Clinical trial NCT05248867
Conditions: Glabellar Lines
Keywords: Glabellar Lines AGN-151586
Sponsor: AbbVie
Start date: 2022-03-16; Completion date: 2023-03-17
Enrollment: 638 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Facial lines that develop from repeated facial expression, such as glabellar lines (GL), are typically treated by selectively weakening specific muscles with small quantities of botulinum toxin. AGN-151586 is an investigational product being developed for the treatment of GL. The purpose of this study was to evaluate the safety and efficacy of AGN-151586 for the treatment of GL in participants with moderate to severe GL.

This was a 12-week study in which eligible subjects were enrolled into the study containing 2 treatment periods, double-blind period and open-label period. Participants were randomly assigned to receive AGN-151586 or placebo. There was 1 in a 4 chance that participants would receive placebo. Around 600 adult participants with moderate to severe GL were to be enrolled in the study in approximately 38 sites across the world.

Participants received either AGN-151586 or Placebo administered as 5 intramuscular injections to the glabellar complex on Day 1. Participants meeting retreatment criteria may have received an open-label treatment of AGN-151586 during the study.

Participants attended regular visits during the study at a study site. The effect of the treatment was checked by medical assessments, blood tests, telephone calls, questionnaires and checking for side effects.

Detailed description:

Arms: arm 1: Participants received 5 intramuscular injections of placebo in the glabellar complex on Day 1. Based on meeting the retreatment criteria, the participants may have also received 1 open-label treatment of AGN-151586 on Day 43. arm 2: Participants received 5 intramuscular injections of AGN-151586 in the glabellar complex on Day 1. Based on meeting the retreatment criteria, participants may also have received 1 open-label treatment of AGN-151586 on Day 43.
Interventions: intervention 1: Placebo intervention 2: AGN-151586
Intervention descriptions: intervention 1: Placebo solution for injection intervention 2: AGN-151586 solution for injection

Protocol documents:
Prot_000.pdf: 


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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
15
3.3
SECONDARY ENDPOINTS
15
3.4
ADDITIONAL EFFICACY ENDPOINTS
16
3.5
SAFETY ENDPOINTS
17
3.6
IMMUNOGENICITY ASSESSMENT
17
4
INVESTIGATIONAL PLAN
18
4.1
OVERALL STUDY DESIGN AND PLAN
18
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
36
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
44
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
46
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
48
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
49
APPENDIX D.
ACTIVITY SCHEDULE
50
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
55
APPENDIX F.
OPERATIONS MANUAL
58
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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 
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. 
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 
(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 
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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 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 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 
Intent-to-treat 
(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.
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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 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.
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 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 (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.
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.
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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)

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 
ANOVA models 
 
 
  Endpoints 
will be evaluated outside 
of the gated hierarchical 
testing.
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
 
 
 
 
 
 
 
 
 
 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.
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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
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
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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)*
l.
Time to return to baseline FWS according to subject assessment of FWS at maximum frown 
(double-blind period)* 
m. Time to return to baseline FWS according to investigator assessment 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 the Global Assessment of Change 
in Glabellar Lines (GAC-GL) over time*
* Endpoints will be evaluated outside of the gated hierarchical testing.
3.4
Additional Efficacy Endpoints
 
 
 
 
 
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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.  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). 
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 AGN-151586:placebo).  Randomization will be stratified by investigator site, toxin use history (for 
aesthetic purpose), 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.
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The efficacy measures include investigator FWS, subject FWS, FLO-11, FLSQ, GAC-GL, 
 
. 
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.  
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.
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Suitability of Subject Population
The study population will be 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.  
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.
2. Subjects must be adult male or female, at least 18 years old.
4. Subjects must be able to accurately assess their facial lines without the use of eyeglasses 
(contact lens use is acceptable).
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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 received treatment with any botulinum neurotoxin of any serotype 
for aesthetic treatment within the last 6 months prior to Baseline Day 1 and for therapeutic 
treatment within the last 12 months 
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).
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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.
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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).
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
 
 
 
 
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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.
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
Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

Subject is significantly noncompliant with study procedures.

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.
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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.
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 
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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. 
  
 
 
  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
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, toxin use history (for aesthetic purpose), 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), toxin use 
history (for aesthetic purpose), 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 
Investigational Medicinal 
Product
AGN-151586
Placebo for AGN-151586
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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.
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.
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All follow-up information is to be reported to the sponsor (or an authorized representative) and 
documented in source as required by the sponsor.  Product complaints associated with AEs will be 
reported in the study summary.  All other complaints will be monitored on an ongoing basis.  Product 
complaints occurring during the study will be followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding 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) immediately without 
undue delay, but no later than 24 hours, from when the site is made aware of the SAE (refer to 
Section 4.2 of the Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
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Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event. 
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 investigational medicinal product (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.
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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.
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 immediately without undue delay, but no later than 
24 hours, from when the site is made 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 
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medically reviewed on a regular basis throughout the duration of the study and will be summarized in 
the study clinical study report (CSR). 
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.
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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:

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 in 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
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
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 
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 investigator site, toxin use history, and baseline FWS.  (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
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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 
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
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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 
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
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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)
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 600 subjects will be enrolled at approximately 38 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 600 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 improvement, 
 
For the EU regulatory agencies, a sample size of 600 subjects for the ITT population will have >99% 
power (and the subgroup population of an estimated 360 subjects will provide > 99% power) to detect a 
difference between the AGN-151586 group and the placebo group at Day 7 for the coprimary endpoints, 
 
 
 
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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. 
 
 
 
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.
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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 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.
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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
WOCBP
Women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-500:  A Phase 3, Multicenter Study to Evaluate the Safety and Efficacy of AGN-151586 for the 
Treatment of Glabellar Lines 
Protocol Date:  01 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
Version 1.1 (Germany Only)
19 July 2022
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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SAP_001.pdf: 
AGN-151586 (botulinum toxin type E) 
M21-500 – Statistical Analysis Plan
Version 5.0 – 08 April 2023
1
Statistical Analysis Plan for Study M21-500
A Phase 3, Multicenter Study to Evaluate the Safety 
and Efficacy of AGN-151586 for the Treatment of 
Glabellar Lines
Date:  08 April 2023
Version 5.0
 
NCT05248867


AGN-151586 (botulinum toxin type E) 
M21-500 – Statistical Analysis Plan
Version 5.0 – 08 April 2023
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Table of Contents
1.0
Introduction...........................................................................5
2.0
Study Design and Objectives ................................................5
2.1
Objectives, Hypotheses and Estimands................................................... 5
2.2
Study Design Overview.......................................................................... 7
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 8
3.0
Endpoints...............................................................................8
3.1
Primary Endpoints.................................................................................. 8
3.2
Secondary Endpoints.............................................................................. 9
3.3
Other Efficacy Endpoints ..................................................................... 11
3.4
Safety Endpoints .................................................................................. 12
3.5
Additional Endpoints............................................................................ 12
4.0
Analysis Populations ...........................................................12
5.0
Subject Disposition..............................................................13
6.0
Study Drug Duration and Compliance ..............................14
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................14
7.1
Demographics and Baseline Characteristics.......................................... 14
7.2
Medical History and Prior and Concurrent Procedures.......................... 15
7.3
Prior and Concomitant Medications...................................................... 16
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints ............................16
9.0
Efficacy Analyses.................................................................17
9.1
General Considerations......................................................................... 17
9.2
Handling of Missing Data..................................................................... 19
9.3
Primary Efficacy Endpoints and Analyses ............................................ 21
9.3.1
Primary Efficacy Endpoints.................................................................. 21
9.3.2
Main Analysis of Primary Efficacy Endpoints ...................................... 22
9.3.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoints ............................................................................................. 23
9.4
Secondary Efficacy Endpoints and Analyses ........................................ 24
 


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9.4.1
Secondary Efficacy Endpoints.............................................................. 24
9.4.2
Main Analyses of Secondary Efficacy Endpoints.................................. 28
9.4.3
Sensitivity and Supplementary Analyses for Secondary Efficacy 
Endpoints ............................................................................................. 33
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses....................... 33
9.5
Additional Efficacy Analyses ............................................................... 33
9.6
Efficacy Subgroup Analyses................................................................. 33
10.0
Safety Analyses....................................................................34
10.1
General Considerations......................................................................... 34
10.2
Adverse Events..................................................................................... 34
10.2.1
Treatment-Emergent Adverse Events.................................................... 34
10.2.2
Adverse Event Overview...................................................................... 35
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 36
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure .............................................................................................. 36
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 36
10.2.6
Possible Distant Spread of Toxin Adverse Events................................. 36
10.2.7
Neurological Assessment Adverse Events ............................................ 37
10.3
Analysis of Laboratory Data................................................................. 37
10.4
Analysis of Vital Signs......................................................................... 38
10.5
Safety Subgroup Analyses.................................................................... 39
10.6
Other Safety Analyses .......................................................................... 39
11.0
Other Analyses ....................................................................40
12.0
Interim Analyses..................................................................40
12.1
Data Monitoring Committee................................................................. 40
13.0
Overall Type-I Error Control.............................................40
14.0
Version History ...................................................................44
15.0
References............................................................................46
 


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List of Tables
Table 1.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoints ............................................................................................. 23
Table 2.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints ............................................................................................. 29
Table 3.
SAP Version History Summary ............................................................ 44
List of Figures
Figure 1.
Study Schematic..................................................................................... 7
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 47
 


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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for AGN-151586 
Study M21-500: A Phase 3, Multicenter Study to Evaluate the Safety and Efficacy of 
AGN-151586 for the Treatment of Glabellar Lines.
Study M21-500 examines the safety and efficacy of AGN-151586 (containing botulinum 
toxin type E) for treatment in subjects with moderate to severe glabellar lines.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 
(SAS Institute Inc., Cary, NC 27513) or later under the Linux operating system.
This SAP includes changes to analyses described in the protocol.  Details are outlined in 
Section 14.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses and Estimands
The study objective is to evaluate the safety and efficacy of AGN-151586 for the 
treatment of glabellar lines (GL) in subjects with moderate to severe GL.
The clinical hypothesis is that AGN-151586 is more effective than placebo in treating GL, 
as measured by both investigator and subject assessment of GL severity at maximum 
frown using the Facial Wrinkle Scale (FWS), and that it has an acceptable safety profile 
after single and repeat treatments.
Estimands: Primary Endpoints
The attributes of the estimands corresponding to the primary and coprimary efficacy 
endpoints are summarized in Table 1 (see Section 9.3.2).  In addition, the attribute of 
treatment is a single dose of AGN-151586 or placebo.
 


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For the US FDA, the estimand for the primary composite endpoint is defined as follows: 
●
Difference in the proportion of subjects who would achieve a Grade 0 or 1 
(none or mild) and at least a 2-grade improvement from baseline in composite 
FWS (as assessed by both investigator and by subject) at Day 7 had they not 
missed FWS assessments, for the AGN-151586 group in comparison with 
placebo in the ITT population
For EU Regulatory Agencies, the estimands for the coprimary endpoints are defined as 
follows:
●
Difference in the proportion of subjects who would achieve ≥ 2-grade 
improvement from baseline in FWS as assessed by investigator at Day 7 had 
they not missed FWS assessments, for the AGN-151586 group in comparison 
with placebo in the ITT population, and
●
Difference in the proportion of subjects who would achieve ≥ 2-grade 
improvement from baseline in FWS as assessed by subject at Day 7 had they 
not missed FWS assessments, for the AGN-151586 group in comparison with 
placebo in the ITT population
Any missing assessments will be assumed to be missing at random and imputed using 
multiple imputation.  Statistical significance of the difference will be tested using 
Cochran-Mantel-Haenszel (CMH) test 
 
.
Estimands: Secondary Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2 (see Section 9.4.2).  Treatment is the same as for the primary 
efficacy endpoints. For both US FDA and EU variables/endpoints, the population is the 
ITT population (all randomized).  For the EU, subgroup analyses will be performed for 
the coprimary and key secondary endpoints for the ITT population that also has baseline 
11-item Facial Line Outcomes (FLO-11) total scores (transformed) ≤ 50.  The 
 




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2.4
Sample Size Determination
Approximately 600 subjects will be randomized into the study in a 3:1 ratio, yielding 
approximately 450 subjects in the AGN-151586 group and 150 subjects in the placebo 
group in the treatment period.  
For the US FDA, a sample size of 600 subjects 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 improvement, 
 
 
. 
For the EU regulatory agencies, a sample size of 600 subjects for the ITT population will 
have >99% power (and the subgroup population of an estimated 360 subjects will provide 
> 99% power) to detect a difference between the AGN-151586 group and the placebo 
group at Day 7 for each of the coprimary endpoints, 
 
 
 
 
 
.
Sample size calculations were based on the two group χ2 two-sided test of equal 
proportions using nQuery (Version 7.0) at a 0.05 level of significance.
3.0
Endpoints
3.1
Primary Endpoints
For the FDA, the primary composite endpoint is the achievement of a Grade 0 or 1 (none 
or mild) and at least a 2-grade improvement from baseline on the FWS according to both 
investigator and subject assessments of GL severity using FWS at maximum frown at Day 
7.
 


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For EU regulatory agencies, the coprimary endpoints are the achievement of at least a 
2-grade improvement from baseline on the FWS according to: (1) subject assessment of 
GL severity at maximum frown at Day 7, and (2) investigator assessment of GL severity 
using FWS at maximum frown at Day 7.
3.2
Secondary Endpoints
For US FDA:
●
Key secondary endpoint: a Grade 0 or 1 (none or mild) and at least a 2-grade 
improvement from baseline on the FWS according to both investigator and 
subject assessments (i.e., concurrent composite) of GL severity at maximum 
frown over time (DB period)*
●
Key secondary endpoint: a Grade 0 or 1 (none or mild) and at least a 2-grade 
improvement from baseline on the FWS according to investigator assessment
of GL severity at maximum frown over time (DB period)*
●
Key secondary endpoint: a Grade 0 or 1 (none or mild) and at least a 2-grade 
improvement from baseline on the FWS according to subject assessment of 
GL severity at maximum frown over time (DB period)*
●
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5
(overall satisfaction) for GL at Day 7
●
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
For EU regulatory agencies:
●
Key secondary endpoint: ≥ 20-point improvement from baseline in FLO-11 
total scores for GL at Day 7
●
≥ 2-grade improvement from baseline on the FWS according to subject
assessment of GL severity at maximum frown at Hour 24
 


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●
≥ 2-grade improvement from baseline on the FWS according to investigator
assessment of GL severity at maximum frown at Hour 24
●
≥ 1-grade improvement from baseline on the FWS according to subject
assessment of GL severity at maximum frown at Hour 24
●
≥ 1-grade improvement from baseline on the FWS according to investigator
assessment of GL severity at maximum frown at Hour 24
●
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
●
Time to the first ≥1-grade improvement from baseline on the FWS according 
to subject assessment of GL severity at maximum frown over time (DB
period)*
●
Time to the first ≥1-grade improvement from baseline on the FWS according 
to investigator assessment of GL severity at maximum frown over time (DB
period)*
●
≥ 2-grade improvement from baseline on the FWS according to subject 
assessment of GL severity at maximum frown over time (DB period)*
●
≥ 2-grade improvement from baseline on the FWS according to investigator 
assessment of GL severity at maximum frown at over time (DB period)*
●
Time to return to baseline FWS criterion† according to subject assessment of 
FWS at maximum frown (DB period)*
●
Time to return to baseline FWS criterion† according to investigator assessment 
of FWS at maximum frown (DB period)*
●
Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 
(overall satisfaction) for GL over time*
●
≥ 4-point improvement from baseline in FLO-11 Item 10 (look angry) for GL 
at Day 7
●
≥ 4-point improvement from baseline in FLO-11 Item 5 (look less attractive) 
for GL at Day 7
●
Subject-reported global assessment of change in GL based on the Global 
Assessment of Change in Glabellar Lines (GAC-GL) over time* 
 


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*
Endpoints will be excluded from hierarchical testing.
 
3.3
Other Efficacy Endpoints
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively.  For both the US FDA and EU regulatory agencies, analyses for additional 
efficacy endpoints will be performed on the ITT population. The additional efficacy 
endpoints are as follows:
 
 
 
 
 
 
 
 
 
 


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3.4
Safety Endpoints
The safety endpoints are the incidence of AEs for the entire study population, change 
from baseline in vital signs parameters, change from baseline in electrocardiogram (ECG) 
parameters, change from baseline in laboratory evaluations (hematology and chemistry), 
and presence of binding and neutralizing antidrug antibodies.  Results of a neurological 
assessment (which includes assessment of cranial nerves II through VII) will be reviewed
as an additional safety measure. After the screening visit, clinically significant (as per 
investigator) neurological assessment abnormalities (or worsening of a baseline condition) 
will be captured as AEs.
3.5
Additional Endpoints
Not applicable.
4.0
Analysis Populations
The following population sets will be used for the analyses.
The Intent-to-Treat (ITT) Population includes all randomized subjects.  For the DB period 
analyses, subjects will be included in the analysis according to the treatment groups to 
which they were randomized.  For the OL period analyses, data will be analyzed 
according to the treatments randomized in the DB period and received in the OL period 
(i.e., AGN-151586/AGN-151586, AGN-151586/None, Placebo/AGN-151586, 
Placebo/None).
 


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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 DB period analysis according to the treatment groups to which they were 
randomized.  For the OL period analyses, data will be analyzed according to the 
treatments randomized in the DB period and received in the OL period, as above.
Additionally, for EU regulatory agencies only, subgroup analyses will be performed on 
the ITT population that also has a baseline FLO-11 total score (transformed) ≤ 50.  
Analyses will consist of the EU coprimary and key secondary endpoints.
The Safety Population 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 the DB period/OL 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 DB period, and for OL period.  The Safety Population will be used for all 
safety analyses.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and treated will 
be summarized for the ITT population.  A summary of subject accountability will be 
provided where the number of subjects in each of the following categories will be 
summarized for each treatment group and for the DB period and the OL period:
●
Subjects enrolled (randomized) in the study;
●
Subjects treated with at least one dose of study drug;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued study (with reason),
Subjects in each analysis population will also be summarized.
 


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For end of study participation, the number and percentage of subjects who completed the 
protocol defined follow-up period will be summarized overall and by treatment group.  
6.0
Study Drug Duration and Compliance
For the Safety Population, the number of subjects treated will be presented by treatment 
group for the double-blind period, as well as the open-label period.  Duration on treatment 
is assumed for the duration of the study period or until study exit.  If a subject does not 
receive the full dose, this will be indicated; significant deviations to dosing will be 
reported.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, prior and concurrent 
procedures, and prior and concomitant medications will be summarized for the ITT 
population overall and by treatment group. Categorical variables will be summarized with 
the number and percentage of subjects; percentages will be calculated based on the 
number of non-missing observations. Continuous variables will be summarized with 
descriptive statistics (number of non-missing observations, mean and standard deviation, 
median, Q1, Q3, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively, overall and 
by treatment group.  Unless otherwise specified, baseline is defined as the last non-
missing value prior to the first administration of study drug. 
Continuous demographic variables include age, weight, height, and body mass index 
(BMI). Continuous baseline characteristic variables include FLO-11 total scores 
(transformed) and item scores (for items 1-10), and FLSQ treatment expectations and 
impact domain scores.
Categorical demographic and baseline characteristic variables include:
 


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●
Sex
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Race
●
Age (< 65, ≥65 years)
●
Region (North America, EU)
●
BMI (< 25, ≥ 25 kg/m2).
●
Nicotine user (current, former, never, unknown)
●
Alcohol user (current, former, never, unknown)
●
Prior aesthetic toxin use (prior use, no prior use)
●
FWS at maximum frown
○
As assessed by investigator
○
As assessed by subject
●
FWS at rest
○
As assessed by investigator
○
As assessed by subject
●
FLO-11 total score (transformed) (≤50, >50)
●
FLSQ item scores 
●
Fitzpatrick Skin Type
7.2
Medical History and Prior and Concurrent Procedures
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 Medical Dictionary for Regulatory Activities (MedDRA). The actual version of 
the MedDRA coding dictionary will be noted in the statistical tables and clinical study 
report. The number and percentage of subjects in each medical history category (by 
MedDRA system organ class and preferred term) will be summarized overall and by 
treatment group. Similarly, the number and percentage of subjects in each prior 
procedures category will be summarized overall and by treatment group.  The system 
organ class (SOC) will be presented in alphabetical order, and the preferred terms will be 
 


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presented in alphabetical order within each SOC. Subjects reporting more than one
condition/diagnosis will be counted only once in each row (SOC or preferred term).
In addition, any concurrent procedures, defined as any procedure performed on or after 
the date of first treatment, will be summarized by term in each treatment group for the ITT 
population.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name for the ITT 
population. A prior medication is defined as any medication taken prior to the date of the 
first dose of study drug. A concomitant medication is defined as any medication that 
started prior to the date of the first dose of study drug and continued to be taken after the 
first dose of study drug or any medication that started on or after the date of the dose of 
study drug, but not after the date of the last visit assessment. The number and percentage 
of subjects taking medications will be summarized by generic drug name based on the 
World Health Organization (WHO) Drug Dictionary for both prior and concomitant 
medications.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The primary composite and coprimary endpoints for the US FDA and for the EU 
regulatory agencies (defined in Section 3.1), respectively, will be analyzed based on the 
ITT population, and the following methods will be used to address potential intercurrent 
events:
●
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 (transformed) 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 composite or coprimary endpoints will be 
considered as part of the ITT population.
 


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●
Subjects who die before assessment of the primary composite or coprimary 
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 
composite or coprimary 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 composite or coprimary endpoints will 
count as though they hypothetically continued in the study.
●
Subjects who are missing data for any other reason for the primary composite 
or coprimary endpoints will count as though they hypothetically continued in 
the study.
The secondary efficacy analysis of secondary endpoints (defined in Section 3.2) will be 
analyzed based on the same populations as above with similar methods for addressing 
potential intercurrent events.
9.0
Efficacy Analyses
9.1
General Considerations
All efficacy analyses will be conducted in the ITT Population for the US and EU 
regulatory agencies.
Analyses for the DB period will be conducted using a gated hierarchical testing procedure 
to preserve a familywise Type I error rate of α = 0.05.  DB treatment groups will be 
AGN-151586 and placebo.  Analyses for the OL period will be performed outside of the 
testing hierarchy.  Treatment groups reported for the OL period will include both the DB 
and OL period treatment group combinations (i.e., AGN-151586/AGN-151586, 
AGN-151586/None, Placebo/AGN-151586, Placebo/None).
For the DB period, to control the family-wise Type I error rate at 0.05 for multiplicity 
across the primary and secondary analyses, a hierarchical testing strategy1 will be used.
The hierarchical testing strategy starts with the primary efficacy endpoint followed by 
 


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sequential testing of the secondary endpoints, in the order listed for the US and EU 
regulatory agencies, respectively (see Section 13.0). Statistical significance will be
evaluated in order. If statistical significance at the 0.05 alpha level (2-sided testing) is 
shown for the first variable in the ranking order, then the next variable in the immediate 
subsequent order will be evaluated for statistical significance. If statistical significance is 
shown for the second variable in the ranking order, then the analysis will continue in the 
same manner for subsequent variables. If no statistical significance is shown at the 0.05 
alpha level for any variable in the ranking order, then that variable and all subsequent 
variables will not be considered statistically significant, regardless of their p-values.
Nominal p-values will then be provided.
The Primary Analysis will be performed after all ongoing subjects have completed both 
the DB period and the OL period and the database has been locked.  This will be the only 
and final analysis for the composite, coprimary and secondary efficacy endpoints, as well 
as all other efficacy endpoints in the DB period.  Descriptive analyses will be provided for 
the OL period measures over time.
Unless otherwise specified, categorical variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, 
 
.  Continuous variables will be analyzed using analysis 
of covariance (ANCOVA) 
 
.
A subject who is randomized based on a wrong stratum will be analyzed according to the
subject’s actual stratum. However, if a subject has a baseline FWS lower than moderate 
severity at maximum frown, then the subject will be included in stratified analyses within 
the moderate GL severity at maximum frown stratum. In analyses not stratified by 
baseline FWS, the observed baseline FWS will be used.
For efficacy analyses of FWS assessments, “baseline” refers to the last non-missing 
observation before either the first administration of study drug or randomization if no 
study drug is given or the administration of study drug during retreatment.  The change 
 


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from baseline values will be computed as the post-baseline value minus the observed 
baseline value.
 
 
  
 
 
 
 
9.2
Handling of Missing Data
Missing data will be imputed for the DB Period only using the following methods for the 
efficacy analyses:
●
Multiple Imputation: The Multiple Imputation approach will be used as a 
primary analysis for the primary endpoint, as well as for all secondary 
endpoints.  
 
 
 
 


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●
Non-responder Imputation (NRI): The NRI analysis will categorize any subject 
who does not have evaluation during a specific visit window as a non-
responder for that visit.  The NRI will be one of the sensitivity analysis 
approaches in the analyses of categorical variables for the primary efficacy 
endpoints.
●
As Observed (AO): The AO analysis will not impute values for missing 
evaluations, and thus a subject who does not have an evaluation on a scheduled 
visit will be excluded from the AO analysis for that visit. AO will include all 
values collected in the study and will be used for sensitivity analyses for the 
primary efficacy endpoints.
9.3
Primary Efficacy Endpoints and Analyses
9.3.1
Primary Efficacy Endpoints
The assessments of the severity of GL at maximum frown using the validated FWS is 
based on the following scale (for both investigator and subject):
●
0 = None
●
1 = Mild
●
2 = Moderate
●
3 = Severe
The primary composite endpoint for FDA is the following:
●
A Grade 0 or 1 (none or mild) and at least a 2-grade improvement from 
baseline on the FWS according to both investigator and subject assessments of 
GL severity at maximum frown at Day 7
The coprimary endpoints for EU regulatory agencies are the following:
●
≥ 2-grade improvement from baseline on the FWS according to subject 
assessment of GL severity at maximum frown at Day 7, and
 


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●
≥ 2-grade improvement from baseline on the FWS according to investigator 
assessment of GL severity at maximum frown at Day 7.
9.3.2
Main Analysis of Primary Efficacy Endpoints
The attributes of the estimands corresponding to the primary efficacy endpoints for the US 
FDA and EU regulatory agencies are summarized in Table 1.  In addition, the attribute of 
treatment is a single dose of AGN-151586 or placebo.
US FDA: The primary composite responder endpoint for a Grade 0 or 1 (none or mild) 
and at least a 2-grade improvement will be analyzed using the CMH method 
 
 
.  The primary composite endpoint must meet p ≤ 
0.05 to be considered successful.
EU 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 composite 
or coprimary endpoints at Day 7 will be based on the CMH test 
 
 
 
 
 
.  The 95% confidence interval for the treatment responder rate differences 
will be constructed using the normal approximation to the binomial distribution.
 




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responses. As-observed data analysis, as well as missing as non-responder (using NRI) 
analysis, 
 for sensitivity 
analyses.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4
Secondary Efficacy Endpoints and Analyses
9.4.1
Secondary Efficacy Endpoints
Analysis of the secondary endpoints will be conducted on the ITT population based on 
treatment as randomized for the US FDA and EU regulatory agencies.
Secondary efficacy endpoints for the US FDA and EU regulatory agencies are listed in 
Section 3.2, and include other response definitions for the FWS by investigator and 
subject, as well as for the FLO-11, FLSQ, and GAC-GL.
 


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The FLO-11, FLSQ, and GAC-GL instruments are described below.
FLO-11: The FLO-11 is a validated 11-item COA instrument to assess emotional and 
appearance-related impacts of upper facial lines from a subject's perspective.  Each item is 
on an 11-point numeric rating scale that ranges from 0 (not at all) to 10 (very much) with 
a middle label of somewhat.  For scoring, all items are transformed to a 0 to 100 scale, 
with higher scores indicating better outcomes.  Total score is calculated as the sum of the 
reverse score (i.e., 10 minus the original score) of Items 1 to 10 plus the raw score of Item 
11 (Item 11 does not need to be a reverse score).  Total scores are transformed to a 0 
(worst) to 100 (best) point scale by setting the lowest and highest possible scores at 0 and 
100, respectively; these are the transformed scale scores.  The 50% rule is applied for the 
total score, such that scales with at least 50% non-missing item responses will be scored 
as the average of the non-missing responses.  If the total scale is missing more than 50% 
of the item responses, then the total scale score will be set as missing.
 
 
 
 
 
 
FLSQ: The FLSQ consists of 2 versions (baseline and follow-up versions) to assess study 
intervention (i.e., treatment) expectations, treatment satisfaction, and impact of hyper 
functional upper facial lines (LCL, forehead lines, and/or GL).  The baseline version 
consists of 11 items (2 multi-item domains: treatment expectations and impact), while the 
follow-up version consists of 13 items (2 multi-item domains: treatment satisfaction, and 
impact; 3 single item domains:  met treatment expectations, continue treatment, and 
recommend to others). Additionally, FLSQ follow-up items 2, 3, 4, 5, 9, and 11 are 
 


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validated for use as stand-alone items. 
 
 
 
 
  
 
 


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GAC-GL: The GAC-GL is a 2-item measure that assesses the appearance of the subject's 
GL "now" in comparison with their perspective before treatment at rest and at maximum 
frown. The response options are scored on a 7-point numerical rating scale ranging 
from Very much improved to Very much worse. Scores are unique for at rest and 
maximum contraction, and they are simply the responses to the items.   
 
 
 
 
 


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9.4.2
Main Analyses of Secondary Efficacy Endpoints
The attributes of the estimands corresponding to the secondary efficacy endpoints are 
summarized in Table 2.  Analysis of the secondary endpoints will be conducted on the 
ITT population based on treatment as randomized for the US FDA and 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 ANCOVA 
 
.
 
 
 
 
 
 
 
 
 










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9.4.3
Sensitivity and Supplementary Analyses for Secondary 
Efficacy Endpoints
Additional sensitivity analyses may be performed as needed to assess impact of missing 
data for secondary endpoints due to a pandemic or natural disaster.
9.4.4
Supportive Secondary Efficacy Endpoints and Analyses
Not applicable.
9.5
Additional Efficacy Analyses
For both the US FDA and EU regulatory agencies, analyses for additional efficacy 
endpoints will be performed on the ITT population using data as observed.  The additional 
efficacy endpoints are listed in Section 3.3.
9.6
Efficacy Subgroup Analyses
For the primary and key secondary endpoints, analyses will be conducted using the 
following subgroups and descriptive summary statistics provided:
Analyses will be conducted using the following subgroups:
●
Sex (Female, Male) 
●
Age group (<65, ≥65 years)
●
Race (White, non-White)
●
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
●
Region (North America, EU)
●
Baseline FWS at maximum frown (moderate, severe)
●
Baseline FLO-11 total score (transformed) ≤ 50
●
Fitzpatrick skin type (Types I & II, Types III & IV, Types V & VI) 
 


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10.0
Safety Analyses
10.1
General Considerations
Safety data will be summarized for the Safety Population.  Safety summaries will be 
presented by treatment group, by overall study, by study period, and by treatments 
received in the DB Period and in the OL Period (i.e., AGN-151586/AGN-151586, 
AGN-151586/None, Placebo/AGN-151586, Placebo/None).
For the safety analysis, subjects are assigned to a treatment group based on the treatment 
actually received, regardless of the treatment randomized.
The safety parameters will include AEs, vital signs, 12-lead ECGs, laboratory evaluations 
(hematology and chemistry), neurological assessment (including examination of cranial 
nerves II through VII), and presence of antidrug antibodies. For change from baseline 
safety parameters, “baseline” refers to the last non-missing observation before the first 
study drug administration in the study.
10.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of 
the MedDRA coding dictionary used will be noted in the AE tables and in the clinical 
study report. Specific adverse events will be counted once for each subject for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a subject, the highest severity and level of relationship to 
investigational product will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAEs) 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 
 


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treatment administration. All TEAEs will be summarized overall, as well as by primary 
MedDRA SOC and PT. The SOCs will be presented in alphabetical order, and the PTs 
will be presented in alphabetical order within each SOC. The number and percentage of 
subjects experiencing treatment-emergent AEs will be summarized. 
In addition, for both possible distant spread of toxin (PDSOT) TEAEs and treatment-
related TEAEs, onset after study drug administration and duration will be evaluated.  
TEAE onset will be reported by number of days subsequent to the most recent study drug
administration and will be summarized with descriptive statistics.  TEAE duration will be 
defined as ((end date minus start date) + 1 day) and will be summarized with descriptive 
statistics.
10.2.2
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any TEAE
●
Any TEAE related to study treatment according to the investigator
○
Any TEAE related to study drug according to the investigator
○
Any TEAE related to study procedure according to the investigator
●
Any mild TEAE
○
Any mild TEAE related to study treatment according to the investigator
●
Any moderate TEAE
○
Any moderate TEAE related to study treatment according to the 
investigator
●
Any severe TEAE
○
Any severe TEAE related to study treatment according to the investigator
●
Any serious TEAE
○
Any serious TEAE related to study treatment according to the investigator
●
Any TEAE leading to discontinuation of study drug
●
Any TEAE leading to death
 


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Any PDSOT TEAE
●
Any neurological assessment associated TEAE
●
All deaths
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT
TEAEs will be summarized by SOC and PT; TEAEs considered related to study treatment 
as assessed by the investigator (i.e., reasonable possibility) by SOC and PT; by maximum 
severity by SOC and PT; and listed by subject number by SOC and PT. Specific adverse 
events will be counted once for each subject for calculating percentages, unless stated 
otherwise. In addition, if the same adverse event occurs multiple times within a subject, 
the adverse event will be counted only once and the highest severity and level of 
relationship to study drug will be reported.
In addition, TEAEs will be summarized by PT and sorted by decreasing frequency for the 
total active group after first dose of AGN-151586. Frequent TEAE incidence will be 
reported for PTs with ≥5% subject incidence, listed by SOC and PT.
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure
Not applicable.
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
Serious AEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format.
10.2.6
Possible Distant Spread of Toxin Adverse Events
PDSOT TEAEs will be summarized by PT.  The PTs 
 
will be based on the current MedDRA version used for the study prior to database lock.
Tabular listings of PDSOT TEAEs will be provided.
 


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10.2.7
Neurological Assessment Adverse Events
The neurological assessment, which is comprised of a Focused Symptoms Questionnaire 
and a Focused Neurological Examination, will be conducted at selected study visits per 
protocol.  Neurological assessment-associated TEAEs will be summarized by PT. The 
PTs will be based on the current MedDRA version prior to database lock.
Tables and listings of AEs related to the neurological assessment will be provided.
10.3
Analysis of Laboratory Data
Laboratory evaluations consisting of chemistry and hematology, and changes from 
baseline at each assessment timepoint will be summarized by treatment group and study 
period.  In addition, potentially clinically important (PCI) laboratory values will be 
summarized.
Each laboratory value will be summarized for all time points (starting with Baseline) with 
the number of non-missing observations, mean and standard deviation, median, minimum, 
and maximum.  Mean change from baseline to each applicable post-baseline visit will be 
summarized for each laboratory parameter, with the number of observations, baseline 
mean, and visit mean.  The change from baseline mean, standard error, and 95% 
confidence interval will be presented for the mean change from baseline within each 
treatment group.
Changes in laboratory values will be tabulated using shift tables categorized as low, 
normal, or high based on the normal ranges of the laboratory used for each sample
 
 
.
Laboratory values will be evaluated 
.  For 
each laboratory PCI criterion, the number and percentage of subjects who have a post-
baseline laboratory value meeting the criteria will be summarized.  
 
 


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.
Listings will be provided to summarize subject-level laboratory data for subjects meeting 
PCI criteria.
10.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, and
temperature, and changes from baseline at each assessment timepoint will be summarized
by treatment group and study period.  In addition, potentially clinically important vital 
signs values will be summarized.
Each vital sign variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum, and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for each vital sign parameter, with the number of observations, 
baseline mean, and visit mean.  The change from baseline descriptive statistics of mean, 
standard error, and 95% confidence interval will be presented for the mean change from 
baseline within each treatment group.
Vital sign variables will be evaluated based on PCI criteria 
  
 
 
 
 
 
 
 
 
 


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Listings will be provided to summarize subject-level vital sign data for subjects meeting 
PCI criteria.
10.5
Safety Subgroup Analyses
Not applicable. 
10.6
Other Safety Analyses
Electrocardiogram (ECG): Descriptive statistics for quantitative ECG parameters 
(i.e., heart rate, QRS duration, QTcB interval, QTcF interval, RR interval, and PR 
interval) at baseline, post-baseline, and changes from baseline values at each post-baseline 
timepoint will be presented.
ECG parameters are considered PCI if ECG values meet either the actual value or change 
from baseline PCI high criteria 
.  The number and 
percentage of subjects with PCI post-baseline values will be tabulated.  
 
 
A supportive listing of subjects with PCI post-baseline values will be provided.  
Immunogenicity Assessment: 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 post-baseline data.  Immunogenicity findings 
(positive) will be tabulated with the number and percentage of subjects at each visit 
separately for each treatment group.  Percentages will be based on the number of treated 
subjects with interpretable antibody assays in each treatment group at the specified visit.
 


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11.0
Other Analyses
Not applicable.
12.0
Interim Analyses
No interim analysis is planned for this study.
12.1
Data Monitoring Committee
No data monitoring committee (DMC) will be used for this study.
13.0
Overall Type-I Error Control
For the DB period, to control the family-wise Type I error rate at 0.05 for multiplicity 
across the primary and secondary analyses, a hierarchical testing strategy1 will be used.  
The hierarchical testing strategy starts with the primary 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: A Grade 0 or 1 (none or mild) and 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
1.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 
(overall satisfaction) for GL at Day 7
 


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2.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 
(overall satisfaction) for GL at Hour 24
3.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 4 
(natural look) for GL at Day 7
For the US FDA, the following secondary endpoints will be evaluated outside of the gated 
hierarchical testing sequence:
1.
Key Secondary: A Grade 0 or 1 (none or mild) and at least a 2-grade improvement 
from baseline in GL severity at maximum frown according to the investigator and 
subject assessments (i.e., concurrent composite) using the FWS over time (DB 
period)
2.
Key Secondary: A Grade 0 or 1 (none or mild) and at least a 2-grade improvement 
from baseline in GL severity at maximum frown according to the investigator 
assessment using the FWS over time (DB period)
3.
Key Secondary: A Grade 0 or 1 (none or mild) and at least a 2-grade improvement 
from baseline in GL severity at maximum frown according to the subject 
assessment using the FWS over time (DB 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
 


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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: At least 4-point improvement from baseline in FLO-11 Item 10 (look 
angry) for GL at Day 7
10.
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 (DB period)
2.
Secondary: Time to the first ≥ 1-grade improvement from baseline on the FWS 
according to investigator assessments of GL severity at maximum frown (DB 
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 (DB period)
 


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4.
Secondary: At least 2-grade improvement from baseline on the FWS according to 
investigator assessments of GL severity at maximum frown over time (DB period)
5.
Secondary: Time to return to baseline FWS criterion† according to subject 
assessments of FWS at maximum frown (DB period)
6.
Secondary: Time to return to baseline FWS criterion† according to investigator 
assessments of FWS at maximum frown (DB period)
7.
Secondary: Mostly satisfied or Very satisfied on the FLSQ follow-up version Item 5 
(overall satisfaction) over time 
8.
Secondary: Subject-reported global assessment of change in GL based on the 
GAC-GL over time 
 


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14.0
Version History
Table 3.
SAP Version History Summary
 






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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study treatment.
●
Subject took prohibited concomitant medication.
 


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