analyses will be performed using the safety population (i.e., Safety Analysis Set).  The safety 
parameters will include AEs, vital sign measurements, 12-lead ECG, laboratory evaluations (hematology 
and chemistry), neurological assessment (examination to consist of assessment of cranial nerves II 
through VII), physical examination, and immunogenicity.  The last nonmissing safety assessment before 
study drug administration will be used as the baseline for all analyses of that endpoint.
Treatment-emergent AEs are defined as any AE with the onset that is after the first dose of study drug.  
Events where the onset date is the same as the study drug start date are assumed to be treatment-
emergent, unless known to have started prior to study treatment 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:
1.
Any TEAE
2.
Any TEAE related to study treatment according to the investigator (i.e., study drug-related, study 
injection procedure-related)
3.
Any severe TEAE
a.
Any severe TEAE related to study treatment according to the investigator
4.
Any serious TEAE
a.
Any serious TEAE related to study treatment according to the investigator
5.
Any TEAE leading to discontinuation of study drug
6.
Any TEAE leading to death
7.
PDSOT TEAEs
8.
Neurological assessment TEAEs
9.
All deaths
Treatment-emergent AEs will be summarized by system organ class (SOC) and PT; by maximum 
relationship to study treatment (i.e., study drug related, study injection procedure related) as assessed 
by the investigator (e.g., reasonable possibility or no reasonable possibility) and SOC and PT; by 
maximum severity and SOC and PT; and by subject number and SOC and PT.  Specific treatment-
emergent AEs will be counted once for each subject for calculating percentages, unless stated 
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otherwise.  In addition, if the same AE occurs multiple times within a subject, the AE will be counted 
only once, and the highest severity and level of relationship to investigational product will be reported.
Serious AEs (including deaths) and AEs leading to study drug discontinuation will be summarized by SOC 
and PT and in listing format.
Possible distant spread of toxin PTs will be identified in the SAP and PDSOT TEAEs will be summarized by 
PT. 
Neurological assessment TEAEs will be summarized by PT.
Vital sign measurements and 12-lead ECG parameters will be summarized for each assessment 
timepoint, as well as for changes from baseline at each assessment timepoint.  In addition, potentially 
clinically significant vital signs values will be summarized.  Details will be provided in the SAP.
Immunogenicity results, manifested as the presence of binding antibodies (positive) and neutralizing 
antibodies (positive) to AGN-151586, will be summarized in a table for baseline and postbaseline data.  
Immunogenicity findings (positive) will be tabulated with the number and percentage of subjects at each 
visit.  Percentages will be based on the number of treated subjects with interpretable antibody assays at 
the specified visit.  Immunogenicity results including additional analysis of antibody response to other 
neurotoxin serotypes will be documented in the CSR or in a separate report.
7.6
Overall Type I Error Control
For the double-blind period, to control the family-wise Type I error rate at 0.05 for multiplicity across 
the primary and secondary analyses, a hierarchical testing strategy11 will be used.  The hierarchical 
testing strategy starts with the coprimary endpoint followed by sequential testing of the secondary 
endpoints.  The statistical significance will be evaluated in the following order: if a statistical significance 
at the 0.05 level (2-sided) is shown for the first endpoint in the ranking order, then the next endpoint in 
the immediate subsequent order will be evaluated; evaluation of subsequent endpoint will continue in 
the same manner.  If no statistical significance is shown at α = 0.05 at any endpoint, then the endpoint 
and all subsequent endpoints will not be considered statistically significant, regardless of their nominal 
p-values.
The hierarchical testing order follows for US FDA:
1.
Primary: At least a 2-grade improvement from baseline based on the following:

Investigator and subject assessments (composite) of GL severity at maximum frown at 
Day 7.
2.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall 
satisfaction) for GL at Day 7
3.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall 
satisfaction) for GL at Hour 24
4.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 4 (natural look) 
for GL at Day 7 
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For the US FDA, the following secondary endpoints will be evaluated outside of the gated hierarchical 
testing sequence at each time point:
1.
Key Secondary: At least 2-grade improvement from baseline in GL severity at maximum frown 
according to the investigator assessment using the FWS over time (double-blind period)
2.
Key Secondary: At least 2-grade improvement from baseline in GL severity at maximum frown 
according to the subject assessment using the FWS over time (double-blind period).
The hierarchical testing order follows for EU regulatory agencies:
1.
Coprimary: At least a 2-grade improvement based on the following:

Subject assessment using FWS at maximum frown at Day 7, and 

Investigator assessment using FWS at maximum frown at Day 7.
2.
Key Secondary: At least 20-point improvement from baseline in FLO-11 total scores for GL at 
Day 7
3.
Secondary: At least 2-grade improvement from baseline in GL severity at maximum frown 
according to the subject assessment using the FWS at Hour 24
4.
Secondary: At least 2-grade improvement from baseline in GL severity at maximum frown 
according to the investigator assessment using the FWS at Hour 24
5.
Secondary: At least 1-grade improvement from baseline in GL severity at maximum frown 
according to the subject assessment using the FWS at Hour 24
6.
Secondary: At least 1-grade improvement from baseline in GL severity at maximum frown 
according to the investigator assessment using the FWS at Hour 24
7.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall 
satisfaction) for GL at Hour 24
8.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 4 (natural look) 
for GL at Day 7 
9.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 (overall 
satisfaction) over time 
10. Secondary: At least 4-point improvement from baseline in FLO-11 Item 10 (look angry) for GL at 
Day 7
11. Secondary: At least 4-point improvement from baseline in FLO-11 Item 5 (look less attractive) 
for GL at Day 7
For the EU, the following secondary endpoints will be evaluated outside of the gated hierarchical testing 
sequence:
1.
Secondary: Time to the first ≥ 1-grade improvement from baseline on the FWS according to 
subject assessments of GL severity at maximum frown (double-blind period)
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2.
Secondary: Time to the first ≥ 1-grade improvement from baseline on the FWS according to 
investigator assessments of GL severity at maximum frown (double-blind period).
3.
Secondary: At least 2-grade improvement from baseline on the FWS according to subject 
assessments of GL severity at maximum frown over time (double-blind period)
4.
Secondary: At least 2-grade improvement from baseline on the FWS according to investigator 
assessments of GL severity at maximum frown over time (double-blind period)
5.
Secondary: Time to return to baseline FWS according to subject assessments of FWS at 
maximum frown (double-blind period)
6.
Secondary: Time to return to baseline FWS according to investigator assessments of FWS at 
maximum frown (double-blind period)
7.
Secondary: Subject-reported global assessment of change in GL based on the GAC-GL over time
7.7
Sample Size Determination
Approximately 300 subjects will be enrolled at approximately 15 study sites. 
 
  For the US FDA and EU regulatory agencies, the ITT 
population will consist of all randomized subjects.  Additionally, for the EU regulatory agencies, 
subgroup analyses will be performed for the coprimary and key secondary endpoint with the ITT 
population that also has a baseline FLO-11 total score ≤50.
For the US FDA, a sample size of 300 subjects with a 3:1 randomization ratio (AGN-151586:Placebo) will 
have > 99% power to detect a difference on Day 7 between the AGN-151586 group and the placebo 
group using the composite endpoint of ≥2-grade
 
For the EU regulatory agencies, a sample size of 300 subjects for the ITT population will have >99% 
power (and 180 of the subgroup population will provide a power of approximately 93%) to detect a 
difference between the AGN-151586 group and the placebo group at Day 7 for the coprimary endpoints, 
 
 
 
For the FDA and EU regulatory agencies, a gate-keeping testing strategy will be used to compare the 
AGN-151586 group versus the placebo group, starting with the primary endpoint(s) and sequentially 
testing in the endpoint hierarchy at the 0.05 significance level. 
 
 
 
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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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
Investigators should notify AbbVie if any urgent safety measures are taken to protect the subjects 
against any immediate hazard.
8.3
Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated 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 
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will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated.
The end of study is defined as the date of end of study participation by the last subject in the last 
country where the study was conducted.
12
REFERENCES
1.
Blitzer A, Binder WJ, Aviv JE, et al. The management of hyperfunctional facial lines with botulinum 
toxin. A collaborative study of 210 injection sites in 162 patients. Arch Otolaryngol Head Neck Surg. 
1997;123(4):389-92.
2.
Carruthers A, Carruthers J. Botulinum toxin type A for the treatment of glabellar rhytides. Dermatol 
Clin. 2004;22(2):137-44.
3.
Garcia A, Fulton JE, Jr. Cosmetic denervation of the muscles of facial expression with botulinum 
toxin. A dose-response study. Dermatol Surg. 1996;22(1):39-43.
4.
Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: a double-blind, placebo-
controlled study with an electromyographic injection technique. J Am Acad Dermatol. 
1996;35(4):569-72.
5.
Pribitkin EA, Greco TM, Goode RL, 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.
Beer KR. Comparative evaluation of the safety and efficacy of botulinum toxin type A and topical 
creams for treating moderate-to-severe glabellar rhytids. Dermatol Surg. 2006;32(2):184-97.
7.
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.
8.
Charles FJ, Cox SE, Earl ML. Social implications of hyperfunctional facial lines. Dermatol Surg. 
2003;29(5):450-5.
9.
Eleopra R, Tugnoli V, Rossetto O, et al. Different time courses of recovery after poisoning with 
botulinum neurotoxin serotypes A and E in humans. Neurosci Lett. 1998;256(3):135-8.
10. Adler M, Keller JE, Sheridan RE, et al. Persistence of botulinum neurotoxin A demonstrated by 
sequential administration of serotypes A and E in rat EDL muscle. Toxicon. 2001;39(2-3):233-43.
11. Dmitrienko A, Molenberghs G, Chuang-Stein C, et al. Gatekeeping Strategies.  Analysis of Clinical 
Trials Using SAS: A Practical Guide. Cary, NC: SAS Institute; 2005. p. 104-8.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
ADR
adverse drug reaction
AE
adverse event
BoNT/A
Botulinum Neurotoxin Serotype A
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease – 2019
CSR
clinical study report
DHEA
Dehydroepiandrosterone
ECG
Electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EU
European Union
FDA
Food and Drug Administration
FLO-11
11-item Facial Line Outcomes 
FLSQ
Facial Line Satisfaction Questionnaire
FWS
Facial Wrinkle Scale
GAC-GL
Global Assessment of Change in Glabellar Lines
GCP
good clinical practice
GL
Glabellar lines
HRT
hormone replacement therapy
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
MedDRA
Medical Dictionary for Regulatory Activities
NRI
non-responder imputation
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Abbreviation
Definition
PDSOT
possible distant spread of toxin
PRO
patient reported outcome
PTs
preferred terms
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
VDS
verbal descriptor scale
WOCBP
Women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-508:  A Phase 3, Multicenter Study to Evaluate the Safety and Efficacy of AGN-151586 for the 
Treatment of Glabellar Lines in Toxin-Naïve Subjects
Protocol Date:  12 August 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and local 
regulations and guidelines governing the study at the site location.  In signing the Investigator Agreement, the 
investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary 
to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for investigational 
purposes and complying with the requirements relating to informed consent and ethics committees (e.g., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about their 
obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records available 
for inspection by representatives of AbbVie and/or the appropriate regulatory agency, and retaining all 
study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial clinical 
protocol and all of its amendments.
9.
Reporting promptly to AbbVie, the ethics committee/institutional review boards (as required) and other 
appropriate individuals (e.g., coordinating investigator, institution director):

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Vice President,
Head of Clinical Development, Aesthetics Medicine
Therapeutic Area
Executive Director
Statistics 
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APPENDIX D. ACTIVITY SCHEDULE
 
 
  
  
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol 
Date
Version 1.0
10 November 2021
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
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