Clinical trial NCT04096326
Conditions: Glabellar Lines
Sponsor: Allergan
Start date: 2019-09-26; Completion date: 2020-09-09
Enrollment: 198 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of AGN-151586 over a range of doses for the treatment of moderate to severe glabellar lines (GL).

Detailed description:

Arms: arm 1: Participants received AGN-151586-matching placebo, intramuscular (IM) injections in the glabellar complex on Day 1 in Cohort 1. arm 2: Participants received AGN-151586 lowest dose, IM injections in the glabellar complex on Day 1. arm 3: Participants received AGN-151586-matching placebo, IM injections in the glabellar complex on Day 1 in Cohort 2. arm 4: Participants received AGN-151586, IM injections in the glabellar complex on Day 1. arm 5: Participants received AGN-151586-matching placebo, IM injections in the glabellar complex on Day 1 in Cohort 3. arm 6: Participants received AGN-151586, IM injections in the glabellar complex on Day 1. arm 7: Participants received AGN-151586-matching placebo, IM injections in the glabellar complex on Day 1 in Cohort 4. arm 8: Participants received AGN-151586, IM injections in the glabellar complex on Day 1. arm 9: Participants received AGN-151586-matching placebo, IM injections in the glabellar complex on Day 1 in Cohort 5. arm 10: Participants received AGN-151586 highest dose, IM injections in the glabellar complex on Day 1.
Interventions: intervention 1: AGN-151586 intervention 2: Placebo
Intervention descriptions: intervention 1: AGN-151586 solution for injection. intervention 2: Placebo solution for injection.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL
Protocol 2034-201-008 Amd 1
AGN-151586
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GRD-CLN-T-01-01 v2.0
Title Page
Protocol Title: A Phase 2b Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate 
the Safety and Efficacy of AGN-151586 in Participants With Moderate to Severe Glabellar Lines
Protocol Number: 2034-201-008
Amendment Number:  1
Product: AGN-151586 (Botulinum Neurotoxin Serotype E, BoNT/E) for injection
Brief Protocol Title: AGN-151586 Dose-Ranging Study for Treatment of Glabellar Lines
Development Phase: 2b
Sponsor Name: Allergan Sales LLC
Legal Registered Address:
Allergan Sales LLC
5 Giralda Farms
Madison, NJ 07940
USA
Regulatory Agency Identifying Number: IND Number 130880
Emergency Telephone Number
Refer to the study contacts page
SAE Reporting Fax Number/Email:
Business Unit 
/Legacy 
Organization
Email
Phone
Fax
Allergan
IR-Clinical-SAE@allergan.com
Not applicable
+1-714-796-9504 
Backup: 
+1-714-246-5295
Sponsor Signatory:
Vice President, Head of Clinical Development, Aesthetic Medicine
Refer to the final page of this protocol for electronic signature and date of approval.
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 1
June 2020
Original Protocol
July 2019
Amendment 1 (June 2020)
Overall Rationale for the Amendment:
The primary purpose of this protocol amendment is to update study processes related to the 
analysis of immunogenicity samples for optional exploratory research and improve clarity of 
study processes as summarized below.
Section No. and Name
Description of Change
Brief Rationale
Title Page
Updated sponsor signatory’s title
Update
8.2.5/Electrocardiograms
Added statement that exclusion alerts based 
on prespecified significant abnormal 
electrocardiogram findings are considered 
exclusionary for study eligibility (consistent 
with exclusion criteria in Section 5.2).
Improve clarity
8.8/Biomarkers and Other 
Assessments
Added statements that immunogenicity 
samples may be used for additional 
characterization of antibody response to 
other neurotoxin subtype(s) and described 
the informed consent process for this 
optional exploratory research.
Update
9.4.3.1/Immunogenicity 
Analyses
Added statement that additional 
immunogenicity exploratory analyses may 
be performed.
Update
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Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes Table .........................................................................2
Table of Contents...........................................................................................................................3
List of Tables ..................................................................................................................................5
List of Figures.................................................................................................................................6
1.
Protocol Summary ..........................................................................................................7
1.1.
Synopsis............................................................................................................................7
1.2.
Schema............................................................................................................................10
1.3.
Schedule of Activities (SoA)..........................................................................................11
2.
Introduction...................................................................................................................15
2.1.
Study Rationale...............................................................................................................15
2.2.
Background.....................................................................................................................15
2.3.
Benefit/Risk Assessment ................................................................................................17
3.
Objectives and Endpoints ............................................................................................19
4.
Study Design..................................................................................................................20
4.1.
Overall Design ................................................................................................................20
4.1.1.
Clinical Hypotheses ........................................................................................................21
4.2.
Scientific Rationale for Study Design ............................................................................21
4.3.
Justification for Dose......................................................................................................22
4.4.
End of Study Definition..................................................................................................24
5.
Study Population...........................................................................................................25
5.1.
Inclusion Criteria ............................................................................................................25
5.2.
Exclusion Criteria ...........................................................................................................27
5.3.
Lifestyle Considerations .................................................................................................29
5.4.
Screen Failures................................................................................................................29
6.
Study Intervention........................................................................................................30
6.1.
Study Interventions Administered ..................................................................................30
6.1.1.
Study Supplies ................................................................................................................30
6.1.2.
Instructions for Use and Administration.........................................................................32
6.2.
Preparation/Handling/Storage/Accountability................................................................32
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................33
6.4.
Study Intervention Compliance ......................................................................................34
6.5.
Concomitant Therapy .....................................................................................................34
6.5.1.
Prohibited Interventions..................................................................................................34
6.5.2.
Permitted Interventions...................................................................................................35
6.5.3.
Rescue Medicine.............................................................................................................35
6.6.
Dose Modification ..........................................................................................................35
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9.4.1.
Efficacy Analyses ...........................................................................................................50
9.4.2.
Safety Analyses...............................................................................................................51
9.4.3.
Other Analyses................................................................................................................52
9.5.
Interim Analyses.............................................................................................................53
10.
Supporting Documentation and Operational Considerations..................................54
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................55
10.1.1.
Regulatory and Ethical Considerations...........................................................................55
10.1.2.
Financial Disclosure........................................................................................................55
10.1.3.
Informed Consent Process ..............................................................................................55
10.1.4.
Data Protection................................................................................................................56
10.1.5.
Posting Clinical Study Data............................................................................................56
10.1.6.
Data Quality Assurance ..................................................................................................56
10.1.7.
Source Documents ..........................................................................................................57
10.1.8.
Study and Site Closure....................................................................................................57
10.1.9.
Publication Policy...........................................................................................................58
10.1.10. Compliance with Protocol...............................................................................................58
10.2.
Appendix 2: Clinical Laboratory Tests...........................................................................59
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................60
10.4.
Appendix 4: Abbreviations.............................................................................................65
10.5.
Appendix 5: Standard Discontinuation Criteria..............................................................67
10.6.
Appendix 6: Study Tabular Summary ............................................................................69
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information
...............................71
...............................75
...............................78
...............................78
...............................80
...............................85
...............................90
11.
References......................................................................................................................92
List of Tables
Table 4-1
AGN-151586 Completed Clinical Studies............................................................ 23
Table 10-1
Protocol-Required Safety Laboratory Assessmentsa ............................................ 59
Table 10-2
Highly Effective Contraceptive Methods ............................................................. 72
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List of Figures
Figure 6–1
(A) The Procerus and Corrugator (Glabellar Line Area) on 1 Side of the Face and 
(B) Locations of the 5 Glabellar Line Injections .................................................. 32
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 2b Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate 
the Safety and Efficacy of AGN-151586 in Participants With Moderate to Severe Glabellar Lines
Protocol Number: 2034-201-008
Amendment Number: 1 
Brief Title: AGN-151586 Dose-Ranging Study for Treatment of Glabellar Lines
Study Phase: 2b
Study Rationale:
The purpose of this Phase 2b study is to evaluate the safety and efficacy of AGN-151586 over a 
range of doses for the treatment of moderate to severe glabellar lines (GL).
Objectives and Endpoints:
Objectives
Endpoints
Primary

Efficacy: To compare the efficacy between placebo 
and a range of doses of AGN-151586 for the 
treatment of GL in participants with moderate to 
severe GL

Safety: To compare the safety between placebo and 
a range of doses of AGN-151586 for the treatment 
of GL in participants with moderate to severe GL

Achievement of a ≥ 2-grade improvement from 
baseline on the Facial Wrinkle Scale With 
Photonumeric Guide (FWS) according to 
investigator assessments of GL severity at 
maximum frown at any postintervention timepoint
through Day 7.

Incidence of adverse events; change from baseline 
in 
hematology/chemistry/urinalysis
laboratory, 
vital 
sign,
and 
electrocardiogram 
(ECG) 
parameters; and presence of antidrug antibodies
Overall Study Design:

This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation 
study to evaluate the safety and efficacy of a single study intervention cycle of 
AGN-151586 in participants with moderate to severe GL.  

Participants are adults 18 to 65 years old, with moderate to severe GL at maximum frown 
(as assessed by the investigator using the FWS).

Up to 5 doses of AGN-151586 will be evaluated and compared with placebo in a 
sequential cohort design, starting with the lowest dose.  

Each cohort will enroll a balanced distribution of participants with moderate or severe 
GL severity at maximum frown per investigator assessment (at least 40% and no more 
than 60% of either).
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
The primary efficacy measure is the investigator’s assessments of GL at maximum frown 
using the FWS.

Participants will undergo a Screening Visit up to 30 days before randomization on Day 1. 
All screening data must be available to the investigator prior to randomization on Day 1.

On Day 1, participants will be randomly assigned in a 3:1 ratio to receive AGN-151586 
or placebo. Enrollment stratification will be by baseline GL severity at maximum frown, 
assessed by the clinician (principal investigator or physician subinvestigator) using the
FWS. 

Study intervention on Day 1 will be administered as 5 injections in the glabellar complex 
(1 in the procerus and 2 in each corrugator).

Participants will remain in the clinic for the first 12 hours after administration of study 
intervention for serial assessments at Hours 4, 8 and 12. Thereafter, participants return to 
the clinic on Day 2 (Hour 24 and Hour 36), Day 3 (Hour 48 and Hour 60), Day 7, 
Day 14, Day 21, Day 28, Day 35, and Day 42.  

For each dose group, an internal data monitoring committee (DMC), independent from 
the study team, will review select safety and efficacy data from a subset of participants 
(n ≥16) with data through 14 days postintervention (in addition to cumulative data from 
the prior cohort[s]).

The DMC may recommend proceeding with the nominal dose for the next cohort, request 
additional data (eg, data from additional participants in the cohort, data from visits after 
Day 14), request to repeat the current dose or a lower dose, request an intermediate dose 
be evaluated (between the dose of the current cohort and the nominal dose for the next 
cohort), or request dose escalation be terminated.
Number of Participants:
Approximately 200 participants will be enrolled. Accounting for a dropout rate of 10%, it is 
anticipated that approximately 180 participants will complete the study. A total of up to 5 dose 
cohorts are planned with a randomization allocation of 3:1 for AGN-151586 (n = 30) and 
placebo (n = 10) for each cohort.
Number of Sites:
Approximately 10 US investigational sites
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Intervention Groups and Study Duration:
The total duration of study participation for each participant is up to approximately 72 days. 
Participants will attend the following visits:

Screening (up to 30 days before randomization)

Day 1
o
Hour 0 (randomization and administration of study intervention)
o
Hour 4
o
Hour 8
o
Hour 12

Follow-up visits:
o
Day 2, Hour 24
o
Day 2, Hour 36
o
Day 3, Hour 48
o
Day 3, Hour 60
o
Weekly (Days 7, 14, 21, 28, and 35)

Exit (Day 42) 
Data Monitoring Committee: Yes
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
Study Period
Screening 
(Days −30
to −1)
Randomization
and Study
Intervention 
(Day 1)a
Day 1b
Follow-up
End of 
Study
(Day 42 
or 
Early 
Exit)
Day 2
Day 3
Day 
7
Day 
14
Day 
21
Day 
28
Day 
35
Time after 
administration of 
study intervention
--
--
4 h
8 h
12 h
24 h
36 h
48 h
60 h
Visit windows
--
--
± 1 h
± 1 h
± 1 h
± 2 h
± 2 h
± 2 h
± 2 h
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 
day
± 1 day
Collection of blood 
samples for 
immunogenicity 
testing
X
X
X
X
Adverse events
X
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study intervention 
administration
X (0 h)
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ECG = electrocardiogram; 
; 
GL = glabellar lines; WOCBP = women of childbearing potential
a
All makeup must be removed and hair not obscuring the upper face prior to completing any assessment. All assessments must be completed before administration of study 
intervention at Hour 0.
b
Participants must remain at the investigational site on Day 1 (ie, from baseline procedures through Hour 12 assessment).
c
The investigator and participant must grade the severity of GL using the FWS at the same time, first at rest, then at maximum frown. The investigator and participant must not 
discuss their results with each other. 
d
A complete physical examination is to be done at the Screening Visit and EOS/Early Exit Visit. An abbreviated physical examination is to be done at other visits. The 
abbreviated physical examination is limited to an examination of general appearance, heart, lungs, and abdomen.
e
Vital sign measurements includes pulse rate, respiration rate, blood pressure, and body temperature. Participants are to be seated for at least 2 minutes before measurements 
are collected.
f
The neurologic assessment includes the Focused Symptom Questionnaire and Focused Neurologic Examination. 
g
Women of childbearing potential (WOCBP) must have a negative pregnancy test at the Screening Visit and on Day 1 prior to randomization. The investigator may ask the 
participant to perform a urine pregnancy test at any time, which must be conducted at the investigational site. At each visit, site personnel must discuss with WOCBP and 
males with partners who are WOCBP compliance with contraceptive use.
h
A 12-lead ECG will be taken with the participant in a semirecumbent position for ≥10 minutes before starting the tracing. 
i
Nonfasting
j
Participant must be observed for at least 30 minutes after study intervention for adverse events.
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2.
Introduction
2.1.
Study Rationale
The purpose of this Phase 2b study is to evaluate the safety and efficacy of AGN-151586 over a 
range of doses for the treatment of moderate to severe GL.
2.2.
Background
Botulinum Neurotoxin Serotype E
The bacterium clostridium botulinum produces several distinct serotypes of botulinum 
neurotoxins designated A through G (Barash 2014; Keller 2006). These neurotoxins are some of 
the most potent molecules in nature, and all have the capability to block skeletal muscle 
contraction by blocking presynaptic acetylcholine release at the neuromuscular nerve junction.
Even though they have similar modes of action, each serotype has distinct properties that 
differentiate them from each other. 
Botulinum Neurotoxin Serotype E has been shown to inhibit muscle contraction by preventing 
the acetylcholine release at the neuromuscular junction. This effect has been shown in animals as 
well as humans (Adler 2001; Eleopra 1998). Epidemiologic studies in humans who have 
contracted botulism caused by BoNT/E have shown classic signs of systemic disease 
characterized by flaccid paralysis with earlier onset than classic botulism with BoNT/A 
(McLaughlin 2004).
In the published literature, BoNT/E has a distinct profile with a faster onset and shorter duration 
of effect compared with BoNT/A. Nonclinical studies have shown BoNT/E to have faster 
translocation in neurons (Keller 2004) and faster inhibition on neuromuscular transmission
(Wang 2008), suggesting its potential effect of faster onset of action in comparison with 
BoNT/A. A clinical trial in humans showed that participants recovered faster from paralysis after 
BoNT/E was injected into extensor digitorum brevis muscles, suggesting its duration of 
conferring paralytic effect might be shorter than BoNT/A (Eleopra 1998). 
Indication
Glabellar lines are deep furrows or frown lines in the glabellar area of the face and result from 
the repetitive functional action of the underlying mimetic facial musculature during animation 
(Blitzer 1993). The development of facial lines (such as GL) is an age-related change of the face 
that occurs because of the repetitive muscle contractions that are associated with common facial 
expressions. Thus, these facial lines can be observed with contraction (dynamic rhytides) or in 
more severe cases in repose (static rhytides). Increasing severity in the appearance of facial lines 
has been associated with a patient’s perception of reduced attractiveness and a negative effect on 
self-esteem and sense of well-being (Koblenzer 1996). Furthermore, the appearance of these 
facial lines can lead to a miscommunication of an emotional state of anger, anxiety, disapproval, 
or sadness (Khan 2001), causing distress and affecting social interactions (Finn 2003).
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Evidence supports that unattractive or aging skin is indeed related to psychological and 
psychosocial impacts (Farage 2010). Psychological or psychosocial impacts can be characterized 
as changes in confidence, attractiveness, self-esteem, emotional burdensomeness, self-
perceptions of appearance or age, emotional distress, and state of bother. The evaluation of 
psychological or psychosocial impacts associated with aging facial skin should be assessed from 
patients’ perspectives since these impacts are dependent on their perceptions.
The popularity of BoNT/A cosmetic treatment of GL in adults is related to its proven efficacy for 
reducing moderate to severe facial lines (Beer 2006); well documented safety profile
(Brin 2009); and positive impact on psychological well-being and the resulting psychosocial 
benefits (Finn 2003).
When injected at therapeutic doses, it is expected that BoNT/E, like BoNT/A, produces partial 
chemical denervation of the muscle, resulting in localized reduction in muscle activity. Because 
GL result from muscular activity, the muscle relaxation leads to a temporary relief of facial lines. 
While it was previously thought that these facial lines were structural and permanent, the effects 
of these injections demonstrate the lines are part functional and may be associated with persistent 
increased muscle tone (Garcia 1996; Le Louarn 2007).
Based on published data for BoNT/E, in addition to preclinical and clinical experiences with 
AGN-151586, it is anticipated that at a clinically efficacious dose, AGN-151586 will exhibit a 
faster onset of improvement in GL severity compared with BoNT/A, with shorter duration of 
treatment effect.
AGN-151586
AGN-151586 (previously referred to as EB-001) is a BoNT/E and has been evaluated in clinical 
studies for various indications up to a total dose of 
U. These studies are briefly summarized 
below. For additional information and details, please refer to the IB.
The first-in-human study (EB001-GL201) determined that over a limited range of doses up to 
U, AGN-151586 was well tolerated when injected in the glabellar complex (procerus and 
bilateral corrugator muscles) and exhibited a trend of fast onset (within 24 hours) and a limited
duration of clinical effect (approximately 2 weeks) compared with the well characterized clinical 
profile of BoNT/A for the treatment of GL. 
In a Phase 2 exploratory study (EB001-SR201), a single dose of
U AGN-151586 was 
administered as 5 injections (divided equally) to the frontalis muscle during Mohs surgery in the 
forehead. The data suggested favorable safety and tolerability at the tested dose. During the 
wound healing and acute scar formation phase (up to Day 30), descriptive results of some of the 
exploratory analyses were consistent with the hypotheses that AGN-151586 may improve overall 
scar appearance, decrease itch and pain associated with the surgical wound, and improve the scar 
color and stiffness. However, it should be noted that only a single dose of AGN-151586 was 
evaluated, which may not have been sufficient to capture the optimal efficacy response for 
postsurgical scar reduction. 
The safety and efficacy of AGN-151586 injections in reducing postsurgical musculoskeletal pain 
in participants undergoing elective augmentation mammoplasty was evaluated in 
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Study EB001-MA201. Six doses of AGN-151586 (ranging from 
U) were 
evaluated. No dose response was observed, and there was no statistically significant difference in 
pain reduction between any dose group compared with placebo. This study showed favorable 
safety and tolerability.
The safety and efficacy of AGN-151586 in reducing musculoskeletal pain was also evaluated in 
Study EB001-ABD201 in participants undergoing elective abdominoplasty. This study evaluated
3 doses of AGN-151586 ranging from 
U. The study was terminated early as a 
result of a business decision. The available data suggested favorable safety and tolerability, but 
no efficacy conclusion could be drawn.
AGN-151586 has been evaluated in a series of pharmacology and nonclinical toxicology studies 
in mice, rats, and monkeys. In addition to faster onset and shorter duration of effect when 
compared with BoNT/A in these animal models, it is also less potent in terms of extent of muscle 
paralysis at peak efficacy. The magnitude of lower potency of BoNT/E compared with BoNT/A 
is varied, depending on the species and on the assays (Donald 2018). Higher doses may be 
needed to achieve demonstrable therapeutic responses.
For additional information, please refer to the IB.
2.3.
Benefit/Risk Assessment
Generally, the popularity of BoNT/A cosmetic treatment of GL in adults is related to its proven
efficacy for reducing moderate to severe facial lines (Beer 2006); well documented safety profile
(Brin 2009); and positive impact on psychological well-being and the resulting psychosocial 
benefits (Finn 2003). Compared with the general class of BoNT/A treatments, AGN-151586 may 
provide additional benefits. For one, it is provided as a ready-to-use liquid product and requires 
no reconstitution. Secondly, it offers the potential for faster onset of efficacy compared with the 
BoNT/A products.
Four controlled, Phase 2 clinical studies with AGN-151586 have been completed. In total, 103
participants have received a single study intervention cycle of AGN-151586 (highest exposure 
was 
U, and 41 participants have received placebo (identical to AGN-151586 but without 
toxin). Of those who received AGN-151586, headache (n = 2), vital capacity decreased (n = 2), 
pruritus/pruritus generalized (n = 2), and nausea (n = 1) were the only adverse events considered 
treatment-related by the investigator. These adverse events were mild to moderate in severity and 
resolved. The adverse event profile associated with AGN-151586 showed no unusual findings; 
no safety signal was identified.
The relevant anatomy and any alterations to the anatomy due to prior surgical procedures must 
be understood prior to administering AGN-151586, and care should be taken when injecting in 
or near vulnerable anatomic structures. Caution should also be exercised when AGN-151586 is 
used in the presence of inflammation at the proposed injection site(s) or when excessive 
weakness or atrophy is present in the target muscle. As is expected for any injection procedure, 
localized pain, inflammation, paresthesia, hypoesthesia, tenderness, swelling/edema, erythema, 
localized infection, bleeding, and/or bruising may be associated with the injection of 
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AGN-151586 or placebo. Needle-related pain and/or anxiety could result in vasovagal responses, 
including transient symptomatic hypotension and syncope.
In some cases, botulinum toxin effect may be observed beyond the site of local injection. The 
symptoms are consistent with the mechanism of action of botulinum toxin and may include 
asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, 
urinary retention, and breathing difficulties. These symptoms have been reported hours to weeks 
after injection. Swallowing and breathing difficulties can be life threatening, and there have been 
reports of death related to spread of toxin effects. The risk of symptoms is probably greatest in 
children treated for spasticity, but symptoms can also occur in adults treated for spasticity and 
other conditions, and particularly in those patients who have an underlying condition that would 
predispose them to these symptoms.
Reduced blinking has been reported after BoNT/A product injection to the orbicularis muscle, 
and can lead to corneal exposure, persistent epithelial defect, and corneal ulceration with 
perforation. For treatment of blepharospasm using a BoNT/A product, corneal perforation in an 
aphakic eye requiring corneal grafting has occurred because of this effect. Although these effects 
mentioned above have not been reported for BoNT/E, these may be anticipated because the 
mechanism of action of BoNT/E is similar to BoNT/A.
In addition to investigator and the sponsor’s MSP oversight, a DMC has been instituted to 
provide oversight in this study. The dose-escalation design of this study allows for careful review 
of select safety and efficacy data by the DMC to perform informed risk/benefit assessments prior 
to escalation to the next higher dose. The DMC may recommend proceeding with the nominal 
dose for the next cohort, request additional data, request to repeat the current dose or a lower 
dose, request an intermediate dose be evaluated (between the dose of the current cohort and the 
nominal dose for the next cohort), or request dose escalation be terminated.
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events of AGN-151586, and measures to control these risks can be found in the IB.
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3.
Objectives and Endpoints
Objectives
Endpoints
Primary

Efficacy: To compare the efficacy between placebo 
and a range of doses of AGN-151586 for the 
treatment of GL in participants with moderate to 
severe GL

Safety: To compare the safety between placebo and 
a range of doses of AGN-151586 for the treatment 
of GL in participants with moderate to severe GL

Achievement of a ≥ 2-grade improvement from 
baseline on the FWS according to investigator 
assessments of GL severity at maximum frown at 
any postintervention timepoint through Day 7.

Incidence of adverse events; change from baseline 
in hematology/chemistry/urinalysis laboratory, 
vital sign, and ECG parameters; and presence of
antidrug antibodies
Nonprimary assessments are specified in the SAP and COA SAP.
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4.
Study Design
4.1.
Overall Design

This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation 
study to evaluate the safety and efficacy of a single study intervention cycle of 
AGN-151586 in participants with moderate to severe GL.  

Participants are adults 18 to 65 years old, with moderate to severe GL at maximum frown 
(as assessed by the investigator using the FWS).

Up to 5 doses of AGN-151586 will be evaluated and compared with placebo in a 
sequential cohort design, starting with the lowest dose.

Each cohort will enroll a balanced distribution of participants with moderate or severe 
GL severity at maximum frown per investigator assessment (at least 40% and no more 
than 60% of either).

The primary efficacy measure is the investigator’s assessments of GL at maximum frown 
using the FWS.

Participants will undergo a Screening Visit up to 30 days before randomization on Day 1. 
All screening data must be available to the investigator prior to randomization on Day 1.

On Day 1, participants will be randomly assigned in a 3:1 ratio to receive AGN-151586 
or placebo. Enrollment stratification will be by baseline GL severity at maximum frown, 
assessed by the clinician (principal investigator or physician subinvestigator) using the
FWS.  

Study intervention on Day 1 will be administered as 5 injections in the glabellar complex 
(1 in the procerus and 2 in each corrugator).

Participants will attend the following visits:
o
Screening (up to 30 days before randomization)
o
Day 1

Hour 0 (randomization and administration of study intervention)

Hour 4

Hour 8

Hour 12
o
Follow-up visits:

Day 2, Hour 24

Day 2, Hour 36
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
Day 3, Hour 48

Day 3, Hour 60

Weekly (Days 7, 14, 21, 28, and 35)
o
Exit (Day 42)

Participants will remain in the clinic for the first 12 hours after administration of study 
intervention for serial assessments at Hours 4, 8 and 12. The total duration of study 
participation for each participant is up to approximately 72 days.
Data Monitoring Committee
An internal DMC, independent from the study team, has been instituted to provide oversight in 
this study. Starting with Cohort 1, the DMC will convene to review select safety and efficacy 
data after the first subset of participants in Cohort 1 have completed the Day 14 visit. Following 
this review, the DMC will determine whether the study will proceed to Cohort 2 of dose 
escalation. After Cohort 2 proceeds, a similar review process will occur to determine whether 
Cohort 3 will proceed. This pattern repeats prior to the start of each new cohort. At each DMC 
review, data through Day 14 from a subset of participants (n ≥16) for any given cohort will be 
reviewed. Additionally, cumulative data from participants from the prior cohort(s) will also be 
included in the DMC review.  
At each DMC review, the DMC may recommend proceeding with the nominal dose for the next 
cohort, request additional data (eg, data from additional participants in the cohort, data from 
visits after Day 14), request to repeat the current dose or a lower dose, request an intermediate 
dose be evaluated (between the dose of the current cohort and the nominal dose for the next 
cohort), or request dose escalation be terminated. 
The dose-escalation design of this study allows for careful review of select safety and efficacy 
data by the DMC to assess risk/benefit prior to escalation to the next higher dose. Details of the 
activities and composition of the DMC are further described in the DMC charter.
4.1.1.
Clinical Hypotheses
Efficacy: A single study intervention cycle of AGN-151586 within the dose range evaluated is 
more effective than placebo in the treatment of GL, measured by investigators’ assessments of 
GL severity at maximum frown using the FWS.
Safety: A single study intervention cycle of AGN-151586 has an acceptable safety profile at the 
doses evaluated. 
4.2.
Scientific Rationale for Study Design
AGN-151586 is a BoNT/E product being developed for IM injections in the treatment of GL. 
Currently, this indication is commonly treated with BoNT/A products. AGN-151586 may offer a 
different treatment option to patients with its potential for faster onset of treatment effect. This 
study is designed to evaluate the tolerability and efficacy profiles of AGN-151586 for the 
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5.
Study Population
Adult participants with GL of moderate to severe rating at maximum frown, as assessed using 
the FWS by the investigator and participant.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent.
2.
Type of Participant and Characteristics
2.01
Moderate to severe GL at maximum frown (as assessed by the investigator and 
participant) at Screening and on Day 1 prior to study intervention administration using 
the FWS
2.02
Participants must have sufficient visual acuity without the use of eyeglasses (contact 
lens use acceptable) to accurately assess their facial lines, in the opinion of the 
investigator.
3.
Sex
3.01
Male or female
4.
Contraceptives
4.01
Female participants willing to minimize the risk of inducing pregnancy for the duration 
of the clinical study and follow-up period (at least 10 weeks after study intervention)
4.02
A female participant is eligible to participate if she is 1) not a WOCBP*, or 2) a 
WOCBP who is not pregnant (ie, has a negative pregnancy test at the Screening Visit 
and prior to randomization; see Appendix 7), is not breastfeeding, is not planning a 
pregnancy during the study, and agrees to follow the contraceptive guidance in 
Appendix 7 during the study and for at least 4 weeks after study completion (at least 
10 weeks after administration of study intervention).
*A woman is considered NOT to be of childbearing potential if she is premenarchal, postmenopausal (at 
least 12 consecutive months of amenorrhea), or surgically sterilized (eg, hysterectomy or bilateral 
oophorectomy).
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4.03
Nonvasectomized male participants with female partners of childbearing potential are 
eligible to participate if they agree to ONE of the following during the study and for at 
least 6 weeks after administration of study intervention: 

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent

Agree to use a male condom with spermicide plus partner use of a contraceptive 
method with a failure rate of < 1% per year as described in Appendix 7 when having 
penile-vaginal intercourse with a woman of childbearing potential who is not 
currently pregnant
In addition, nonvasectomized male participants must refrain from donating sperm for the 
duration of the study and for at least 6 weeks after study intervention.
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree 
to remain abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration during the study and for at least 6 weeks after 
administration of study intervention.
5.
Informed Consent
5.01
Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and this protocol
5.02
Written informed consent from the participant has been obtained prior to any study-
related procedures 
5.03
Written documentation has been obtained in accordance with the relevant local privacy 
requirements, where applicable.
6.
Other
6.01
Participants in good health as determined by medical history, physical examination, 
neurological assessment, clinical laboratory evaluations, ECG, vital signs, and 
investigator’s judgment
6.02
Ability to follow study instructions, including completing study assessment tools 
without any assistance or alteration to the assessment tools and likely to complete all 
required visits
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5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Any condition that precludes a participant’s ability to comply with study requirements, 
including completion of the study visits or inability to read, understand, and/or self-
assess GL severity using the FWS
1.02
Known immunization or hypersensitivity to any botulinum neurotoxin serotype
1.03
Known allergy or sensitivity to any of the components of the study interventions or any 
materials used in the study procedures
1.04
Any medical condition that may put the participant at increased risk with exposure to 
AGN-151586, including diagnosed myasthenia gravis, Eaton-Lambert syndrome,
amyotrophic lateral sclerosis, or any other condition that might interfere with 
neuromuscular function
1.05
Any history of significant cardiovascular disease, family history of long QT syndrome, 
or a clinically significant ECG abnormality at the Screening Visit
1.06
Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick 
sebaceous skin, or the inability to substantially lessen facial lines even by physically 
spreading them apart, as determined by the investigator
1.07
Any brow or eyelid ptosis, as determined by the investigator
1.08
Infection or skin disorder at the injection sites
1.09
History of facial nerve palsy
1.10
Any uncontrolled systemic disease
1.11
Any medical condition that, in the opinion of the investigator, puts the participant at 
undue safety risk
1.12
History of alcohol or drug abuse within 3 months of randomization based on the 
investigator’s judgment
1.13
Anticipated need for treatment with botulinum neurotoxin of any serotype for any reason 
during the study (other than study intervention)
1.14
Anticipated need for surgery or overnight hospitalization during the study
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2.
Prior/Concomitant Therapy
2.01
Reported use of any botulinum neurotoxin of any serotype for aesthetic treatment within 
the last 6 months prior to screening and for therapeutic treatment within the last 12
months prior to screening.
2.02
Any of the following procedures or treatments occurring in the specified period before 
randomization (Day 1):
3 months: any facial nonablative resurfacing laser, light or ultrasound treatment, 
microdermabrasion, monopolar radiofrequency, or superficial peels
6 months: any facial cosmetic procedure with medium depth or deep depth 
chemical peels (eg, TCA and phenol); periorbital, mid-facial, or upper-facial skin 
resurfacing; or permanent make-up in the mid-facial (extending from inferior 
orbital margin to level of the nasal base) or upper facial areas
12 months: any periorbital, mid-facial, or upper-facial treatment with 
nonpermanent soft tissue fillers
2.03
Participants on topical retinoid therapy and/or topical hormone cream applied to the 
face, who have not been on a consistent dose regimen for at least 6 months before 
randomization and who are unable to maintain the same regimen for the study
2.04
Participants on oral retinoid therapy within 1 year before study enrollment
2.05
Prior periorbital surgery, facial lift (full face or mid-face), thread lift, brow lift, or related 
procedures (eg, eyelid [blepharoplasty] and/or eyebrow surgery)
2.06
Prior facial treatment with permanent soft tissue fillers, synthetic implantation (eg, Gore-
Tex®), and/or autologous fat transplantation
3.
Prior/Concurrent Clinical Study Experience
3.01
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of Screening
4.
Other
4.01
Participants who plan for an extended absence away from the immediate area of the 
study site that would preclude them from returning for all protocol-specified study visits
4.02
Participants who, in the investigator’s opinion, are unable or unwilling to maintain their 
standardized skin care regimen throughout the study period
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4.03
Participants who have tattoos, jewelry, or clothing which obscure the target area of 
interest and cannot be removed
4.04
Participants who are directly or indirectly involved in the conduct and administration of 
this study as a principal investigator, subinvestigator, study coordinator, or other study 
staff member; or employee of the sponsor, or a first-degree family member, significant 
other, or relative residing with one of the above persons involved directly or indirectly in 
the study
4.05
The participant has a condition or is in a situation which, in the investigator’s opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with participation in the study.
5.3.
Lifestyle Considerations
No restrictions are required.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes indicating screen failure as reason for 
ending the study, demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the eligibility criteria for participation in this study (screen failures) 
may be allowed to be rescreened. Rescreening of participants must only occur after discussion 
with the sponsor. Rescreened participants must be assigned new participant identification 
numbers. Rescreening can only occur once for any given potential participant.
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6.1.2.
Instructions for Use and Administration
Only a qualified physician trained in the study-specific injection technique may administer study 
intervention. 
Study intervention is administered as IM injections at 5 injection sites in the glabellar complex, 1 
in the procerus and 2 in each corrugator muscle (Figure 6-1A).
Participants must be observed for adverse events for at least 30 minutes after study intervention 
injection.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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6.4.
Study Intervention Compliance
Participants will receive all doses under the direct supervision of study center personnel. Study
intervention compliance will not be calculated because participants will receive all doses under 
the direct supervision of study center personnel.
The study site will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration.
6.5.
Concomitant Therapy
Concomitant therapy and/or medications considered necessary for the study participant’s welfare 
may be given at the discretion of the investigator.
The use of any medication during the study (including prescription or over-the-counter
medication, vitamins, and/or herbal supplements) is to be recorded on the participant’s eCRF at 
each visit along with the reason the medication is taken, dates of use, and dosing regimen.
Study site personnel must notify the sponsor immediately if a participant uses any concomitant 
medications not permitted by the protocol. Participants who admit to using prohibited 
concomitant medications may be discontinued from the study at the discretion of the investigator 
or sponsor.
6.5.1.
Prohibited Interventions
The decision to administer a prohibited medication/treatment is done with the safety of the 
participant as the primary consideration. When possible, the sponsor must be notified before the 
prohibited medication/treatment is administered. Co-administration of aminoglycosides or agents 
that could interfere with neuromuscular transmission (eg, curare-like agents) or muscle relaxants 
must be used with caution as the effects of the toxin, theoretically, could be potentiated.
No other facial cosmetic procedures or treatments are to be performed throughout the duration of 
the study. Prohibited treatments and procedures include, but are not limited to:

Oral retinoids

New or changes to regimen of topical hormone cream to the face

New or changes to regimen of topical retinoids to the face

Microdermabrasion to the face

Medium depth to deep facial chemical peels (ie, TCA and phenol)

Energy-based facial treatments (eg, intense pulsed light, Clear + Brilliant®, monopolar 
radiofrequency, microfocused ultrasound)

Facial lift (mid or full face)

Blepharoplasty

Synthetic implantation (eg, Gore-Tex) to the upper half of the face
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
Autologous fat transplantation to the face

Soft-tissue fillers to the face

Permanent make-up to the face

Concurrent treatment with botulinum neurotoxin of any serotype for any indication (other 
than the study intervention)
6.5.2.
Permitted Interventions
Any medication (including prescription or over-the-counter medication, vaccines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Indication

Dates of administration, including start and end dates

Dosage information including dose, frequency, and route of administration
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor.
The sponsor must be contacted if there are any questions regarding concomitant or prior therapy.
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the end of study visit will be recorded in the eCRF as a concomitant medication; 
any medication started after the End-of-Study Visit will not be considered a concomitant 
medication and should not be captured in the eCRF.
6.5.3.
Rescue Medicine
Not applicable.
6.6.
Dose Modification
Any deviation from the planned doses are only at the request of the DMC. After review of safety 
and efficacy data, the DMC may recommend proceeding with the nominal dose for the next 
cohort, request additional data (eg, data from additional participants in the cohort, data from 
visits after Day 14), request to repeat the current dose or a lower dose, request an intermediate
dose be evaluated (between the dose of the current cohort and the nominal dose for the next 
cohort), or request dose escalation be terminated.
6.7.
Intervention after the End of the Study
No interventions after the end of study are planned.
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7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the protocol-
defined study procedures.
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
case report form.
Definitions of the standard terms are provided in Appendix 5.
Reasons for discontinuation of the study intervention and/or from the study may include the 
following commonly used terms:
Commonly Used Terms
Adverse event
Completed
Lack of efficacy
Lost to follow-up
Other
Physician decision
Pregnancya
Protocol deviation
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by participant
a
Women who test positive for urine pregnancy test prior to randomization will NOT receive study intervention
and will be discontinued from the study.
7.1.
Discontinuation of Study Intervention
If a participant does not tolerate study injections, the participant will be observed until the
intolerability has either resolved or satisfactorily stabilized in the judgement of the investigator,
and the participant may choose to exit the study or to remain in the study for all safety follow-up
assessments through the End of Study Visit.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
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7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral,
compliance, or administrative reasons.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.

See the SoA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.

Women who test positive for urine pregnancy test prior to randomization will NOT 
receive study intervention and will be discontinued from the study.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts will be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

The maximum amount of blood collected from each participant over the duration of the 
study for clinical laboratory and immunogenicity tests, including any extra assessments 
that may be required, will not exceed 250 mL. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples.
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8.1.3.
Facial Photography
Standardized digital facial photography will be performed prior to injection of study intervention 
for all participants and at the times shown in the SoA (Section 1.3). Images will be taken of each 
participant’s face from the front at rest and at maximum frown. Each site will receive 
documented training and instructions on taking photographs. 
Conditions of photography will be standardized across all photographs, including camera 
equipment, exposure, background, lighting, and focal length. Ideally, the same photographer will 
take all required photographs. A qualified third-party vendor will provide instructions for taking
photographs and processing digital photographs. All digital images will be transferred to the 
sponsor at the end of the study. 
Photographs will be taken for research purposes, and may also be used for education,
commercial, and/or marketing purposes. To participate in this study, the participant must consent
to having photographs taken for research but may still participate if he/she declines use of the
photographs for other purposes. The sponsor shall have full ownership rights to any photographs
derived from the study.
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
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8.2.1.
Adverse Events
The investigator will question the participant to ascertain whether any adverse events were 
experienced since the previous visit. Additionally, the participants will be observed for at 
least 30 minutes following study intervention. All pertinent information regarding adverse events
(ie, date of onset and stop date, duration, outcome, seriousness, severity, relationship to study 
intervention, treatment required, action taken with study intervention, etc) will be obtained and 
recorded in the source documents and appropriate eCRF page.
8.2.2.
Physical Examinations
A full physical examination will be conducted at the Screening Visit and at the End-of-
Study/Early Exit Visit and includes the assessment of general appearance, HEENT, 
heart/cardiovascular function, lungs, abdomen, extremities, back, musculoskeletal function, 
lymphatic function, neurologic function, and skin. Abbreviated physical examinations will be 
conducted throughout the study as described in the SoA and limited to an examination of general 
appearance, heart, lungs, and abdomen.
Before study intervention, if the physical examination finding is clinically significant, the finding 
must be captured in the medical history eCRF. After study intervention, if the pre-existing 
finding becomes worse and is clinically significant or the new physical examination finding is 
clinically significant, it must be captured as an adverse event in the adverse event eCRF.
8.2.3.
Neurologic Assessment
The neurologic assessment comprises 2 elements, a Focused Symptoms Questionnaire and 
Focused Neurologic Examination that will be performed by trained physician investigators as 
described in the SOA. The neurologic assessment must be performed prior to randomization on 
Day 1, and is to be performed after adverse event assessment at all subsequent timepoints. See 
Appendix 8 for instructions for both elements.
Participants with any abnormal findings at Screening or Day 1 (prior to randomization), which 
meet exclusion criteria or may impact a participant’s safety or the interpretation of efficacy, will 
be excluded from the study. For participants who meet the inclusion/exclusion criteria, images of 
the face at natural smile and at rest will be captured at Day 1 (prior to randomization) in order to 
document baseline gross facial symmetry. These images will be referenced for the Focused 
Neurologic Examination.
8.2.4.
Vital Signs
Vital signs will be assessed as follows:

Pulse rate (beats per minute): Participants are to be seated for at least 2 minutes, and 
pulse rate will be counted over 60 seconds and recorded in the source document and 
eCRF as beats per minute.

Blood pressure (mm Hg): Participants are to be seated for at least 2 minutes, and 
systolic/diastolic blood pressure will be measured.
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Respiration rate (breaths per minute): Participants are to be seated for at least 2 minutes, 
and breaths will be counted for 30 seconds and multiplied by 2.

When applicable, vital sign data will be collected prior to blood draws.

Body temperature will be taken.
Before study intervention, if the vital sign finding is clinically significant, it must be captured in 
the medical history eCRF. After study intervention, if the pre-existing finding becomes worse 
and is clinically significant or the new vital sign finding is clinically significant, it must be 
captured as an adverse event in the adverse event eCRF.
8.2.5.
Electrocardiograms

All participants will undergo conventional 12-lead ECG using standardized equipment 
and electrode placement at the visits outlined in the SoA. Participants are to be in a 
semirecumbent position for at least 10 minutes prior to starting the tracing. During 
screening, a 12-lead ECG trace will be taken to assess entry eligibility.

A qualified third-party vendor will read the ECGs and report the findings as normal, 
abnormal, or unable to evaluate.

For screening ECGs, prespecified significant abnormal findings will be flagged as 
exclusion alerts, and a third-party vendor will generate an exclusion alert for the site and 
the sponsor. Exclusion alerts are considered exclusionary for study eligibility (see 
Exclusion Criterion 1.05 in Section 5.2 which excludes any participant with a ‘clinically 
significant ECG abnormality at the Screening Visit’). For all subsequent ECGs, a 
qualified third-party vendor will also report the appearance of any new, prespecified 
significant abnormal findings and generate a protocol alert for the site and the sponsor.

The cardiologists will be blinded to participant study intervention assignments. If the 
ECG finding is abnormal, they will specify the abnormality or give a diagnosis, whenever 
it is possible. Electrocardiogram reports will be provided to the investigator and the 
sponsor via a secure portal within 24 hours of screening and within 72 hours for all other 
visits.

Before study intervention, if the ECG finding is clinically significant, it must be captured
in the medical history eCRF. After study intervention, if the pre-existing finding becomes 
worse and is clinically significant or the new ECG finding is clinically significant, it must 
be captured as an adverse event in the adverse event eCRF. Hard copies of the ECG 
tracings will be kept in the study files at the investigator’s site.

The ECG will be assessed for the following: heart rate, QRS duration, QT interval, QTcB 
interval, QTcF interval, ST segment, RR interval, PR interval, and qualitative results.
8.2.6.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for 
the timing and frequency.
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
At screening, the investigator will assess the clinical significance of any values outside 
the reference ranges provided by the laboratory, and participants with abnormalities 
judged to be clinically significant will be excluded from the study.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.

All laboratory tests with values considered clinically significant during participation in 
the study, including the End-of-Study/Early Exit Visit, should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
investigator or MSP.
o
If such values do not return to normal/baseline within a period of time judged
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
o
If laboratory values from nonprotocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in participant management or 
are considered clinically significant by the investigator (eg, SAE or adverse event
or dose modification), then the results must be recorded in the eCRF.
8.2.7.
Urine Pregnancy Test
Urine dipstick kits will be used to conduct pregnancy tests at the timepoints specified in the SoA, 
or more frequently at the investigator’s discretion.
8.2.8.
Suicidal Risk Monitoring
Suicidal risk monitoring is not applicable for this study.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an adverse event or SAE can be found in Appendix 3.
Adverse events will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an adverse event or SAE and remain responsible for 
following up adverse events that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Section 7).
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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
All SAEs and adverse events from the signing of the ICF will be collected at the timepoints 
specified in the SoA (Section 1.3), and as observed or reported spontaneously by study 
participants.
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the adverse event section of the eCRF and will be 
considered pretreatment adverse events.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek adverse event or SAE information after 
conclusion of the study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.
The method of recording, evaluating, and assessing causality of adverse events and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events and/or SAEs. Open-ended 
and nonleading verbal questioning of the participant is the preferred method to inquire about 
adverse event occurrences.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial adverse event/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All adverse events/SAEs will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up 
(as defined in Section 7.3).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the adverse event or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed eCRF.
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The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.3.5.
Pregnancy

Details of all pregnancies, including pregnancy outcome, in female participants and 
consented female partners of male participants will be collected; pregnancies include 
those with onset after study intervention, and until 10 weeks after study intervention for 
female participants and until 6 weeks after study intervention for female partners of male 
participants.

At each visit, site personnel must discuss with WOCBP and males with partners who are 
WOCBP compliance with contraceptive use.

Urine pregnancy testing will be conducted for WOCBP at the Screening Visit, prior to 
randomization at Day 1, at the study exit visit, and at the discretion of the investigator. 
See Appendix 7 for detailed information on definition of WOCBP, use of contraceptives,
and pregnancy.

Women who test positive for urine pregnancy test prior to randomization will NOT 
receive treatment and will be discontinued from the study.

If a pregnancy is confirmed after the participant has received study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or remain in 
the study for all safety and efficacy follow-up assessments.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
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
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.

Abnormal pregnancy outcomes (eg, spontaneous or elective abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether 
leading to an elective abortion or not) are considered SAEs.
8.3.6.
Adverse Events of Special Interest
There are no AESIs for this study because they are not clinically indicated. 
8.3.7.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows:

Wrong study intervention

Wrong dose (including dosing regimen, strength, form, concentration, amount)

Wrong route of administration

Wrong participant (ie, not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study intervention.
Overdose: Unintentional administration of a quantity of the study intervention given per 
administration that is above the maximum recommended dose according to the protocol for the 
study intervention. See Section 8.4 for information of treatment of overdose.
Underdose: Unintentional administration of a quantity of the study intervention given per 
administration that is under the minimum recommended dose according to the protocol. 
8.4.
Treatment of Overdose
Overdose of AGN-151586 is a relative term and depends upon dose, site of injection, and 
underlying tissue properties. Signs and symptoms of overdose are likely not to be apparent 
immediately postinjection. Excessive doses may produce local, or distant, generalized and
profound neuromuscular paralysis.
Because AGN-151586 is administered as injections by physicians, for this study, the chance of 
overdose is extremely low. Should accidental injection occur or overdose be suspected, the 
participant should be medically monitored for up to several weeks for progressive signs or 
symptoms of systemic muscular weakness that could be local or distant from the site of injection, 
which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness, or respiratory 
failure. Eyelid ptosis, diplopia, or vision blurred are known local effects of BoNT/A during 
treatment of glabellar lines, which may also occur with BoNT/E. These participants should be 
considered for further medical evaluation and appropriate medical therapy immediately
instituted, which may include hospitalization.
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If the musculature of the oropharynx and esophagus is affected, aspiration may occur, which may 
lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or 
sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes 
place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical 
ventilation, in addition to other general supportive care.
In the event of an overdose, the investigator should:
1. Contact the MSP immediately.
2. Closely monitor the participant for any AE/SAE.
3. Document the quantity of the excess dose in the eCRF.
8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers and Other Assessments
Immunogenicity Assessments
Validated assays will be used to assess the presence of antidrug antibodies to AGN-151586, 
using blood samples collected during the course of the study.  
Blood samples for immunogenicity testing will be collected from each participant at Screening, 
and at the Day 7, Day 28, and End-of-Study visits. Collected samples (approximately 20 mL per 
sample) will be processed to yield serum for analysis.
Detection of binding antibodies against AGN-151586 in participants’ serum will be carried out
using the validated ELISA in a 3-tier format (screening, confirmation, and titering). Only 
samples that are confirmed positive in the confirmatory assay will be stored and analyzed for
presence of neutralizing antibodies to AGN-151586 when a validated assay becomes available.
These samples may also be used for additional characterization of antibody response to other 
neurotoxin subtype(s). The findings from this exploratory analysis will be documented in the 
clinical study report or in a separate report. The ICF will contain a separate appendix that 
addresses the use of immunogenicity samples for this optional exploratory research. The 
investigator or his/her representative will explain to each participant that their participation is 
voluntary. With regards to using their blood samples for this exploratory characterization of 
antibody response to other neurotoxin subtype(s), participants may give consent, refuse to give 
consent, or may give consent and later withdraw their consent at any time and for any reason 
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during the storage period. A separate signature will be required to document a participant's 
agreement or refusal to allow specimens to be used for this exploratory research. 
8.9.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.
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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The following hypotheses will be used to compare each dose group of AGN-151586 with
placebo:

Null hypothesis: AGN-151586 and placebo are equally effective in the probability of 
reducing GL severity at maximum frown as measured by a ≥2-grade improvement from
baseline based on the investigator-rated FWS at any posttreatment timepoint through Day 7.

Alternative hypothesis: AGN-151586 and placebo are not equally effective in the 
probability of reducing GL severity at maximum frown as measured by a ≥2-grade
improvement from baseline based on the investigator-rated FWS at any posttreatment 
timepoint through Day 7.
9.2.
Sample Size Determination
For each cohort, there will be approximately 40 participants (AGN-151586: n = 30; placebo: 
n = 10) with a 3:1 randomization allocation; up to 5 dose cohorts are planned. For a cohort of 30 
participants treated with AGN-151586, there is an approximately 60% chance of detecting an
adverse event which occurs at a 3% incidence (eg, eyelid ptosis).
Approximately 200 participants will be randomized to have approximately 180 participants 
complete the study based on an anticipated dropout rate of 10%. Approximately 150 participants
are expected to have a single dose exposure to AGN-151586 with an approximately 78% chance to
detect any adverse event at a 1% incidence, and a 95% chance to detect any adverse event at a 
2% incidence.
The primary efficacy analysis will be conducted on the mITT population, which consists of 
randomized participants who have been dosed and have a posttreatment measurement of 
investigator-rated FWS at maximum frown. A sample size of 40 participants per cohort will have 
approximately 87% power to detect a difference between an AGN-151586 dose group and the 
placebo group, assuming a 10% dropout rate and responder rates of 70% for the AGN-151586 
study intervention group and 10% for the placebo group.
The calculation is based on a 2-sided Chi-squared test (Fisher’s exact test) with a 0.05 
significance level using nQuery Advisor version 7.0. 
9.3.
Populations for Analyses
For the efficacy analyses, the mITT population will be used and include all randomized 
participants who received study intervention and who had a posttreatment investigator-rated 
FWS measurement at maximum frown. The safety analysis will be performed using the safety 
population that includes all participants who received study intervention. All analyses will be 
performed on an as-treated basis.
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9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and unblinding, and will describe 
the participant populations to be included in the analyses, along with procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and exploratory endpoints.
9.4.1.
Efficacy Analyses
9.4.1.1.
Primary Efficacy Endpoints
The efficacy endpoint is the achievement of a ≥ 2-grade improvement from baseline on the FWS 
according to investigator assessments of GL severity at maximum frown at any postintervention 
timepoint through Day 7.
9.4.1.2.
Primary Efficacy Analyses
The purpose of the primary analyses is to test for the primary endpoint, that is, the achievement 
of a ≥2-grade improvement in FWS according to investigator assessments of GL severity at 
maximum frown from Day 1 through Day 7 for each cohort. Safety will be assessed by the 
DMC.

The purpose of the primary analyses will be to test for the primary endpoint (ie, at least a
2-grade improvement response from investigator) during any timepoint after study
intervention administration through Day 7 for each AGN-151586 intervention dose group 
versus placebo group for each cohort. For example, if it is determined by the investigator-
rated FWS that participants have at least a 2-grade improvement at any postintervention 
assessment through Day 7, they will meet the responder definition for each assessment 
timepoint this applies.

The proportion of responders for the primary endpoint for each AGN-151586 study 
intervention group versus placebo will be analyzed using CMH tests stratified by baseline 
GL severity at maximum frown, using observed data without imputation or adjustment 
for multiplicity. In addition, 2-sided 95% CIs for the treatment differences in response 
rates will be provided. Between group comparisons will only be performed for each 
AGN-151586 group against the placebo group. Nominal p-values will be presented for 
each statistical test.

Observed data without imputation will be used with stratification based on baseline GL 
severity for the primary analysis described above. In addition, sensitivity analyses of the 
primary efficacy variable will be performed to establish consistency and robustness and
further characterize the extent of participants’ responses (eg, missing as 
nonresponder). In addition, placebo groups across cohorts can be pooled to compare with 
each AGN-151586 group as a supportive analysis.  Details will be provided in the SAP.
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Baseline and posttreatment values will be summarized using descriptive statistics for the AGN-
151586 dose groups and placebo group for each cohort at each assessment timepoint. Details will 
be provided in the SAP.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be defined in the SAP. 
The safety parameters will include:

Incidence of adverse events, including adverse event severity and causality as assessed by 
the investigator

Change from baseline and values over time in clinical laboratory tests, physical 
examinations, vital signs, and ECGs
9.4.2.1.
Adverse Events
An adverse event will be considered a TEAE if:

The adverse event began on or after the date and time of the study intervention; or

The adverse event was present before the date and time of the study intervention, but 
increased in severity or became serious on or after the date and time of the study 
intervention.
An adverse event that occurs after the End-of-Study Visit (Day 42) will not be counted as a 
TEAE.
An adverse event will be considered a TESAE if it is a TEAE that additionally meets any SAE 
criteria.
The number and percentage of participants reporting TEAEs in each study intervention group
will be tabulated by system organ class and preferred term and by system organ class, preferred
term, and severity.
The number and percentage of participants reporting treatment-related TEAEs in each study 
intervention group will be tabulated by system organ class and preferred term.
If more than 1 adverse event is coded to the same preferred term for the same participant, the 
participant will be counted only once for that preferred term using the most severe and most 
related occurrence for the summaries by severity and causality.
The causality and severity of all adverse events will be assessed by the investigator.
The number and percentage of participants reporting TEAEs that are included in the PDSOT 
term list will be tabulated by study intervention group. The PDSOT term list will be included in 
the SAP.
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Summary tables will be provided for participants with TESAEs and participants with TEAEs
leading to discontinuation if 5 or more participants reported such events. Listings of all adverse 
events, SAEs, and adverse events leading to discontinuation by participant will be presented.
The definitions of an adverse event and SAE can be found in Appendix 3.
9.4.2.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline (screening) and 
changes from baseline at each assessment will be presented by study intervention for each 
clinical laboratory assessment.
The criteria for PCS laboratory values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated by study 
intervention at each assessment. The percentages will be calculated relative to the number of 
participants who have available non-PCS baseline values and at least 1 postbaseline assessment. 
The numerator will be the total number of participants with at least 1 PCS postbaseline value. A 
supportive listing of participants with PCS postbaseline values will be provided for the safety 
population. 
9.4.2.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, respiration 
rate, body temperature) at baseline prior to receiving study intervention (or screening value just 
prior to baseline if baseline values are not available) and changes from baseline at each 
assessment will be presented by study intervention.
The criteria for PCS vital signs will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline vital signs will be tabulated by study intervention at 
each assessment. The percentages will be calculated relative to the number of participants who 
have available non-PCS baseline values and at least 1 postbaseline assessment. The numerator 
will be the total number of participants with at least 1 PCS postbaseline value. A supportive 
listing of participants with PCS postbaseline values will be provided for the safety population.
9.4.2.4.
Electrocardiograms
Electrocardiogram evaluations by investigators are captured in the eCRF and are classified into 3 
categories: normal, abnormal, or not evaluable. These data will be summarized by study 
intervention group as the number and percent of participants in each category at each visit. Data 
listings which include ECG basic parameters and any ECG abnormalities will be produced.
9.4.3.
Other Analyses
9.4.3.1.
Immunogenicity Analyses
Immunogenicity results, manifested as the presence of binding antibodies, and neutralizing 
antibodies if a validated assay becomes available, to AGN-151586, will be summarized in a table
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and reported for each sampling timepoint. Additional immunogenicity exploratory analyses may 
be performed; results will be summarized in the clinical study report or in a separate report.
9.5.
Interim Analyses
No interim analysis is planned.
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10.
Supporting Documentation and Operational Considerations
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10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
o
Applicable ICH/ISO Good Clinical Practice (GCP) guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. 
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
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC 
or study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 

Participants who are rescreened are not required to sign a new ICF if rescreening occurs 
within 30 days of first signing the ICF.
10.1.4.
Data Protection

Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 

The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5.
Posting Clinical Study Data

Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor. 

Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required.

Company-sponsored study information and tabular study results will be posted on the US 
National Institutes of Health’s website www.ClinicalTrials.gov and other publicly accessible 
sites.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
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responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.
10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate the
integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. 

Definition of what constitutes source data can be found in Section 4.0 of ICH E6, Good 
Clinical Practice: Consolidated Guidance and must follow ALCOA, ie, records must be 
attributable, legible, contemporaneous, original, and accurate.

All study photographs will be uploaded to a secure server via the internet. Secure digital 
cards will remain at the site and serve as the source documentation for subject photographs. 
10.1.8.
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.1.9.
Publication Policy

Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript
composition will reflect joint cooperation between multiple investigators and sites and
Allergan personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.

The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally support
publication of multicenter studies only in their entirety and not as individual site data.

Authorship will be determined by mutual agreement and in line with International Committee
of Medical Journal Editors authorship requirements.
10.1.10.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements.
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10-1 will be performed by the central laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 10-1
Protocol-Required Safety Laboratory Assessmentsa
Serum Chemistry
Hematology
Total bilirubin
Hemoglobin
AST (SGOT)
Hematocrit (PCV)
ALT (SGPT)
RBC count
GGT
MCV
LDH 
RDW
Alkaline phosphatase
MCH
Total protein
MCHC
Albumin
WBC count and differentialc
Calcium
- Neutrophil count
Creatinine
- Lymphocyte count
BUN
- Monocyte count
Sodium
- Basophil count
Potassium
- Eosinophil count
Bicarbonate
Platelet count
Chloride
Inorganic phosphate
Urinalysis
Uric acid 
Color
Glucose
Appearance
Magnesium
pH
Specific gravity
Other
Glucose
Urine pregnancyb
Protein
Ketone
Blood
Urine microscopyd
ALT = alanine aminotransferase (= serum glutamic pyruvic transaminase [SGPT]); AST = aspartate aminotransferase (= serum 
glutamic oxaloacetic transaminase [SGOT]); BUN = blood urea nitrogen; GGT = glutamyl- transferase; LDH = lactate 
dehydrogenase; MCH = mean cell hemoglobin; MCHC = mean cell hemoglobin concentration; MCV = mean (red) cell volume; 
PCV = packed cell volume; RBC = red blood cell; RDW = red (cell) distribution width; WBC = white blood cell (leukocyte)
a Laboratory samples for hematology, chemistry, and urinalysis testing will be collected under random conditions; participants do 
not need to be fasting.
b Urine pregnancy tests are performed only in females of childbearing potential and must be conducted at the investigational site.
c Differential count to be provided as absolute counts for neutrophils, lymphocytes, monocytes, basophils, and eosinophils (rather 
than as percentages of WBC)
d Crystals, casts, RBC, WBC, bacteria
Investigators must document their review of each laboratory safety report.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
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10.4.
Appendix 4: Abbreviations
AESI
adverse event of special interest
AUC
area under the curve
AUC12-96
area under the curve over the period of 12 to 96 hours post-surgery
AUC16-96
area under the curve over the period of 16 to 96 hours post-surgery
BoNT/A
Botulinum Neurotoxin Serotype A
BoNT/E
Botulinum Neurotoxin Serotype E
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
COA
clinical outcome assessment
CONSORT
Consolidated Standards of Reporting Trials
DAS
digital abduction score
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
ire
FWS
Facial Wrinkle Scale With Photonumeric Guide
FWS-IA
Facial Wrinkle Scale – Investigator Assessment
GCP
Good Clinical Practice
GL
glabellar lines
HEENT
head, eyes, ear, nose, and throat
IB
investigator’s brochure
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICF
informed consent form
IEC
independent ethics committee
IM
intramuscular
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IR-2
Investigator assessment of a 2-grade improvement (reduction) 
from baseline in GL severity
IRB
institutional review board
ISO
International Organization for Standardization
IWRS
interactive web response system
LCL
lateral canthal lines
mITT
modified intent-to-treat
MSP
medical safety physician
NOAEL
no-observed-adverse-effect level
PCS
potentially clinically significant
PDSOT
possible distant spread of toxin
SAE
serious adverse event
SAP
statistical analysis plan
SI
Le Système International d’Unités (International System of Units)
SoA
schedule of assessments
SUSAR
serious adverse reactions
TCA
trichloroacetic acid
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
USB
universal serial bus
VAS
Visual Analog Scale
WOCBP
woman of childbearing potential
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10.5.
Appendix 5: Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or 
clinical investigation participant administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this
treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal 
(investigational) product, whether or not related to 
the medicinal (investigational) product. For further 
information, see the ICH Guideline for Clinical 
Safety Data Management: Definitions and 
Standards for Expedited Reporting (modified from 
ICH E2A) Synonyms: side effect, adverse 
experience. See also serious adverse event, serious 
adverse experience. (CDISC glossary)
Completed
To possess every necessary or normal part or 
component or step; having come or been brought to 
a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Failure to meet randomization criteria
An indication that the participant has been unable 
to fulfill/satisfy the criteria required for assignment 
into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a 
therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a participant to 
follow-up
Non-compliance with study drug
An indication that a participant has not agreed with 
or followed the instructions related to the study 
medication (NCI)
Other
Different than the one(s) previously specified or 
mentioned (NCI)
Physician decision
A position, opinion or judgment reached after 
consideration by a physician with reference to 
participant (NCI)
Pregnancy
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI)
Progressive disease
A disease process that is increasing in extent or 
severity (NCI)
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CDISC Submission Value
CDISC Definition
Protocol deviation
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI)
Recovery
A healing process and/or an outcome implying 
relative health. The term is typically used in the 
context of direct and indirect effects of sickness or 
injury. (NCI)
Screen failure
The potential participant who does not meet one or 
more criteria required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a 
particular site by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by 
its sponsor (NCI)
Technical problems
A problem with some technical aspect of a clinical 
study, usually related to an instrument (NCI)
Withdrawal by parent/guardian
An indication that a study participant has been 
removed from the study by the parent or legal 
guardian
Withdrawal by participant
An indication that a study participant has removed 
itself from the study (NCI)
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10.6.
Appendix 6: Study Tabular Summary
Parameter Group
Parameter
Value
Trial information
Trial Title
A Phase 2b Double-Blind, Placebo-
Controlled, Dose-Ranging Study to 
Evaluate the Safety and Efficacy of 
AGN-151586 in Participants With 
Moderate to Severe Glabellar Lines
Clinical Study Sponsor
Allergan Sales LLC
Trial Phase Classification
Phase 2b
Trial Indication
Glabellar lines
Trial Indication Type
Treatment
Trial Type
Efficacy
Safety
Trial Length
72 days (from the Screening to Day 42
visits)
Planned Country of Investigational Sites
United States
Planned Number of Participants
200
FDA-Regulated Device Study
No
FDA-Regulated Drug Study
Yes
Pediatric Study
No
Participant
information
Diagnosis Group
Presence of GL of moderate to severe 
rating at maximum frown
Healthy Participant Indicator
No
Planned Minimum Age of Participants
18
Planned Maximum Age of Participants
65
Sex of Participants
Male or Female
Stable Disease Minimum Duration
Not applicable
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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to use one of
the nonestrogen hormonal highly 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.
Contraception Guidance:
Male Participants
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following during the study and for at least 6 weeks after 
administration of study intervention: 

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
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
Agree to use a male condom with spermicide plus partner use of a contraceptive method 
with a failure rate of < 1% per year as described in Table 10-2 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant
In addition, nonvasectomized male participants must refrain from donating sperm for the 
duration of the study and for at least 6 weeks after study intervention.
Nonvasectomized male participants with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the study and for at least 6 weeks after administration of study 
intervention.
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Pregnancy Testing:

Pregnancy testing will be performed according to instructions provided in the pregnancy 
test kit.

WOCBP should only be included after a confirmed menstrual period and a negative urine
pregnancy test at Day 1.

Additional pregnancy testing is not required during the study other than at the End-of-
Study/Early Exit Visit.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected at the discretion of the investigator.
Collection of Pregnancy Information:
Male Participants with Partners Who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the sponsor. Generally, the follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Female Participants Who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.
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
While pregnancy itself is not considered to be an adverse event or SAE, any pregnancy 
complication will be reported as an adverse event or SAE. A spontaneous or elective 
abortion is always considered to be an SAE and will be reported as such. Any poststudy 
pregnancy-related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting. 

Any female participants who becomes pregnant while participating in the study after 
receiving study intervention may choose to exit the study after appropriate safety follow-
up or remain in the study for all safety and efficacy follow-up assessments.
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11.
References
Adler M, Keller JE, Sheridan RE, Deshpande SS. Persistence of botulinum neurotoxin A 
demonstrated by sequential administration of serotypes A and E in rat EDL muscle. Toxicon. 
2001;39:233-243.
Barash J, Arnon S. A novel strain of clostridium botulinum that produces type B and type H 
botulinum toxins. J Infect Dis; 2014:209:183-191.
Beer K. 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;32:184-192.
Blitzer A, Brin MF, Keen MS, Aviv JE. Botulinum toxin for the treatment of hyperfunctional 
lines of the face. Arch Otolaryngol Head Neck Surg. 1993;119:1018-1022.
Brin M, Boodhoo T, Pogoda J, James L, Demos G, Terashima Y. 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;61:961-970.
Donald S, Elliott M, Gray B, Hornby F, Lewandowska A, Marlin S, et al. A comparison of 
biological activity of commercially available purified native botulinum neurotoxin serotypes A1 
to F1 in vitro, ex vivo, and in vivo. Pharmacol Res Perspect. 2018;e00446. 
http://doi.org/10.1002/prp2.446.
Eleopra R, Tugnoli V, Rossetto O, et al. Different time courses of recovery after poisoning with 
botulinum neurotoxin serotypes A and E in humans. Neuroscience Letters. 1998; 256:135-138.
Farage M, Miller K, Berardesca E, Maibach H. Psychological and social implications of aging 
skin: normal aging and the effects of cutaneous disease. Textbook of Aging Skin. Springer 
Verlag Berlin Heidelberg. 2010:949-957.
Finn C, Cox S, Earl M. Social implications of hyperfunctional facial lines. Dermatol Surg. 
2003;29:450-455. 
Garcia A, Fulton J. Cosmetic denervation of the muscles of facial expression with botulinum 
toxin: a dose-response study. Dermatol Surg. 1996;22:39-43.
Keller J, Cai F, Neale E. Uptake of botulinum neurotoxin into cultured neurons. Biochemistry. 
2004;42:526-532
Keller J. Recovery from botulinum neurotoxin poisoning in vivo. Neuroscience. 
2006;139:629-637.
Khan JA. Aesthetic surgery: diagnosing and healing the miscues of human facial expression. 
Ophthal Plastic Reconstr Surg. 2001;17:4-6.
Koblenzer CS. Psychologic aspects of aging and the skin. Clin Dermatol. 1996;14:171-177.
Approval Date: 05-Jun-2020 18:45:11 (GMT)
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Le Louarn C, Buthiau D, Buis J. Structural aging: the facial recurve concept. Aesth Plast Surg. 
2007;31:213-218.
McLaughlin JB. Botulism type E outbreak associated with eating a beached whale, Alaska. 
Emerg Infect Dis. 2004;10:1685-1687.
Wang J, Meng J, Lawrence G, Zurawski T, Sasse A, Bodeker M, et al. Novel chimeras of 
botulinum neurotoxins A and E unveil contributions from the binding, translocation, and 
protease domains to their functional characteristics. J Biol Chem. 2008;283:16993-17002
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SAP_001.pdf: 
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Statistical Analysis Plan Amendment 1
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STATISTICAL ANALYSIS PLAN
Protocol Title: A Phase 2b Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate 
the Safety and Efficacy of AGN-151586 in Participants With Moderate to Severe Glabellar Lines
Protocol Number: 2034-201-008
Compound Number: AGN-151586 (Botulinum Neurotoxin Serotype E, BoNT/E) for injection
Short Title: AGN-151586 Dose-Ranging Study for Treatment of Glabellar Lines
Sponsor Name: Allergan Sales LLC
Legal Registered Address: Allergan Sales LLC
5 Giralda Farms
Madison, NJ 07940
USA
Regulatory Agency Identifier Number(s) : IND Number 130880
Author:
Version 1.0: 
15 NOVEMBER 2019
Amendment 1:
13 OCTOBER 2020
 
 
 
NCT04096326


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Table of Contents
Table of Contents.............................................................................................................................2
List of Tables ...................................................................................................................................3
SAP Version History........................................................................................................................4
1.
Introduction.......................................................................................................................5
Objectives and Endpoints .................................................................................................6
Study Design...................................................................................................................10
2.
Statistical Hypotheses.....................................................................................................15
3.
Sample Size Determination ............................................................................................16
4.
Populations for Analysis.................................................................................................17
5.
Statistical Analyses.........................................................................................................18
General Considerations...................................................................................................18
Participant Disposition....................................................................................................19
Primary Effectiveness Endpoint Analysis ......................................................................19
5.3.1.
Definition of Endpoint....................................................................................................19
5.3.2.
Main Analytical Approach..............................................................................................20
5.3.3.
Sensitivity Analysis ........................................................................................................20
5.3.4.
Supplemental Approach..................................................................................................21
Secondary and Exploratory Effectiveness Endpoint Analyses.......................................21
5.4.1.
Secondary and Exploratory Effectiveness Endpoints.....................................................21
5.4.2.
Main Analytical Approach..............................................................................................25
Safety Analyses...............................................................................................................25
5.5.1.
Treatment Administration...............................................................................................25
5.5.2.
Adverse Events ...............................................................................................................25
5.5.3.
Clinical Laboratory Assessments....................................................................................28
5.5.4.
Vital Signs.......................................................................................................................29
5.5.5.
Electrocardiogram...........................................................................................................30
5.5.6.
Pregnancy Test Analyses ................................................................................................30
Other Analyses................................................................................................................30
5.6.1.
Immunogenicity Analyses ..............................................................................................30
Interim Analyses.............................................................................................................30
Data Monitoring Committee (DMC) Analyses ..............................................................30
6.
Supporting Documentation.............................................................................................32
Appendix 1 List of Abbreviations ..................................................................................33
Appendix 2: Changes to Protocol-Planned Analyses .....................................................34
Appendix 3: Supporting Study Information ...................................................................35
6.3.1.
Demographics .................................................................................................................35
6.3.2.
Baseline and Disease Characteristics..............................................................................35
6.3.3.
Protocol Deviations.........................................................................................................35
6.3.4.
Medical History ..............................................................................................................35
6.3.5.
Prior/Concomitant Medications......................................................................................35
6.3.6.
Criteria for Potentially Clinically Significant Laboratory Results .................................36
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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SAP Version History
This Statistical Analysis Plan (SAP) Amendment 1 for study 2034-201-008 is based on the 
Protocol Amendment 1 (dated 05 June 2020).
In addition to minor typographical corrections, other updates from the previous SAP version 1.0 
(dated 15 November 2019) include the following:

Section 1.1: Objectives and Endpoints table added based on objectives and endpoints stated 
in previous SAP.  Estimand framework table updated 
 
.

Section 5.1: SAS version and MedDRA version updated to current versions. Added 
information about COVID-19-related reasons for modified visits to be reported as a listing.

Section 5.3.2: Clarification provided for 95% confidence intervals that will be computed 
using the normal approximation (ie, Wald).  In addition, p-values will be based on the 
stratified CMH tests, but the rate differences are not based on stratification.

 
 

Section 5.5: Added that study period (prior to, during, after study intervention 
administration) will be presented for safety data listings.

Section 5.5.2: Added a breakdown for treatment-related AEs to consist of study drug-related
AEs and study procedure-related AEs.  In addition, PDSOTs will be summarized as part of 
the overall AE table. Removed from summary the TESAEs leading to study discontinuation. 
Neurologic assessments will be summarized using descriptive statistics, and a listing will 
be provided.  Treatment-emergent neurologic assessment-related AEs will also be presented 
by SOC and PT.

Section 5.6.1: Updated immunogenicity analysis planned summary and stated that the 
results would be summarized if ready by time of the immunogenicity database lock.

Sections 5.7 & 5.8: Stated that interim analyses are not applicable to the study, and the DMC 
analyses were moved to a separate section.

Section 6.2: Added that a change to the protocol-specified analyses would be the 
summarization of TEAEs, not just AEs, per the primary safety endpoint.
 
 
 


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1.
Introduction
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in study 
2034-201-008 Protocol Amendment 1 (Approved version dated 05 June 2020). Specifications of 
tables, figures, and data listings are contained in a separate document.
 
 
 






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Estimand Framework:
Objective
Clinical 
Category
Statistical 
Category
Estimand/Variable
Primary Objectives:

Efficacy: To compare the efficacy between placebo and a range of doses of AGN-151586 for the 
treatment of glabellar lines (GL) in participants with moderate to severe GL

Safety: To compare the safety between placebo and a range of doses of AGN-151586 for the treatment 
of GL in participants with moderate to severe GL
Effectiveness1
Primary

Variable: Achievement of a ≥ 2 grade improvement from baseline on 
the Facial Wrinkle Scale (FWS) With Photonumeric Guide according 
to investigator assessments of GL severity at maximum frown at any 
postintervention timepoint through Day 7

Population: The target population is the randomized population that 
has met the inclusion and exclusion criteria; the analysis population is 
the modified intention-to-treat (mITT) population (randomized 
participants who have received study intervention and have at least one
postintervention measurement of investigator-rated FWS at maximum 
frown)

IES: Participants with no valid assessments at any postintervention 
timepoint through Day 7 will be excluded from the analysis

PLS: Response rates between each dose group of AGN-151586 and 
placebo

Analysis: Cochran-Mantel-Haenzsel (CMH) test stratified by baseline 
GL severity at maximum frown (investigator assessment), using 
observed data without imputation or adjustment for multiplicity. 
Between group comparisons will only be performed for each cohort’s 
AGN-151586 group against the cohort’s placebo group. Nominal p-
values will be presented for each statistical test.  
Secondary

Variables: Achievement of a none or mild grade on the FWS 
according to investigator assessment of GL severity at maximum 
frown at any postintervention timepoint through Day 7

Population: The target population is the randomized population that 
has met the inclusion and exclusion criteria; the analysis population is 
the mITT population

IES: Participants with no valid assessments at any postintervention 
timepoint through Day 7 will be excluded from the analyses

PLS: Response rates between each cohort dose group of AGN-151586 
and placebo

Analysis: CMH test stratified by baseline GL severity at maximum 
frown using observed data without imputation or adjustment for 
multiplicity
 
 
 


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Objective
Clinical 
Category
Statistical 
Category
Estimand/Variable
 
 
 
 
Safety
Primary

Variable: Incidence of treatment-emergent adverse events (TEAEs); 
change from baseline in hematology/chemistry/urinalysis laboratory, 
vital signs, and electrocardiogram (ECG) parameters; and presence of 
antidrug antibodies

Population: Safety Population (participants who have received study 
intervention)

Analysis: Descriptive statistics
IES = Intercurrent event(s) strategy; PLS = Population-level summary.
1 All estimand attributes explicitly identified for primary/secondary and select key estimands only.  Other secondary and 
exploratory estimands are similar.
 
 
 


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Study Design

This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation study 
to evaluate the safety and efficacy of a single study intervention cycle of AGN-151586 in 
participants with moderate to severe GL.  

Participants are adults 18 to 65 years old, with moderate to severe GL at maximum frown 
(as assessed by the investigator and participant using the FWS).

Up to 5 doses of AGN-151586 will be evaluated and compared with placebo in a sequential 
cohort design, starting with the lowest dose.  

Each cohort will enroll a balanced distribution of participants with moderate or severe GL 
severity at maximum frown per investigator assessment (at least 40% and no more than 60% 
of either).

The primary efficacy measure is the investigator’s assessments of GL at maximum frown 
using the FWS.

Participants will undergo a Screening Visit up to 30 days before randomization on Day 1. 
All screening data must be available to the investigator prior to randomization on Day 1.

On Day 1, participants will be randomly assigned in a 3:1 ratio to receive AGN-151586 or 
placebo. Enrollment stratification will be by baseline GL severity at maximum frown, 
assessed by the clinician (principal investigator or physician subinvestigator) using the FWS.

Study intervention on Day 1 will be administered as 5 injections in the glabellar complex (1 
in the procerus and 2 in each corrugator).

Participants will remain in the clinic for the first 12 hours after administration of study 
intervention for serial assessments at Hours 4, 8 and 12. Thereafter, participants return to 
the clinic on Day 2 (Hour 24 and Hour 36), Day 3 (Hour 48 and Hour 60), Day 7, Day 14, 
Day 21, Day 28, Day 35, and Day 42.  

For each dose group, an internal data monitoring committee (DMC), independent from the 
study team, will review select safety and efficacy data from a subset of participants (n ≥16) 
with data through 14 days postintervention (in addition to cumulative data from the prior 
cohort[s]).

The DMC may recommend proceeding with the nominal dose for the next cohort, request 
additional data (eg, data from additional participants in the cohort, data from visits after 
Day 14), request to repeat the current dose or a lower dose, request an intermediate dose be 
evaluated (between the dose of the current cohort and the nominal dose for the next cohort), 
or request dose escalation be terminated.
 
 
 
 






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Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
Study Period
Screen
ing 
(Days 
−30 to 
−1)
Randomiz
ation and 
Study 
Interventi
on 
(Day 1)a
Day 1b
Follow-up
End 
of 
Study
(Day
42 or 
Early 
Exit)
Day 2
Day 3
Da
y 7
Da
y 
14
Da
y 
21
Da
y 
28
Da
y 
35
Time after 
administrati
on of study 
intervention
--
--
4 
h
8
h
12
h
24
h
36
h
48 
h
60 
h
Visit 
windows
--
--
± 1 
h
± 
1
h
± 
1 h
± 
2 h
± 
2 h
± 
2 h
± 
2 h
± 1 
da
y
± 1 
da
y
± 1 
da
y
± 1 
da
y
± 1 
da
y
± 1 
day
Vital sign 
measurement
se
X
X
X
X
X
X
X
X
X
X
X
Neurologic 
assessmentsf
X
X
X
X
X
X
X
X
X
X
X
Urine 
pregnancy 
test 
(WOCBP)g
X
X
X
12-lead ECGh
X
X
X
X
X
Collection of 
blood and 
urine samples 
for 
hematology, 
chemistry, 
and urinalysis 
laboratory 
testingi
X
X
X
X
Collection of 
blood 
samples for 
immunogenic
ity testing
X
X
X
X
Adverse 
events
X
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 




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2.
Statistical Hypotheses
The following hypotheses will be used to compare each dose group of AGN-151586 with placebo
within a cohort:

Null hypothesis: AGN-151586 and placebo are equally effective in the probability of reducing
GL severity at maximum frown as measured by a ≥2-grade improvement from baseline
based on the investigator-rated FWS at any postintervention timepoint through Day 7.

Alternative hypothesis: AGN-151586 and placebo are not equally effective in the probability 
of reducing GL severity at maximum frown as measured by a ≥2-grade improvement from
baseline based on the investigator-rated FWS at any postintervention timepoint through 
Day 7.
The null and alternative hypotheses are as follows:
H0: Pagn = Ppbo
Ha: Pagn ≠Ppbo
where Pagn and Ppbo are proportions of the participants with reduction in GL severity at maximum 
frown as measured by a ≥ 2-grade improvement from baseline based on the investigator-rated 
FWS at any postintervention timepoint through Day 7 for AGN-151586 group and placebo
group, respectively.
The CMH test with stratification of baseline investigator-rated GL severity at maximum frown 
will be used to test the above hypothesis.
 
 
 




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4.
Populations for Analysis
The analysis populations will consist of participants as defined below: 
Table 4–1
Analysis Populations
Population
Definition
Study Intervention
mITT Population
All randomized participants who receive study intervention and 
who have at least one postintervention investigator-rated FWS 
measurement at maximum frown
As treated 
Safety Population
All participants who receive study intervention
As treated
 
 
 


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5.
Statistical Analyses
General Considerations

The primary analyses will be performed after the database is locked and randomization 
schedule is released.

The effectiveness endpoints will be analyzed based on the mITT Population. Safety analyses 
will be performed using the Safety Population. The analyses will be based on the actual 
study intervention that the participants receive.

For each cohort, the effectiveness and safety endpoints will be analyzed/summarized by 
study intervention group, i.e., AGN-151586 group and placebo group, respectively. In 
addition, placebo groups across cohorts will be pooled to compare with each dose of AGN-
151586 group as a sensitivity analysis.

For applicable effectiveness and safety endpoints, baseline is defined as the last non-missing 
assessment prior to study intervention.

Descriptive statistics for continuous variables include the sample size (N), mean, standard 
deviation, median, 1st and 3rd quartiles, minimum, and maximum.Summary statistics for 
categorical variables include the sample size (N), frequency count, and percentage.

The primary analysis of the effectiveness endpoint, ie, the response rate of the participants 
with achievement of a ≥ 2 grade improvement from baseline on the FWS according to 
investigator assessments of GL severity at maximum frown at any postintervention 
timepoint through Day 7, will be analyzed using CMH tests stratified by baseline GL 
severity at maximum frown, to compare the between-group difference. The observed data 
without imputation will be used. Nominal p-values will be provided for each statistical 
testing. No multiplicity adjustment will be performed to control overall type I error.

Summary of TEAEs, medical history, and concomitant medication will be summarized by 
study intervention group for each cohort. Also, the AGN-151586 groups across cohorts and 
the placebo groups across cohorts will be pooled.

Partial dates will be treated as missing in computations, and will be listed in the data listings 
as they appear on the electronic case report form (eCRFs). No imputation of missing values 
will be performed, unless otherwise specified.

The level of significance used for statistical testing of the effectiveness endpoints will be 
0.05, 2-sided. 
 
 
 
 


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
The change from baseline values will be computed as the value for the postbaseline visit 
minus the baseline value.

All statistical analysis will be performed using SAS version 9.4 or higher.

Medical dictionary for regulatory activities (MedDRA) version 23.0 or higher will be used 
to code AEs and medical history.

World Health Organization (WHO) Drug Dictionary will be used to code medications.

Due to the COVID-19 pandemic, randomization into the study was curtailed for Cohort 3 
only (38 of 40 participants randomized into Cohort 3), and visit assessments were modified 
for Cohorts 3 & 4 only. For Cohort 5, participants were expected to complete the visits as 
per the protocol; hence, no modifications were made to the visits for Cohort 5. These 
changes will be reported as a listing for modified visits due to COVID-19-related reasons.
Participant Disposition
The number of participants in the study populations (mITT and Safety) will be summarized by 
study intervention group; the number of participants screened will be summarized overall.
Summary of study disposition will be provided by study intervention group for the following:

Number of randomized participants 

Number of participants who receive study intervention

Number of participants who discontinue the study

Reasons for discontinuation of the study
Primary Effectiveness Endpoint Analysis
5.3.1.
Definition of Endpoint
The assessments of the severity of GL at maximum frown using the validated FWS, is based on 
the following scale:

0 = None

1 = Mild

2 = Moderate

3 = Severe
 
 
 
 
 


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If a participant is determined to have at least a 2-grade improvement from baseline by the 
investigator-rated FWS at maximum frown at any postintervention assessment through Day 7, 
he/she will be considered as a responder. The primary effectiveness endpoint is the response rate
of the participants with achievement of a ≥ 2-grade improvement from baseline on the FWS 
according to investigator assessments of GL severity at maximum frown at any postintervention 
timepoint through Day 7.
5.3.2.
Main Analytical Approach
The proportion of responders for the primary endpoint will be analyzed based on mITT 
Population using CMH tests stratified by investigator assessment of baseline GL severity at 
maximum frown to compare each AGN-151586 study intervention group versus placebo for each 
cohort. In addition, placebo groups across cohorts will be pooled. Each AGN-151586 group will 
be compared against the pooled placebo groups as a sensitivity analysis. The observed data 
without imputation will be used.
The response rates of the participants with achievement of a ≥ 2-grade improvement from 
baseline on the FWS according to investigator assessments of GL severity at maximum frown at 
any postintervention timepoint through Day 7 will be calculated for each study intervention 
group. The corresponding 95% confidence intervals (CIs) using normal approximation (ie, Wald)
will be provided.
The proportion difference, the corresponding Wald 95% CIs and nominal p-values will be 
provided for the comparison of response rates in the primary endpoint between different study 
intervention groups.  P-values will be calculated based on the stratified CMH tests, but the rate 
differences are presented without stratification.
The p-values presented for each statistical test are deemed nominal. No multiplicity adjustment 
will be performed to control the overall Type I error.
5.3.3.
Sensitivity Analysis
Sensitivity analyses of the primary efficacy variable will be based on the non-responder 
imputation (NRI) method.  If a participant does not have the valid investigator-rated FWS 
assessment at maximum frown at any postintervention assessment through Day 7, he/she will be 
considered as a non-responder. CMH tests stratified by baseline investigator assessment of GL 
severity at maximum frown will be used for the analysis based on the imputed data.  In addition, 
the pooled placebo group will be compared to each AGN study intervention group for proportion 
differences for the primary analysis.
 
 
 


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5.3.4.
Supplemental Approach
Categorical descriptive statistics including the sample size (N), frequency count, and percentage 
for each response score and change from baseline will be provided by study intervention group 
and by visit. Change from baseline values will be computed as the value for the postbaseline visit 
minus the baseline value.
Secondary and Exploratory Effectiveness Endpoint Analyses
5.4.1.
Secondary and Exploratory Effectiveness Endpoints
Secondary effectiveness endpoints include:

Achievement of a ≥ 2-grade improvement from baseline on the FWS according to 
participant assessments of GL severity at maximum frown at any postintervention 
timepoint through Day 7

Achievement of a composite ≥2-grade improvement from baseline on the FWS at maximum 
frown as rated concurrently by the investigator and participant by timepoint

Achievement of a ≥2-grade improvement from baseline on the FWS at maximum frown as 
rated by the investigator by timepoint

Achievement of a ≥1-grade improvement from baseline on the FWS at maximum frown as 
rated by the investigator by timepoint

Achievement of a ≥2-grade improvement from baseline on the FWS at maximum frown as 
rated by the participant by timepoint

Achievement of a ≥1-grade improvement from baseline on the FWS at maximum frown as 
rated by the participant by timepoint

None or mild rating in FWS at maximum frown as rated by investigator by timepoint

None or mild rating in FWS at maximum frown as rated by participant by timepoint

Responders (defined by primary endpoint) achieving none or mild FWS at maximum frown 
as rated by the investigator by timepoint
 
 
 
 


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Exploratory effectiveness endpoints include:
 
 
 


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5.4.2.
Main Analytical Approach
The responder analyses will be analyzed in a similar way as for the primary effectiveness 
endpoint. The nominal p-values based on secondary effectiveness endpoints will be considered 
as supportive.
Descriptive statistics including the sample size (N), mean, standard deviation, median, 1st and 
3rd quartiles, minimum, and maximum will be summarized by study intervention group and 
timepoint using the mITT Population for the FLO-11 item scores and total score, FLSQ item 
scores and domain scores.
Safety Analyses
Safety endpoints will be summarized by AGN-151586 dose group and placebo group in each 
cohort, as well as by total cohort groups and pooled placebo group and pooled AGN group using 
the Safety Population.
Study period in which events are experienced will be presented for safety data listings:
1 = screening period (prior to study intervention administration)
2 = treatment period (at time of study intervention administration)
3 = safety follow-up period (post-intervention through the end of study) 
5.5.1.
Treatment Administration
The treatment administration-related variables including the total dose will summarized by study 
intervention group using descriptive statistics. 
Descriptive statistics will include the sample size (N), frequency count, and percentage for 
categorical endpoints, and sample size (N), mean, standard deviation, median, 1st and 3rd 
quartiles, minimum, and maximum for continuous endpoints.
5.5.2.
Adverse Events
An adverse event (AE) will be considered a treatment-emergent adverse event (TEAE) if:

The AE began on or after the date and time of the study intervention; or

The AE was present before the date and time of the study intervention, but increased in 
severity or became serious on or after the date and time of the study intervention.
A TEAE will be considered a treatment-emergent serious adverse event (TESAE) if it is a TEAE 
that is also a serious adverse event (SAE).
 
 
 
 


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A TEAE will be considered a treatment-related TEAE if it is considered related to the study 
intervention or study procedures by the principal investigator.
The number and percentage of participants with TEAEs as well as the events in the following AE 
categories will be summarized by study intervention group, as well as for all participants who 
received AGN-151586, as described in Table 5-1.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Listings of all TEAEs, TESAEs, TEAEs leading to study discontinuation by participant, and 
death will be presented.
Table 5-1
TEAE Tabular Summaries
Endpoint
Description
Methodology
Overall summary
Overall summary for the following categories:

TEAEs

Treatment-related TEAEs (including study drug-related 
TEAEs, study procedure-related TEAEs)

TESAEs

Treatment-related TESAEs

Possible distant spread of toxin (PDSOT) TEAEs

TEAEs leading to discontinuation from study

Deaths
Categorical descriptive
summary statistics
TEAEs

Overall summary and by system organ class (SOC) and 
preferred term (PT)

Overall summary and by SOC, PT, and maximum 
severity

Overall summary and by PT in descending order
Categorical descriptive
summary statistics 
Treatment-related 
TEAEs
Study drug-related 
TEAEs
Study procedure-
related TEAEs

Overall summary and by SOC and PT 

Overall summary and by SOC, PT, and maximum 
severity

Overall summary by maximum severity, duration, time 
to onset, resolution, and treatment required
Categorical descriptive
summary statistics,
event descriptives
TESAEs
Overall summary and by SOC and PT if 5 or more 
participants overall reported such events
Categorical descriptive
summary statistics 
TEAEs leading to
study discontinuation
Overall summary and by SOC and PT if 5 or more 
participants overall reported such events
Categorical descriptive
summary statistics 
In addition, neurologic assessments (Focused Symptoms Questionnaire and Focused Neurologic 
Examination) will be reported using descriptive statistics for baseline, follow-up visits, and for 
 
 
 


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the entire study period.  Listings will also be provided. Treatment-emergent neurologic 
assessment-related AEs will be identified based on the abnormal findings and reported by SOC 
and PT.
To assess possible distant spread of toxin (PDSOT), MedDRA preferred terms that may be 
associated with botulinum toxin effects have been identified. The number and percentage of 
participants reporting TEAEs that are included in the PDSOT term list will be tabulated. 
Summary tables will be provided for participants with TESAEs and participants with TEAEs 
leading to discontinuation if 5 or more participants reported such events. In addition, all PDSOT 
AEs will be listed by subject. The terms are listed below.
 
 
 


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5.5.3.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in International System of Units [SI] units) 
and changes from the baseline values at each assessment visit will be presented by study 
intervention group for the following laboratory parameters: 
Hematology: Absolute and differential white blood cell count (neutrophil count, lymphocyte 
count, monocyte count, basophil count, eosinophil count), hemoglobin, hematocrit, platelet 
count, red blood cell count, and red blood cell indices (mean corpuscular volume, mean 
 
 
 


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corpuscular hemoglobin, and mean corpuscular hemoglobin concentration, and distribution 
width).
Chemistry:
Sodium, potassium, calcium, chloride, bicarbonate, magnesium, inorganic 
phosphate, glucose, blood urea nitrogen, creatinine, total protein, alkaline phosphatase (ALP), 
albumin, total bilirubin (TBL), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total cholesterol, glutamyl- transferase (GGT), lactate dehydrogenase (LDH), Uric acid 
Urinalysis:
Appearance, color, pH, specific gravity, glucose, protein, ketone, blood, urine 
microscopy
Clinical laboratory test values will be considered potentially clinically significant (PCS) if they 
meet either the lower-limit or higher-limit PCS criteria listed in Table 6-3. The number and 
percentage of participants who have PCS postbaseline clinical laboratory values will be tabulated 
by study intervention group. The percentages will be calculated relative to the number of 
participants with available non-PCS baseline values and at least 1 postbaseline assessment. The 
numerator will be the total number of participants with available non-PCS baseline values and at 
least 1 PCS postbaseline value. A supportive tabular display of participants with PCS 
postbaseline values will be provided, including the PID number, baseline and all postbaseline 
(including non-PCS) values. In this listing, any participant with PCS value (if any) will also be 
included.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline clinical laboratory values will be provided.
5.5.4.
Vital Signs 
Descriptive statistics for vital signs (ie, temperature, respiratory rate, pulse rate, systolic and 
diastolic blood pressure) and changes from baseline values at each assessment visit will be 
presented by study intervention group. 
Vital sign values will be considered as PCS if they meet both the observed-value criteria and the 
change-from-baseline criteria listed in Table 6-4. The number and percentage of participants with 
PCS postbaseline values will be tabulated by study intervention group. The percentages will be 
calculated relative to the number of participants with available non-PCS baseline values and at 
least 1 postbaseline assessment. The numerator will be the total number of participants with 
available non-PCS baseline values and at least 1 PCS postbaseline value. A supportive tabular 
display of participants with PCS postbaseline values will be provided, including the PID number, 
baseline and all postbaseline (including non-PCS) values.
 
 
 


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In addition, a listing showing all AEs that occurred in participants who had PCS postbaseline 
vital sign values will be provided.
5.5.5.
Electrocardiogram 
Electrocardiogram (ECG) evaluations by investigators are captured in the eCRF and are 
classified into 3 categories: normal, abnormal, or not evaluable. These data will be summarized 
by study intervention group as change from baseline for each parameter, as well as the number 
and percent of participants in each category for PCS. Data listings which include ECG basic 
parameters and any ECG abnormalities will be produced.
5.5.6.
Pregnancy Test Analyses
Urine pregnancy tests will be performed at the study center at screening, randomization/study 
intervention, and End of Study (Day 42 or Early Exit). Participants with a positive result will be 
presented in a listing for the Safety Population.
Other Analyses
5.6.1.
Immunogenicity Analyses
Immunogenicity results, manifested as the presence of binding antibodies (positive), and 
neutralizing antibodies (positive) after a validated assay becomes available, to AGN-151586, will 
be summarized in a table for baseline and postbaseline, if available by immunogenicity database 
lock. Immunogenicity findings (positive) will be tabulated with the number and percentage of 
participants at each visit separately for each AGN-151586 treatment group. Percentages will be 
based on the number of treated participants with interpretable antibody assays in each treatment 
group at the specified visit.
Interim Analyses
Not applicable.
Data Monitoring Committee (DMC) Analyses
An internal DMC, independent from the study team, has been instituted to provide oversight in 
this study. Starting with Cohort 1, the DMC will convene to review select safety and efficacy 
data after the first subset of participants in Cohort 1 have completed the Day 14 visit. Following 
this review, the DMC will determine whether the study will proceed to Cohort 2 of dose 
escalation. After Cohort 2 proceeds, a similar review process will occur to determine whether 
Cohort 3 will proceed. This pattern repeats prior to the start of each new cohort. At each DMC 
review, data through Day 14 from a subset of participants (n ≥16) for any given cohort will be 
 
 
 
 
 
 


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reviewed. Additionally, cumulative data from participants from the prior cohort(s) will also be 
included in the DMC review.
At each DMC review, the DMC may recommend proceeding with the nominal dose for the next 
cohort, request additional data (eg, data from additional participants in the cohort, data from 
visits after Day 14), request to repeat the current dose or a lower dose, request an intermediate 
dose be evaluated (between the dose of the current cohort and the nominal dose for the next 
cohort), or request dose escalation be terminated.
The dose-escalation design of this study allows for careful review of select safety and efficacy 
data by the DMC to perform risk/benefit analyses prior to escalation to the next higher dose. 
Details of the activities and composition of the DMC are further described in the DMC charter.
 
 
 


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6.
Supporting Documentation
 
 
 


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Appendix 1 List of Abbreviations
AE
adverse event 
ATC
Anatomical Therapeutic Chemical
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
FWS
Facial Wrinkle Scale With Photonumeric Guide
IES
Intercurrent event(s) strategy
MedDRA
medical dictionary for regulatory activities
mITT
modified intention-to-treat 
PCS
potentially clinically significant
PDSOT
possible distant spread of toxin
PLS
Population-level summary
SAE
serious adverse event
SAP
statistical analysis plan
SI
L Système International d’Unités (International System of Units)
SOC
system organ class
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
WHO
World Health Organization
 
 
 
 


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Appendix 2: Changes to Protocol-Planned Analyses
There is one change to the protocol-planned analyses.  For the primary safety endpoints, TEAEs 
will be summarized, not AEs.
 
 
 
 


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Appendix 3: Supporting Study Information
6.3.1.
Demographics
Demographic parameters (age [years]; sex; race; ethnicity) will be summarized descriptively by 
study intervention group for the mITT and Safety Populations. Age (years) will be calculated 
relative to informed consent date.
6.3.2.
Baseline and Disease Characteristics
Baseline characteristics including weight, height, body mass index, and disease characteristics 
including baseline investigators’ and participants’ assessments of the severity of GL at maximum 
frown and at rest using the validated FWS, baseline FLO-11 and FLSQ scores will be 
summarized descriptively by study intervention group for the mITT Population.
6.3.3.
Protocol Deviations
Protocol deviations will be defined in a separate document. Unique participants reporting 
significant protocol deviations will be summarized in total and by treatment group for the mITT 
Population as described in Table 6-1.
Listing of significant protocol deviations will be provided.
Table 6-1
Protocol Deviation Summary
Endpoint
Description
Methodology
Significant protocol 
deviations
Number (%) of participants with significant protocol deviation 
will be summarized.
Categorical 
descriptive
summary statistics
6.3.4.
Medical History
Abnormalities in participants’ medical, surgical, cosmetic and dental history, encompassing 
abnormalities, surgeries, and procedures reported as occurring before the Screening Visit, will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or newer. 
The number and percentage of participants with abnormalities in medical and surgical histories 
in each system organ class and preferred term will be summarized by study intervention group 
for the mITT Population.
Listings will be provided for the mITT population.
6.3.5.
Prior/Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary, version March 2017 or newer. 
Unique participants who reported medications (Anatomical Therapeutic Chemical [ATC] 4 class 
 
 
 
 
I ==
 
===
,==  


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and PT) will be summarized by study intervention group and by study period using the mITT
Population as described in Table 6-2.
Table 6-2
Prior and Concomitant Medications 
Endpoint
Description
Methodology
Prior medications
Medications taken before the date and time of 
study intervention
Categorical descriptive
summary statistics
Concomitant medications 
Medications on or after the date and time of 
study intervention to End-of-Study Visit 
(Day 42)
Categorical descriptive
summary statistics
6.3.6.
Criteria for Potentially Clinically Significant Laboratory Results
Criteria for potentially clinically significant laboratory results are listing in Table 6-3.
 
 
 


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Table 6-3
Criteria for Potentially Clinically Significant Laboratory Results
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.9 × LLN
> 1.1 × ULN
Alanine aminotransferase 
(ALT)
U/L
—
≥ 3 × ULN
Alkaline phosphatase
U/L
—
≥ 3 × ULN
Aspartate aminotransferase 
(AST)
U/L
—
≥ 3 × ULN
Bilirubin, total
μmol/L
—
> 1.5 × ULN
Calcium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Chloride
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Cholesterol, Total
mmol/L
—
> 1.6× ULN
Creatinine
μmol/L
—
> 1.3 × ULN
Glucose, fasting, serum
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Glucose, random, serum
mmol/L
< 0.8 × LLN
> 1.4 × ULN
Potassium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Protein, total 
g/L
< 0.9 × LLN
> 1.1 × ULN
Sodium
mmol/L
< 0.9 × LLN
> 1.1 × ULN
Urea Nitrogen (BUN)
mmol/L
—
> 1.2 × ULN
HEMATOLOGY
Basophils, absolute cell count 109/L
—
> 3 × ULN
Neutrophils, absolute cell 
count
109/L
< 0.8 × LLN
> 1.5 × ULN
Hematocrit
Ratio 
< 0.9 × LLN
> 1.1 × ULN
Hemoglobin
g/L
< 0.9 × LLN
> 1.1 × ULN
Platelet count
109/L
< 0.5 × LLN
> 1.5 × ULN
Red blood cell count
1012/L
< 0.9 × LLN
> 1.1 × ULN
White blood cell count
109/L
< 0.7 × LLN
> 1.5 × ULN
URINALYSIS
pH
—
< 0.9 × LLN
> 1.1 × ULN
Specific gravity
—
—
> 1.1 × ULN
LLN = lower limit of normal value provided by the laboratory; SI = Le Système International d’Unités (International System of 
Units); ULN = upper limit of normal value provided by the laboratory.
6.3.7.
Criteria for Potentially Clinically Significant Vital Sign Results
Criteria for potentially clinically significant vital sign results are listed in Table 6-4.
 
 
 
 
 
 


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Table 6-4
Criteria for Potentially Clinically Significant Vital Sign Results
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Sitting systolic 
blood pressure, 
mm Hg
High
≥ 160
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Sitting diastolic 
blood pressure, 
mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, 
bpm
High
≥ 110
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
a
A postbaseline value is considered potentially clinically significant if it meets both the observed-value 
and the change-from-baseline criteria.
bpm = beats per minute.
Data Handling Convention
 
 
 
 


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6.4.2.1.
Missing/Incomplete AE Start Date
Imputation of dates with missing day and/or month is only applied to TEAEs. If adequate 
information is available, no imputation is needed. TEAE start dates with missing day or month 
will be imputed as following:

If day and month are missing but year is the same as year of study intervention, then the 
imputed day and month will be the date of study intervention. 

If day is missing but the month and year are available, then the imputed day will be the first 
day of the month, or the date of study intervention, if they have the same month and year, 
whichever is later.
6.4.2.2.
Missing/Incomplete AE/Medication End Date
Imputation of dates with missing day and/or month is only applied to TEAEs when AE duration 
is calculated. If adequate information is available, no imputation is needed. TEAE end dates 
with missing day or month will be imputed as following:

If day and month are missing but year is available, then the imputed day and month will be 
31 Dec or the study exit date if they have the same year, whichever is earlier 
If day is missing but the month and year are available, then the imputed day will be the last day 
of the month or the study exit date if they have the same month and year, whichever is earlier.
 
 
 


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7.
References
N/A