A Phase 2a, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA (DAXI) for Injection for the Treatment of Dynamic Forehead Lines (Frontalis) Following Glabellar Line Injections
Phase: PHASE2
Conditions: Frown Lines
Sponsor: Revance Therapeutics, Inc.

 
 
CLINICAL STUDY PROTOCOL 
Protocol Title:  
A Phase 2a, Multicenter, Open-Label, Dose-Escalation Study to Evaluate 
the Efficacy and Safety of DaxibotulinumtoxinA (DAXI) for Injection for 
the Treatment of Dynamic Forehead Lines (Frontalis) Following Glabellar 
Line Injections 
Protocol Number:  1820202 
Document Type:  
Amended Protocol 
Study Phase:   
Phase 2a 
Short Title:  
Efficacy and Safety of DaxibotulinumtoxinA (DAXI) for Injection for 
Treatment of Forehead Lines (Frontalis) 
Sponsor:  
 
Revance Therapeutics, Inc. 
7555 Gateway Boulevard 
       
Newark, CA 94560 
Version:  
 
Amendment 2;   04 March 2019 
 
This study will be conducted in compliance with the obligations detailed in this protocol and all 
applicable regulations and guidelines (e.g., International Conference on Harmonisation [ICH] 
and Good Clinical Practices [GCP]). 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is provided to you in 
confidence as an investigator, potential investigator, vendor, contractor, or consultant for review 
by you, your staff, and an applicable Institutional Review Board or Independent Ethics 
Committee.  The information is only to be used by you in connection with authorized clinical 
studies of the investigational product(s) described in the protocol.  You will not disclose any of 
the information to others without written authorization, except to the extent necessary to obtain 
informed consent from those persons to whom the investigational product(s) may be 
administered. 
 

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INVESTIGATOR’S AGREEMENT  
I have carefully read the protocol entitled: “A Phase 2a, Multicenter, Open-Label, Dose-
Escalation Study to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA (DAXI) for 
Injection for the Treatment of Dynamic Forehead Lines (Frontalis) Following Glabellar Line 
Injections” and,  
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the trial personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational drug and 
the trial protocol. 
I agree to conduct this clinical trial according to the attached protocol, in compliance with all 
applicable laws and regulations, and in accordance with the ethical principles stipulated in the 
Declaration of Helsinki.  
 
 
Investigator Signature 
 
Date 
 
 
 
 
Printed Name 
 
Institution Name 
 
 
Address 
 
 
City, State, Postal Code, Country 
 
Phone Number 
 
 
 
 

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Table of Contents 
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................21 
1.3. 
Schedule of Assessments (SOA) ....................................................................................22 
2. 
Introduction ...................................................................................................................24 
 
 
 
 
3. 
Objectives and Endpoints ............................................................................................27 
4. 
Study Design ..................................................................................................................32 
4.1. 
Overall Design ................................................................................................................32 
4.1.1. 
FHL Treatment................................................................................................................33 
 
 
 
 
4.4. 
Visit Schedule .................................................................................................................34 
5. 
Study Population ...........................................................................................................36 
5.1. 
Inclusion Criteria ............................................................................................................36 
5.2. 
Exclusion Criteria ...........................................................................................................36 
5.3. 
Informed Consent and Authorization to Release Health 
Information .....................................................................................................................39 
5.4. 
Lifestyle Considerations .................................................................................................39 
5.5. 
Protocol Deviations.........................................................................................................40 
5.6. 
Pregnancy........................................................................................................................40 
6. 
Study Intervention ........................................................................................................42 
6.1. 
Study Intervention(s) Administered................................................................................42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3. 
Concomitant Medications/Therapies ..............................................................................45 
 
 
6.5. 
Dose Modification ..........................................................................................................47 
7. 
Discontinuation of Study Intervention and Subject 
Discontinuation/Withdrawal........................................................................................48 
7.1. 
Subject Discontinuation/Withdrawal from the Study .....................................................48 
7.2. 
Lost to Follow-up............................................................................................................48 
8. 
Study Assessments and Procedures.............................................................................49 
8.1. 
Subject Entry Procedures ................................................................................................49 
8.2. 
Schedule of Visits and Procedures..................................................................................49 
8.2.1. 
Screening Visit ................................................................................................................49 

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8.2.2. 
Treatment Visits (Day 1 and Week 2) ............................................................................50 
8.2.3. 
Week 1 and 3 Follow-Up Phone Call .............................................................................52 
8.2.4. 
Follow-up Visits..............................................................................................................53 
8.2.5. 
Final Evaluation Visit (Week 38) ...................................................................................54 
8.2.6. 
Variation from Scheduled Visit Days .............................................................................55 
8.3. 
Efficacy Assessments .....................................................................................................55 
8.3.1. 
Investigator Global Assessment Frown Wrinkle Severity ..............................................55 
8.3.2. 
Investigator Global Assessment Forehead Wrinkle Severity .........................................56 
8.3.3. 
Patient Frown Wrinkle Severity (PFWS) .......................................................................57 
8.3.4. 
Patient Forehead Wrinkle Severity (PFHWS) ................................................................57 
8.3.5. 
Global Aesthetic Improvement Scale (GAIS) ................................................................58 
8.3.6. 
Facial Age Self Evaluation (FASE) ................................................................................59 
8.3.7. 
FACE-QTM ......................................................................................................................59 
 
 
8.3.9. 
Additional Assessments ..................................................................................................59 
8.4. 
Safety Assessments .........................................................................................................60 
8.4.1. 
Physical Examination......................................................................................................60 
8.4.2. 
Vital Signs .......................................................................................................................60 
8.4.3. 
Pregnancy Testing ...........................................................................................................60 
8.4.4. 
Injection Site Evaluation .................................................................................................61 
8.4.5. 
Clinical Safety Laboratory Assessments ........................................................................61 
 
 
8.5. 
Adverse Events and Serious Adverse Events .................................................................63 
8.5.1. 
Evaluation of Adverse Events and Serious Adverse Events ...........................................63 
8.5.2. 
Assessment and Reporting Requirements .......................................................................64 
8.5.3. 
Serious Adverse Events ..................................................................................................64 
 
 
8.5.5. 
Follow-up of Non-Serious Adverse Events ....................................................................66 
8.5.6. 
Follow-up of Post-Study Serious Adverse Events ..........................................................66 
8.5.7. 
Investigational Product Causality and Severity ..............................................................67 
9. 
Statistical Considerations .............................................................................................68 
9.1. 
Sample Size Determination ............................................................................................68 
9.2. 
Populations for Analyses ................................................................................................68 
9.3. 
Statistical Analyses .........................................................................................................68 
9.3.1. 
Efficacy Analyses ...........................................................................................................69 
9.3.2. 
Safety Analyses ...............................................................................................................69 
9.4. 
Interim Analyses .............................................................................................................70 
9.4.1. 
Data Review Committee .................................................................................................70 
10. 
RECORDS MANAGEMENT ......................................................................................71 
10.1. 
Data Collection ...............................................................................................................71 
10.2. 
File Management at the Study Center.............................................................................72 
10.3. 
Records Retention at the Study Center ...........................................................................72 
11. 
Monitoring and Compliance ........................................................................................74 
 
 

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12. 
ETHICS AND RESPONSIBILITY .............................................................................75 
 
 
 
 
 
 
 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
 
 
 
Table 3: Allowed Variation from Scheduled Visit Days...........................................................55 
Table 4: Investigator Global Assessment Facial Wrinkle Severity 
(IGA-FWS) ....................................................................................................................55 
Table 5: Investigator Global Assessment Forehead Wrinkle Severity 
(IGA-FHWS) .................................................................................................................56 
Table 6: Patient Frown Wrinkle Severity (PFWS) ...................................................................57 
Table 7: Patient Forehead Wrinkle Severity (PFHWS) ...........................................................58 
Table 8: Global Aesthetic Improvement Scale ..........................................................................59 
Table 9: Injection Site Evaluation ..............................................................................................61 
Table 10: Clinical Laboratory Tests ..........................................................................................62 
 
 
LIST OF APPENDICES 
List of Abbreviations .....................................................................................................................8 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
CI 
Confidence interval 
DAXI 
DaxibotulinumtoxinA 
DRC 
Data Review Committee 
eCRF 
Electronic Case Report Form 
FASE 
Facial Age Self Evaluation 
FHL 
Forehead lines 
GAIS 
Global Aesthetic Improvement Scale 
GCP 
Good Clinical Practice 
GL 
Glabellar lines 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
IGA-FWS 
Investigator Global Assessment Frown Wrinkle Severity 
IGA-FHWS 
Investigator Global Assessment Forehead Wrinkle Severity 
IM 
Intramuscular 
IRB 
Institutional Review Board 
kDa 
Kilodalton 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NSAID 
Nonsteroidal anti-inflammatory drug 
PFWS 
Patient Frown Wrinkle Severity 
PFHWS 
Patient Forehead Wrinkle Severity 
PHI 
Protected health information 
PI 
Principal Investigator 
SAE 
Serious adverse event 
SNAP-25 
25 kDa synaptosome associated protein 
SOA 
Schedule of Assessments 
TEAE 
Treatment-emergent adverse event 
UPT 
Urine pregnancy test 
WOCBP 
Women of childbearing potential 

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1. 
Protocol Summary 
1.1. 
 Synopsis 
 
Name of Sponsor/Company: 
Revance Therapeutics, Inc. 
Name of Finished Product: 
DaxibotulinumtoxinA for injection (DAXI for 
injection) 
Name of Active Ingredient: 
DaxibotulinumtoxinA 
Protocol Title: 
A Phase 2a, Multicenter, Open-Label, Dose-Escalation 
Study to Evaluate the Efficacy and Safety of 
DaxibotulinumtoxinA (DAXI) for Injection for the 
Treatment of Dynamic Forehead Lines (Frontalis) 
Following Glabellar Line Injections 
Short Title: 
Efficacy and Safety of DaxibotulinumtoxinA (DAXI) 
for Injection for Treatment of Forehead Lines 
(Frontalis) 
Rationale: 
This phase 2a, multicenter, open-label, dose-escalation 
study will evaluate treatment of moderate or severe 
dynamic forehead lines (FHL) (frontalis) in 
conjunction with treatment of the glabellar complex. 
The proposed dosing regimen will consist of GL 
treatment on Day 1, followed by FHL treatment at 
Week 2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Population: 
Approximately 60 male and female subjects, 18-65 years old, will be enrolled into the study. 
Subjects must meet all the inclusion criteria and none of the exclusion criteria to be eligible for 
this study. 
Inclusion Criteria: 
To be eligible for participation, subjects must: 
1. Provide written informed consent consistent with ICH-GCP guidelines and local laws, 
including authorization to release health information, signed prior to any study 
procedures being performed 
2. Be outpatient, male or female subjects, in good general health, 18-65 years of age 
3. Have a score of moderate (2) or severe (3) FHL during maximum contraction (eyebrow 
elevation) as assessed by the IGA-FHWS 
4. Have a score of moderate (2) or severe (3) FHL during maximum contraction (eyebrow 
elevation) as assessed by the PFHWS 
5. Have a score of moderate (2) or severe (3) GL during maximum frown based on the 
IGA-FWS scale 
6. Have a score of moderate (2) or severe (3) on GL during maximum frown as assessed 
by the PFWS 
7. Have sufficient visual acuity without the use of eyeglasses (contact lens use is 
acceptable) to accurately assess their facial wrinkles 
8. Be willing to refrain from receiving facial fillers, laser treatments, use of any product 
that affects skin remodeling, or a product that may cause an active dermal response in 
the treatment areas (e.g., above the inferior orbital rim) from screening through the end 
of the study 
9. All women of childbearing potential (WOCBP) must have a negative urine pregnancy 
test (UPT) result at the Screening Visit and must practice an effective method of 
contraception throughout the study (e.g., oral contraceptive pill, injection, implant, 
patch, vaginal ring, intrauterine coil, intrauterine device, tubal ligation, barrier method) 
used WITH an additional form of contraception (e.g., sponge, spermicide or condom); 
abstinence; no heterosexual intercourse; or has a vasectomized partner (refer to 
Section 5.6 for additional information)

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10. Able to understand the requirements of the study and be willing and able to follow all 
study procedures, attend all scheduled visits, and successfully complete the study. 
Exclusion Criteria  
Subjects will not be eligible for study participation if they meet any of the following criteria: 
1. Any neurological condition that may place the subject at increased risk with exposure 
to botulinum toxin type A, including peripheral motor neuropathic diseases, such as 
amyotrophic lateral sclerosis and motor neuropathy, and neuromuscular junctional 
disorders, such as Lambert-Eaton syndrome and myasthenia gravis 
2. Any history of facial nerve palsy (e.g., Bell’s Palsy) or muscle weakness or paralysis in 
the treatment areas  
3. Active skin disease, infections, or inflammation at the injection sites 
4. History of or current significant facial asymmetry, eyelid ptosis or history of same, 
excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, or inability of 
the investigator to completely or almost eliminate GL or FHL by physically spreading 
medial brows apart or stretching the forehead skin while at rest 
5. History of or current significant brow ptosis, significant brow or forehead line 
asymmetry at rest or on brow elevation. Evidence that frontalis activity is required to 
maintain eyelid position 
6. Previous treatment with botulinum toxin type A in the face within 6 months prior to 
screening 
7. Plans to receive botulinum toxin type A anywhere in the face (other than study 
treatment) from screening through the end of the study  
8. Has not had within the last 6 months prior to screening, or plans to receive treatment 
through the end of the study with >200 U of any botulinum toxin anywhere else in the 
body outside of the face  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Efficacy Evaluations: 
 IGA-FWS 
 IGA-FHWS 
 PFWS 
 PFHWS 
 GAIS (assessed by the investigator and the subject for GL and FHL) 
 FASE 
 Responses to the FACE-QTM Satisfaction with Forehead and Eyebrows and the 
FACE-QTM Appraisal of Lines: Forehead Lines 
Baseline for all efficacy assessments, unless otherwise noted, refers to the last assessment prior 
to GL treatment (Day 1 Visit). Efficacy outcomes derived from the above list of assessments 
will be summarized descriptively by dose group and by timepoint.  Count and proportion will 
be provided for responder endpoints (defined as proportion of subjects achieving certain 
status). Kaplan-Meier curves will be plotted by treatment group for each time-to-event 
endpoint to assess median duration of effect at maximum eyebrow elevation and at rest for 
selected endpoints. Dose-response will be explored using logistic regressions on the response 
rates (of key responder endpoints) and using log-rank test on the time-to-event endpoints.  The 
effect of study center and baseline severity on the treatment outcome will also be explored. 
Descriptive statistics will be provided for all efficacy variables at all timepoints. 
Safety Evaluations: 
 Clinical laboratory tests (hematology, serum chemistry, prothrombin time [PT], 
urinalysis) 
 
 
 
 
 Injection site evaluation 
 
 
 Concomitant therapies/medications 
 Collection of adverse events (AEs) 
 
 
 Vital signs 
 Physical examination
 
All TEAEs occurring during the study will be recorded and classified according to Medical 
Dictionary for Drug Regulatory Affairs (MedDRA) terminology. All reported TEAEs will be 
summarized, in terms of the number of subjects reporting events, system organ class, preferred 
term, severity, relationship to study drug, and severity. For summarization of event causality 
and severity, subjects will be counted only once within a system organ class or preferred term 
for a given event, using the event with the greatest relationship for causality and the highest 
severity. A summary of AEs leading to discontinuation will also be provided. 

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2. 
Introduction 
Visible signs of facial aging include the formation of facial lines and folds, a decline in skin 
quality, an increase in skin pigmentation, and post-menopausal loss or redistribution of soft 
tissue volume and bone. Forehead lines are produced by the action of the frontalis muscle, a 
large, thin, vertically-oriented muscle which lifts the eyebrows (Hexsel, 2011; Klein, 2004). The 
frontalis muscle serves as an antagonist to the glabellar musculature, a natural depressor that is 
responsible for frowning and associated eyebrow movement. As the eyebrow is considered the 
aesthetic center of the upper face, forehead lines can significantly impact the aesthetic 
appearance of the face, contribute to increased signs of aging and convey unwanted social 
signals. However, both men and women have identified internal factors, such as wanting to look 
good for their age or having a more youthful appearance as very important and have prioritized 
forehead lines as bothersome areas for potential treatment regardless of age or available income 
(Jagdeo, 2016; Narurkar, 2015; Rossi, 2017).  
In women, the first signs of aging can begin around the age of 35 and generally coincide with a 
decrease in self-rated attractiveness and self-confidence (Narurkar, 2015). Following menopause, 
additional changes to soft tissue distribution and bone also begin to appear. 
Facial aging in men occurs earlier and differently. Men generally report the first signs of aging 
between 30 and 50 years of age, with static forehead lines being among one of the first features 
demonstrating the greatest visible change (Rossi, 2017).  
Minimally-invasive injectable treatments have become the most common procedure worldwide 
(Carruthers, 2015) with an increase in frequency over the last decade since the first approval of 
botulinum neurotoxin Type A (Botox Cosmetic [onabotulinumtoxinA] UPSI, Allergan, Inc. 
2013). This is largely the result of years of experience of patients and injectors, and a favorable 
risk-benefit profile. 
Botulinum neurotoxin is produced by Clostridium botulinum, which is a gram-positive, 
spore-forming, anaerobic bacterium, which can both cause disease (e.g., botulism), as well as 
treat it (e.g., dystonia) (Simpson, 2004). There are 7 distinct types (A-G), only types A and B 
have established clinical uses due to a longer duration of action compared to the other types 
(De Boulle, 2007). Botulinum neurotoxin Type A inhibits acetylcholine release at the 
neuromuscular junction, which prevents muscle contractions in injected muscles. The onset of 
muscle weakening typically begins within 48 hours after treatment and usually lasts between 
4 and 5 months, although some patients have reported shorter or longer durations 
(Carruthers, 2015; De Boulle, 2007). 
The efficacy and safety of botulinum toxin type A for the treatment of FHL has been evaluated 
in a number of studies. Solish et al. (2016) conducted the first large-scale, multicenter study of 
onabotulinumtoxinA with 40 U or 30 U total injected into both the frontalis and the glabellar 
complex. Complementary treatment of the glabellar complex in conjunction with the frontalis 
provides more satisfactory results and reduces the potential for eyebrow ptosis. At 4 weeks after 
the first injection, 94.4% of subjects at the 40 U dose and 84.2% of subjects at the 30 U dose 
were satisfied or very satisfied with the reduction in FHL severity. A longer duration of effect 
was noted in the 40 U dose group. There was no observed dose response noted in the incidence 

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of eyebrow- or eyelid-related AEs in either the 40 U and 30 U dose groups. The overall 
incidence of eyebrow ptosis across both doses (coded as facial paresis) was low at 2.3%. 
Two multicenter, randomized, double-blind, placebo-controlled studies have evaluated 
onabotulinumtoxinA for the temporary improvement of moderate to severe FHL with 
simultaneous treatment of GL; one of the studies also assessed simultaneous treatment of lateral 
canthal lines. These studies enrolled 1178 subjects, of which 921 were randomized to receive 
onabotulinumtoxinA and 257 received placebo. A total of 165 and 197 subjects received 3 cycles 
of treatment over 1 year of 40 U and 64 U, respectively. The response rate for FHL was similar 
across all treatment cycles. In both studies, more than 75% of subjects were Very Satisfied or 
Mostly Satisfied with the treatment of facial lines, and the majority of subjects in both treatment 
groups achieved a ≥2-grade improvement from baseline in FHL severity (Botox Cosmetic 
[onabotulinumtoxinA] UPSI, Allergan, Inc. 2013) The overall incidence of reported AEs in these 
studies was low; headache (58 subjects [9%]) was the most frequently reported AE. The overall 
incidence of eyebrow- or eyelid-related AEs was very low. Brow ptosis and eyelid ptosis 
occurred in 13 subjects (2%) and 12 subjects (2%), respectively. 
A large, 12-month, phase 3 study was conducted to examine simultaneous treatment of FHL, GL, 
and lateral canthal lines with onabotulinumtoxinA (De Boulle, 2018). This study enrolled 
787 subjects, of which 313 subjects received onabotulinumtoxinA 64 U and 318 subjects 
received onabotulinumtoxinA 40 U (156 subjects received placebo). In subjects receiving 64 U 
and 40 U of onabotulinumtoxinA, a statistically significant improvement (p<0.001, respectively) 
in the appearance of FHL was observed at the 30-day timepoint and maintained, when compared 
with placebo, through Day 180. In subjects achieving a 2-point improvement in FHL severity 
from baseline, the investigator assessment of FHL improvement was statistically significant at all 
treatment timepoints through Day 180. Significantly more subjects who received 64 U 
onabotulinumtoxinA achieved a rating of none or mild, as assessed by the investigator, at Day 30 
for FHL and GL severity (p<0.001). Additionally, eye-related TEAEs were very low; there were 
2 cases each of eyelid and brow ptosis (0.6%) at the 64 U dose and 5 cases (1.6%) and 6 cases 
(1.9%), respectively, at the 40 U dose. The safety profile of onabotulinumtoxinA is well 
established and enhanced in this study by simultaneous treatment of FHL and GL, which has 
been shown to reduce the incidence of ptosis by stabilizing the elevator muscle. 
As both men and women gain increased awareness of the recognition of aesthetic treatment 
options available to address the signs of facial aging, and as treatment becomes more widely 
used and accepted, it is important to continue examining the potential benefits of such treatments 
in the context of unmet clinical need, improved self-satisfaction, and increased demand. 
Aesthetic products and procedures, while not medically necessary, can significantly improve 
social and psychological functioning, as well as self-satisfaction, which can have a meaningful 
and significant impact on daily life and patient well-being (Fagien, 2008). 
 
 
 
 
 
 
 

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2.2. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of DAXI for injection may be found in the Investigator’s Brochure. 

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4. 
Study Design 
4.1. 
Overall Design 
This is a phase 2a, multicenter, open-label, dose-escalation study to evaluate the safety and 
efficacy of DAXI for injection for the treatment of subjects with moderate to severe FHL in 
conjunction with GL treatment. This study will be conducted at 4 sites in the United States and 
Canada. 
 
 Subjects will be screened for eligibility and enrolled into the study after 
providing informed consent.  
Approximately 60 subjects (18-65 years of age) with moderate to severe FHL will be enrolled 
and sequentially assigned to 1 of 4 treatment cohorts (15 subjects per cohort) to receive DAXI 
for injection. Investigators will make all reasonable efforts to enroll equal proportions of patients 
with moderate and severe FHL (based on baseline assessments) in each dosing cohort. 
 
 
 
 
 
 The total study duration will be up to 40 weeks including up to 2 weeks for screening. 
Subjects will be followed for a minimum of 24 weeks from GL treatment for safety or until all 
scores on the IGA-FWS and PFWS, as well as the IGA-FHWS and PFHWS return to baseline 
(Day 1 Visit prior to GL treatment) or until Week 38, whichever occurs first. Subjects will then 
have a Final Evaluation Visit. If the DRC elects not to proceed with the FHL injection in a given 
dose cohort, subjects assigned to that cohort who have already received GL treatment will be 
followed for 14 weeks from the time of treatment (Day 1). 
Sequential enrollment will occur for each cohort. The first cohort will be enrolled and treated.  
The DRC will convene to review available data (including safety, efficacy, and 
photographs/video) at Week 5 following GL treatment (3 weeks after FHL treatment) for each 
cohort before a decision is made to move forward with the next and subsequent doses. Revance 
reserves the right to terminate or stop the study at any time. Refer to Sections 1.2 and 9.4.1 for 
additional information. 
 

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All subjects will be evaluated for FHL severity using the Revance-validated 4-point IGA-FHWS 
and PFHWS at rest and at maximum eyebrow elevation, as assessed by both the investigator and 
the subject. In addition, to determine the efficacy response to the glabellar complex, subjects will 
be evaluated for improvement on the IGA-FWS and the PFWS at rest and at maximum frown. 
Injection sites will be evaluated at screening for signs of skin inflammation or active disease. The 
GL treatment areas will be evaluated at Day 1 (pre- and post-treatment) and at Weeks 2 and 4. 
The FHL treatment areas will be evaluated at Week 2 (pre- and post-treatment) and at Weeks 4 
and 6. The assessment will be captured as a global evaluation of the injection sites to assess for 
erythema, edema, burning or stinging sensation, itching, or bruising. The glabellar complex will 
be injected in a 5-point injection pattern and the frontalis muscle will be injected in a 3-point 
injection pattern. The same assessment will be used to evaluate all 8 injection sites. 
4.1.1. 
FHL Treatment 
Subjects may receive up to 2 treatments in this study (1 GL treatment and 1 FHL treatment) 
depending on the evaluation of the DRC. Dose escalation for FHL may be stopped at the 
discretion of the DRC. If the DRC elects not to proceed with FHL treatment in a given dose 
cohort, subjects assigned to that cohort who have already received GL treatment will be followed 
for 14 weeks from the time of treatment (Day 1).  
The assessment for whether to proceed in a given dose cohort with FHL treatment will occur 
2 weeks after GL treatment and the following criteria are met:  
1. 
All WOCBP must have a negative UPT prior to treatment. 
2. 
No active skin disease or infections or inflammation at the injection sites. 
3. 
Subject has no condition or situation which, in the investigator’s opinion, puts the 
subject at significant risk. 
4. 
No history or current evidence of ptosis. 
5. 
Presence of frontalis motion/movement ability. 
6. 
DRC approves administration of the intended dose. 

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4.4. 
Visit Schedule 
A Screening Visit will be conducted up to 2 weeks prior to enrollment, and subjects will be 
treated with investigational product at the Day 1 Visit for GL and at the Week 2 visit for FHL. 
Following each treatment, subjects will complete a paper diary for 2 weeks to capture their 
assessment of improvement or satisfaction with the appearance of GL and FHL. Follow-up 
safety phone calls will be conducted at Weeks 1 and 3. Post-treatment on-site follow-up visits 
will occur at Weeks 2, 4, 6, 10, 14, 18, 22, 26, 30, 34, and 38. The total study duration will be up 
to 40 weeks, including up to 2 weeks for screening. Subjects will be followed for a minimum of 
24 weeks from GL treatment for safety or until all scores on the IGA-FWS and PFWS, as well as 
the IGA-FHWS and PFHWS, return to baseline (Day 1 Visit prior to GL treatment) or until 
Week 38, whichever occurs first. Subjects will then have a Final Evaluation Visit. If the DRC 
elects not to proceed with the FHL injection in a given dose cohort, subjects assigned to that 
cohort who have already received GL treatment will be followed for 14 weeks from the time of 
treatment (Day 1). 
Subjects will be evaluated for FHL severity using the Revance-validated 4-point IGA-FHWS and 
PFHWS at rest and at maximum eyebrow elevation. In addition, to determine the efficacy 

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response to GL subjects will be evaluated for improvement to a score of 0 or 1 (none or mild) on 
the IGA-FWS and the PFWS at rest and at maximum frown. 
 

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5. 
Study Population 
Approximately 60 female or male subjects, 18 to 65 years of age, with moderate to severe GL 
and FHL will be enrolled. Investigators will make all reasonable efforts to enroll equal 
proportions of patients with moderate and severe FHL (based on baseline assessments) in each 
dosing cohort. Subjects must meet all of the inclusion criteria and none of the exclusion criteria 
to be eligible for the study. 
5.1. 
Inclusion Criteria 
To be eligible for participation, subjects must: 
1. Provide written informed consent consistent with ICH-GCP guidelines and local laws, 
including authorization to release health information, signed prior to any study 
procedures being performed 
2. Be outpatient, male or female subjects, in good general health, 18 to 65 years of age 
3. Have a score of moderate (2) or severe (3) FHL during maximum contraction (eyebrow 
elevation) as assessed by the IGA-FHWS 
4. Have a score of moderate (2) or severe (3) FHL during maximum contraction (eyebrow 
elevation) as assessed by the PFHWS 
5. Have a score of moderate (2) or severe (3) GL during maximum frown based on the 
IGA-FWS scale 
6. Have a score of moderate (2) or severe (3) on GL during maximum frown as assessed by 
the PFWS 
7. Have sufficient visual acuity without the use of eyeglasses (contact lens use is 
acceptable) to accurately assess their facial wrinkles 
8. Be willing to refrain from receiving facial fillers, laser treatments, use of any product that 
affects skin remodeling, or a product that may cause an active dermal response in the 
treatment areas (e.g., above the inferior orbital rim) from screening through the end of the 
study 
9. All women of childbearing potential (WOCBP) must have a negative urine pregnancy 
test (UPT) result at the Screening Visit and must practice an effective method of 
contraception throughout the study (e.g., oral contraceptive pill, injection, implant, patch, 
vaginal ring, intrauterine coil, intrauterine device, tubal ligation, barrier method) used 
WITH an additional form of contraception (e.g., sponge, spermicide or condom); 
abstinence; no heterosexual intercourse; or has a vasectomized partner (refer to 
Section 5.6 for additional information) 
10. Able to understand the requirements of the study and be willing and able to follow all 
study procedures, attend all scheduled visits, and successfully complete the study. 
5.2. 
Exclusion Criteria  
Subjects will not be eligible for study participation if they meet any of the following criteria: 
1. Any neurological condition that may place the subject at increased risk with exposure to 
botulinum toxin type A, including peripheral motor neuropathic diseases, such as 

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5.3. 
Informed Consent and Authorization to Release Health Information 
Written informed consent will be obtained from all subjects before any study-related procedures 
(including any screening procedures) are performed. The investigator may discuss the trial and 
the possibility for entry with a potential subject without first obtaining consent. However, a 
subject wishing to participate must give written informed consent prior to any study-related 
procedures being conducted, including those performed solely for the purpose of determining 
eligibility for study participation, and including withdrawal from current medication (if required 
prior to study entry). The investigator has both the ethical and legal responsibility to ensure that 
each subject being considered for inclusion in this trial has been given a full explanation of the 
procedures and expectations for study participation, as well as ample time to decide whether or 
not to participate and have all questions answered satisfactorily. 
The site-specific informed consent must be forwarded to Revance or designee for approval prior 
to submission to an Investigational Review Board (IRB)/Independent Ethics Committee (IEC) 
that is registered with the US Department of Health and Human Services or applicable health 
authority. Each subject will sign the consent form that has been approved by the same IRB/IEC 
that was responsible for protocol approval. Each informed consent document must adhere to the 
ethical principles stated in the Declaration of Helsinki and will include the elements required by 
FDA regulations in 21 CFR Part 50, as well as the elements required by ICH GCP guideline, and 
applicable federal and local regulatory requirements. The consent form must also include a 
statement that Revance, their designees, and auditing regulatory agencies will have direct access 
to the subject’s records and medical history for study related purposes. 
Once the appropriate essential information has been provided to the subject and fully explained 
by the investigator (or a qualified designee) and it is felt that the subject understands the 
implications and risks of participating in the trial, the IRB/IEC approved consent document shall 
be signed and dated by both the subject and the person obtaining consent (investigator or 
designee), and by any other parties required by the IRB/IEC or other regulatory authorities. The 
subject will be given a copy of the signed informed consent document with the original kept on 
file by the investigator. All of the above activities must be completed before any study related 
procedures are conducted (including any screening study procedures).  
5.4. 
Lifestyle Considerations 
While enrolled in this study, subjects must agree to refrain from receiving non-ablative laser or 
light treatments, microdermabrasion, or chemical peels (medium depth or deeper, for example 
TCA or phenol) in the treatment areas within 3 months before enrollment through the end of the 
study. Subjects must not have brow tattoos or microblading within 3 months of enrollment or 
plan to have these procedures through the end of the study. Subject must also avoid upper facial 
hair removal in the treatment areas above the orbital rim (e.g., waxing, plucking, or threading) 

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If a serious adverse event (SAE) occurs in conjunction with the pregnancy such as untoward 
outcome of the pregnancy or of the offspring (spontaneous abortion, or abnormality in the 
offspring) then the reporting time frame for an SAE must be met and SAE reporting procedures 
followed. In the event of a normal birth follow-up with the subject will occur with a phone call 
until the first well baby visit to ensure no SAEs are identified in the neonate, at which time active 
follow-up to the pregnancy will cease. 

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6. 
Study Intervention 
The active pharmaceutical ingredient, daxibotulinumtoxinA, is a purified 150 kilodalton (kDa) 
botulinum neurotoxin type A, derived from the Hall strain C. botulinum. Produced by C. 
botulinum as a single inactive polypeptide chain of 150 kDa, daxibotulinumtoxinA undergoes 
proteolytic cleavage by proteases present in the fermentation culture to yield the active di-chain 
molecule comprised of a 100 kDa heavy chain and a 50 kDa light chain linked via both non-
covalent interactions and a disulfide bond (Aoki 2001). The heavy chain plays a role in cell 
binding, internalization, and translocation of daxibotulinumtoxinA into nerve cells. The light 
chain acts as a site-specific metalloprotease causing selective cleavage and inactivation of the 
25 kDa synaptosome associated protein (SNAP-25) which is a cell membrane localized 
component of the vesicular release machinery. This cleavage of SNAP-25 by the light chain of 
botulinum toxin type A blocks the synaptic vesicle exocytosis and subsequent release of 
acetylcholine, thus leading to a dose-dependent weakening of the target muscle. 
6.1. 
Study Intervention(s) Administered 
This is an open-label, non-randomized study. Subjects will be sequentially enrolled by cohort. 
All subjects will receive DAXI for injection according to assigned cohort. Subjects will receive a 
40 U dose of DAXI for injection at the Day 1 Visit) for the treatment of GL and one additional 
dose of DAXI for injection at the Week 2 Visit for the treatment of FHL according to assigned 
cohort.   

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6.2.4. 
Investigational Product Administration 
Investigational product will be administered by the PI to injection site in the designated treatment 
area. 
   
1. Wear protective gloves for investigational product administration 
2. Pull subject’s hair away from the treatment areas (forehead) 
3. Wipe all injection sites with alcohol 
 
 
 
 
 
 
 

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6.3. 
Concomitant Medications/Therapies 
Concomitant medications are any prescription or over-the-counter preparations used by subjects 
during participation in the study. Use of concomitant medications will be recorded on the 
Concomitant Medications electronic case report form (eCRF) beginning at the Screening Visit 
(and including anything taken during the previous 30 days) until the Final Evaluation Visit.  
The dose and dosing regimen of all prescription and non-prescription therapies and medications, 
including herbs, vitamins, or other nutritional supplements administered will be documented. 

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6.5. 
Dose Modification 
Subjects may receive up to 2 treatments in this study (1 GL treatment and 1 FHL treatment) 
depending on the evaluation of the DRC. The DRC may elect not to proceed with FHL treatment 
in a given dose cohort. Therefore, subjects may receive the GL treatment and not the FHL 
treatment in a dose cohort.  
 

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7. 
Discontinuation of Study Intervention and Subject 
Discontinuation/Withdrawal 
7.1. 
Subject Discontinuation/Withdrawal from the Study 
A subject may voluntarily withdraw from study participation at any time. If the subject 
withdraws consent and discontinues from the study, the investigator will attempt to determine the 
reason for discontinuation and record the reason in the subject’s study records and on the eCRF. 
If a subject withdraws consent because of an AE, that AE should be indicated as the reason for 
withdrawal. In the event of early discontinuation, (i.e., prior to the Final Evaluation) where 
consent was not withdrawn, the subject should be asked to return to the study center to complete 
the assessments specified in the Final Evaluation Visit. Subjects who withdraw from the study 
will not be replaced. Subjects who withdraw from the study, but agree to continued follow-up, 
must be reconsented by the investigator for this limited participation in the study (unless this 
situation was adequately described in the original informed consent form [ICF]). 
If at any time during the study, the investigator determines that it is not in the best interest of the 
subject to continue, the subject will be discontinued from participation. The investigator can 
discontinue a subject from study participation at any time if medically necessary or if the subject 
has failed to follow study procedures or keep follow-up appointments. Appropriate 
documentation in the subject’s study record and eCRF regarding the reason for discontinuation 
must be completed. Prior to discontinuing a subject from study participation, the investigator will 
discuss his/her intentions with the Medical Monitor or designee. 
All subjects who fail to return to the study center for the required follow-up visits will be 
contacted by phone to determine the reason(s) why the subject failed to return for the necessary 
visit or elected to discontinue from the study. If a subject is unreachable by telephone after a 
minimum of two documented attempts (one attempt on two different days), a registered letter 
will be sent requesting that contact be made with the investigator.  
Revance has the right to terminate or to stop the study at any time. Should this be necessary, both 
Revance and the investigator will ensure that proper study discontinuation procedures are 
completed. 
7.2. 
Lost to Follow-up 
A subject 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 center. 
Before a subject is deemed lost-to-follow-up, the study center should make every effort to 
contact the subject (see Section 7.1) and reschedule the missed visit as soon as possible. The 
subject should be counseled on the importance of visit compliance and should be questioned as 
to whether he or she wishes to continue in the study. 

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8. 
Study Assessments and Procedures 
8.1. Subject Entry Procedures  
Subject informed consent must be obtained prior to conducting screening procedures. Each 
signature must be personally dated by each signatory and the original retained by the PI as part 
of the study record. A signed copy must be provided to each subject (refer to Section 5.3). 
8.2. Schedule of Visits and Procedures 
It is recommended that study visits be scheduled at approximately the same time of day 
throughout the trial. The IGA-FHWS, IGA-FWS, and Investigator GAIS should be performed by 
the same evaluator throughout the study. If it is not possible to use the same evaluator throughout 
the study, two evaluators should examine the subject together and discuss findings for at least 1 
prior visit. The SOA is provided in Section 1.3. 
8.2.1. 
Screening Visit 
The Screening Visit must take place within 14 days prior to the GL treatment visit (Day 1 Visit).  
The following procedures must be performed and recorded at this visit: 
1. Review study procedures and information regarding the trial and obtain written 
informed consent and privacy authorization (as applicable) 
2. Review eligibility criteria 
3. Obtain medical/surgical history, including prior toxin use, and demographic 
information, including Fitzpatrick skin phototype 
4. Once the investigator has confirmed eligibility criteria, the subject will be enrolled  
 
 
 
 
 
 
 
 
8. Perform a physical examination,
 
 
 
10. Measure and record vital signs (body temperature, respiratory rate, sitting radial 
pulse, and sitting systolic and diastolic blood pressure); subjects should sit for 5 
minutes prior to taking pulse and blood pressure 
 
 
 

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12. Collect blood and urine samples for clinical safety laboratory tests (hematology, 
serum chemistry, PT, and urinalysis)  
 
14. Conduct patient education: Discuss the potential effect of DAXI for injection 
treatment, explain the PFWS and PFHWS measurement and the categories of the 
severity assessment scales, and instruct the subjects to consider depth of lines for 
GL and FHL severity. Use the provided Patient Education Brochure 
 
 
 
 
 
 
The Screening Visit clinical laboratory test results and UPT must be reviewed and signed by the 
investigator; any abnormal results must be determined to be not clinically significant by the 
investigator prior to enrollment. 
8.2.2. 
Treatment Visits (Day 1 and Week 2) 
The GL Treatment Visit (Day 1 Visit) must be performed within 14 days of the Screening Visit. 
The FHL Treatment Visit will occur at the Week 2 Visit. The following procedures must be 
performed and recorded for each visit:  
Prior to Investigational Product Administration 
1. Confirm that all screening visit procedures have been completed, results reviewed, 
and recorded (Day 1 Visit only) 
2. Review eligibility criteria 
3. Update medical/surgical history (Day 1 Visit only) 
4. Once the investigator has confirmed subject eligibility, enroll the subject 
(Day 1 Visit only) 
 
 
 
 
 
 
 
 
 
 
 
 

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15. Physical examination 
 
 
 
17. Measure and record vital signs (body temperature, respiratory rate, sitting radial 
pulse, and sitting systolic and diastolic blood pressure); subjects should sit for 5 
minutes prior to taking pulse and blood pressure 
 
 
 
20. Conduct patient education for GL and FHL evaluation: Discuss the potential effect 
of DAXI for injection treatment, explain the PFWS and PFHWS measurement and 
the categories of the severity assessment scales, and instruct the subjects to consider 
depth of lines for GL and FHL severity. Use the provided Patient Education 
Brochure 
 
 
  
 
23. Record concomitant therapy/medications at the Screening Visit (and in the 30 days 
prior to screening) documenting the dose and dosing regimen of all prescription and 
non-prescription therapies and medications, including herbs, vitamins, or other 
nutritional supplements (Section 6.3). 
Investigational Product Preparation 
The assigned investigational product will be prepared by the trained dose preparer according to 
trial-specific instructions. The prepared investigational product will be provided in a syringe to 
the Investigator for administration. 
Investigational Product Administration 
Investigational product will be administered by the Investigator to injection site in the designated 
treatment area (Refer to Section 6.2.4) while the subject is in a sitting position.  
1. Wear protective gloves for investigational product administration. 

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16. Assess any new or ongoing AEs since the last visit  
 
 
 
8.2.5. 
Final Evaluation Visit (Week 38)  
The following procedures must be performed and recorded at the Final Evaluation Visit for each 
subject. Following treatment, subjects will be followed for at least 24 weeks from GL treatment 
for safety or until all scores on the IGA-FWS and PFWS, as well as the IGA-FHWS and PFHWS 
return to baseline (Day 1 Visit) or until Week 38, whichever occurs first. Subjects will then have 
a Final Evaluation Visit at which time the following procedures must be performed and recorded:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8. Perform a physical examination 
 
 
 
 
 
 
 
 
 
 (hematology, 
serum chemistry, and urinalysis) 
13. Conduct patient education for GL and FHL evaluation: Discuss the potential effect 
of DAXI for injection treatment, explain the PFWS measurement and the categories 

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Rating Score 
Frown Wrinkle Severity  
Description  
0 
None 
No wrinkles 
1 
Mild 
Very shallow wrinkles 
2 
Moderate 
Moderate wrinkles 
3 
Severe 
Deep and furrowed wrinkles 
 
 
 
 
 
 
 
 
8.3.2. 
Investigator Global Assessment Forehead Wrinkle Severity 
At each clinic visit as designated in the SOA (Section 1.3), the investigator will assess the visual 
appearance (at rest and at maximum eyebrow elevation) of the FHL using the IGA-FHWS with 
the following 4-point scale (Table 5). 
Table 5: Investigator Global Assessment Forehead Wrinkle Severity 
(IGA-FHWS) 
Rating Score 
Forehead Wrinkle 
Severity  
Description  
At Rest 
At Maximum Eyebrow Elevation 
0 
None 
No horizontal forehead lines 
None to minimally visible 
horizontal forehead line(s) 
1 
Mild 
Barely visible, shallow horizontal 
forehead line(s) 
Visible, shallow horizontal 
forehead line(s) 
2 
Moderate 
Clearly visible, moderate depth 
horizontal forehead line(s) 
Clearly visible, moderate depth 
horizontal forehead line(s) 
3 
Severe 
Clearly visible, deep horizontal 
forehead line(s) with redundancy of 
skin 
Clearly visible, deep horizontal 
forehead line(s) with redundancy 
of skin 
 
 
 
 
 
 
 
 

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8.3.3. 
Patient Frown Wrinkle Severity (PFWS) 
Subjects will complete the Patient Frown Wrinkle Severity (PFWS) assessment (at rest and at 
maximum frown) to assess the severity of the GL at the Screening Visit, Treatment Visit 
pre-treatment, Follow-up Visits, and Final Evaluation Visit.  
The subject assessment form will be provided directly to the subject to complete while reviewing 
their GL treated area using the supplied handheld mirror. Refer to Appendix 6 for additional 
information. 
 
Table 6: Patient Frown Wrinkle Severity (PFWS) 
Rating Score  
Frown Wrinkle 
Severity  
Description  
0 
None 
No wrinkles 
1 
Mild 
Very shallow wrinkles 
2 
Moderate 
Moderate wrinkles 
3 
Severe 
Deep wrinkles 
 
8.3.4. 
Patient Forehead Wrinkle Severity (PFHWS) 
At each clinic visit as designated in the SOA (Section 1.3), the subject will assess the visual 
appearance of FHL using the PFHWS (at rest and at maximum eyebrow elevation). The 
assessment form will be provided directly to the subject to complete while reviewing the 
treatment areas using the supplied handheld mirror. Subjects who wear contact lenses should 
view the treatment areas while wearing their contact lenses. Subjects who wear glasses must 
have sufficient visual acuity to view the treatment areas without glasses. The subject assessment 
must be completed before the investigator completes the IGA-FHWS assessment. Refer to 
Appendix 7 for additional information.  

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Table 7: Patient Forehead Wrinkle Severity 
(PFHWS) 
Rating 
Score  
Forehead Wrinkle 
Severity  
Description  
At Rest 
At Maximum Eyebrow 
Elevation 
0 
None 
No horizontal forehead lines 
None to minimally visible 
horizontal forehead line(s) 
1 
Mild 
Barely visible, shallow 
horizontal forehead line(s) 
Visible, shallow horizontal 
forehead line(s) 
2 
Moderate 
Clearly visible, moderate 
depth horizontal forehead 
line(s) 
Clearly visible, moderate 
depth horizontal forehead 
line(s) 
3 
Severe 
Clearly visible, deep 
horizontal forehead line(s) 
with redundancy of skin 
Clearly visible, deep 
horizontal forehead line(s) 
with redundancy of skin 
 
The assessment will represent wrinkle severity at each given time point and will not be based on 
a comparison to the pre-treatment defect level. It is recommended that visit assessments be 
completed by the subject as close to the same time of day as possible.  
8.3.5. 
Global Aesthetic Improvement Scale (GAIS) 
The investigator and subject will assess the visual appearance (at maximum eyebrow elevation) 
of the improvement from the baseline condition in FHL and in visual appearance in the 
improvement of GL during maximum frown using the following 7-point severity GAIS 
(Table 8). Subjects will use the baseline assessment photograph for comparison when reviewing 
the visual appearance for GL and FHL to assess improvement following treatment. Assessments 
will be made as designated in the SOA (Section 1.3).  
The Patient GAIS assessment form (Appendix 5) will be provided directly to the subject to 
complete while reviewing the glabellar treatment area (at maximum eyebrow elevation and 
maximum frown) using the supplied handheld mirror as outlined in Appendix 5. Subjects who 
wear contact lenses should view their treatment area while wearing their contact lenses. Subjects 
who wear glasses must have sufficient visual acuity to view their treatment area without glasses. 
The subject assessment must be completed before the investigator completes the IGA-FWS and 
IGA-FHWS assessment. 

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Table 8: Global Aesthetic Improvement Scale 
Rating Score 
Wrinkle Improvement  
-3 
Very Much Worse 
-2 
Much Worse 
-1 
Worse 
0 
No Change 
1 
Improved 
2 
Much Improved 
3 
Very Much Improved 
8.3.6. 
Facial Age Self Evaluation (FASE) 
At each clinic visit designated in the SOA (Section 1.3), the subject will be asked to rate their 
perceived age on a FASE questionnaire (Appendix 9). Following the subject’s completion of the 
Patient GAIS, the subject will be given a questionnaire to rate their perception of how old they 
think they look following the treatment. 
8.3.7. 
FACE-QTM 
At each clinic visit designated in the SOA (Section 1.3), the subject will be asked to complete the 
FACE-QTM Satisfaction with Forehead and Eyebrows and the FACE-QTM Appraisal of Lines: 
Forehead questionnaires (Appendix 11). The questionnaires ask subjects to rate how bothered 
they are by their FHL using 7 questions about general appearance with a rating scale of 1 to 4 
with 1 representing Not Bothered and 4 representing Extremely Bothered. Refer to Appendix 11 
for additional information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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8.3.9.1.2. Subject Global Satisfaction with Treatment Questionnaire 
At each clinic visit designated in the SOA (Section 1.3), the subject will be asked to provide a 
rating of their satisfaction with the treatment results. Following the subject’s completion of the 
Patient GAIS, the subject will be given the Subject Global Satisfaction with Treatment 
Questionnaire to rate their satisfaction with the treatment results. Subjects will be asked how 
satisfied or dissatisfied they are with how the treated area of the face looks (Appendix 10).  
8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SOA (Section 1.3). 
8.4.1. 
Physical Examination  
A targeted physical examination, 
, will be 
conducted at the Screening Visit and at the  Day 1, Week 2 and Final Evaluation Visits. 
Significant physical examination findings that are present prior to investigational product 
administration are to be included on the Medical History eCRF. 
Significant physical examination findings after investigational product administration which 
meet the definition of an AE will be recorded on the AE eCRF. 
8.4.2. 
Vital Signs 
Vital signs (i.e., body temperature, respiration rate, sitting radial pulse rate, and sitting systolic 
and diastolic blood pressures) will be obtained at the Screening Visit and at the Day 1 and 
Week 2 and 38 Visits, or Final Evaluation Visit, 
 
. New abnormal findings or worsening from baseline 
(Day 1 prior to GL treatment) at subsequent assessments, if judged clinically significant, should 
be recorded as an AE. 
8.4.3. 
Pregnancy Testing 
A UPT is required for all WOCBP at screening and a UPT is required at the Screening Visit and 
at the Day 1 (pre-treatment), Week 2 and 38 Visits or Final Evaluation Visit. A positive result 
prior to treatment will exclude the subject from study participation. The results of the UPT will 
be evaluated at each study center. If any subject has a positive UPT, a serum pregnancy test is 
required for confirmation. 
 

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If a female subject becomes pregnant while participating in the study, the investigator or site 
designee must complete a Pregnancy Report Notification Form provided by Revance or designee 
as soon as the pregnancy is confirmed (see Section 5.6). 
8.4.4. 
Injection Site Evaluation 
Injection sites will be evaluated at screening for signs of skin inflammation or active disease. The 
GL treatment areas will be evaluated at the Day 1 Visit (pre- and post-treatment) and at the 
Week 2 and 4 Visits. The FHL treatment areas will be evaluated at the Week 2 Visit (pre- and 
post-treatment) and at the Week 4 and 6 Visits. The assessment will be done as a global 
evaluation of the 5 injection sites for GL and 3 injection sites for FHL (Table 9). (Refer to 
Appendix 12 for additional information.) 
Table 9: Injection Site Evaluation 
Assessment Descriptor 
Present? 
 
Yes 
No 
Erythema 
 
 
Edema 
 
 
Burning or Stinging (sensation as described by 
subject) 
 
 
Itching (sensation as described by subject) 
 
 
Bruising 
 
 
 
If the subject answers yes to any of these items, it should be captured and recorded as an AE in the 
eCRF.  
8.4.5. 
Clinical Safety Laboratory Assessments 
As outlined in Table 10, non-fasting samples for hematology, chemistry, PT (screening only) and 
urinalysis will be collected at screening, Week 4 Visit, and Week 38 or Final Evaluation Visit. 
 
 Blood and urine specimens will be collected using applicable safety precautions and 
will be processed according to the central clinical laboratory’s instructions. Urinalysis will be 
evaluated at the study center using supplies provided by Revance or designee. 

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Table 10: Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Urinalysis 
Additional Tests 
Glucose 
Total bilirubin 
Alanine aminotransferase 
Aspartate 
aminotransferase 
Alkaline phosphatase 
Blood urea nitrogen 
Hemoglobin 
Hematocrit 
Leukocyte Count 
(total) 
Leukocyte Count 
(differential) 
Red Blood Cell 
Count 
Platelet Count 
Specific gravity 
pH 
Glucose 
Protein 
Blood 
Bilirubin 
Ketones 
Prothrombin time (PT) 
(screening only) 
UPT (WOCBP only)* 
 
 
 
 
*If positive at timepoints after study treatment, confirm by serum pregnancy test 
It is the investigator’s responsibility to review the results of all laboratory tests as they become 
available. For each laboratory test result outside the reference range, the investigator must 
ascertain if the abnormal lab result is a clinically significant result for that individual subject. 
Likewise, if laboratory tests are taken at follow-up visits, the investigator must ascertain if this is 
an abnormal and clinically significant change from pretreatment for that individual subject. The 
investigator may repeat the laboratory test or request additional tests to verify the results of the 
original laboratory test.  
The investigator must sign and date all written laboratory results (e.g., urinalysis, hematology, 
chemistry, PT, and pregnancy tests) and note Not Clinically Significant or Clinically Significant 
for each out of range laboratory value. If a laboratory value is determined to be a clinically 
significant result for that subject, this may be considered an AE.  
 
 
 
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8.5. 
Adverse Events and Serious Adverse Events 
8.5.1. 
Evaluation of Adverse Events and Serious Adverse Events 
For this protocol, an adverse event (AE) is any untoward medical occurrence (e.g., sign, 
symptom, disease, syndrome, intercurrent illness, clinically significant abnormal laboratory 
finding, injury or accident) that emerges or worsens following administration of investigational 
product and until the end of study participation that may not necessarily have a causal 
relationship to the administration of the investigational product. An AE can therefore be any 
unfavorable and/or unintended sign (including a clinically significant abnormal laboratory 
result), symptom, or disease temporally associated with the use of an investigational product, if 
considered related to the investigational product. A treatment-emergent AE is one that occurs 
after any period of exposure to treatment. 
Pre-existing conditions, which increase in frequency or severity or a change in nature as a 
consequence of an investigational product use will also be considered an adverse event. 
An unexpected AE is an adverse reaction, the nature or severity of which is not consistent with 
the applicable product information (e.g., Investigator’s Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product). 
Any change in the study safety evaluations, (e.g., vital signs, injection site 
 
) after GL and FHL treatment determined to be clinically 
significant by the investigator must be reported as an AE. 
A serious adverse event (SAE) is any untoward medical occurrence that results in any of the 
following outcomes: 
 Death 
 Life-threatening, (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not apply to an AE that hypothetically 
might have caused death if it were more severe) 
 Persistent or significant disability/incapacity or substantial disruption of the subject’s 
ability to carry out normal life functions 
Requires in-patient hospitalization or prolongs hospitalization (i.e., a prolonged 
hospitalization beyond the expected length of stay;  
NOTE: Hospitalizations for elective medical/surgical procedures, scheduled 
treatments, or routine check-ups are not SAEs by this criterion) 

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 Congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a subject 
exposed to the molecule or investigational product before conception or during 
pregnancy) 
 Does not meet any of the above serious criteria but based upon appropriate medical 
judgement may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above (i.e., is a significant or important medical event) 
8.5.2. 
Assessment and Reporting Requirements 
The investigator will assess subjects after GL and FHL treatment and at each subsequent study 
visit for the occurrence of AEs. To avoid bias in eliciting AEs, subjects should be asked the 
following non-leading question: “How have you felt since your last visit?” All AEs (serious and 
non-serious) will be collected from signing of the ICF until the Final Evaluation Visit at each 
visit. Any AE reported by the subject must be recorded on the source documents and eCRFs.  
All AEs will be collected from Day 1 until Week 38 or Final Evaluation Visit at the time points 
specified in the SOA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
All SAEs will be recorded and reported to Revance or designee immediately within 24 hours of 
their awareness of the event. All fatal or life-threatening SAEs should be telephoned to Revance 
or the designee’s authorized representative as soon as the investigator learns of the event. 
8.5.3. 
Serious Adverse Events 
The investigator must report an SAE to Revance or the designee’s authorized representative 
within 24 hours of their awareness of the event: 
 Complete and return the SAE Form with all information known to date; including the 
investigator’s assessment of causality 
 Contact Revance or the authorized representative for a fatal or life-threatening event as 
soon as the investigator or study staff are aware of the event 
 Obtain and maintain all pertinent medical records (discharge summary, autopsy report, 
etc.) and medical judgments of medical personnel who assisted in subject’s treatment and 
follow-up 
 Provide follow-up information to Revance or the authorized representative within 24 
hours of awareness 
Regulatory Authorities, IRBs/ IECs, and investigators will be notified of SAEs in accordance 
with applicable regulations and requirements (e.g., ICH-GCP Guidelines, national regulations 
and local requirements). 
 
 

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8.5.5. 
Follow-up of Non-Serious Adverse Events 
Any AEs that are identified from Day 1 through the last scheduled study visit (or Final 
Evaluation Visit) must be recorded on the AE eCRF as ongoing. 
Any clinically significant abnormal test results, (e.g., laboratory findings), at the final assessment 
should be followed to resolution or until determined by the investigator to be stabilized. Repeat 
tests may be indicated to establish this. 
If a subject has any clinically significant, study-related AEs at the end of the study, the Medical 
Monitor should be notified, and every effort made by the investigator to arrange follow-up 
evaluations at appropriate intervals to document the course of the abnormalities until the medical 
monitor determines that follow-up is sufficient. 
8.5.6. 
Follow-up of Post-Study Serious Adverse Events 
SAEs that are identified on the last scheduled contact (or Final Evaluation Visit) must be 
recorded on the AE eCRF and reported to Revance or designee according to the reporting 
procedures outlined in Section 8.5.2. This may include unresolved previously reported SAEs, or 
new SAEs. The investigator should follow these SAEs until the events are resolved, follow-up is 
sufficient, or the subject is lost to follow-up. The investigator should continue to report any 
significant follow-up information to the Medical Monitor, Revance or designee, and the IRB/IEC 

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up to the point the event has been resolved. Resolution means the subject has returned to the 
baseline state of health, or the investigator does not expect any further improvement or 
worsening of the subject’s condition. 
Any new SAEs reported by the subject to the investigator that occur after the last scheduled 
contact and are determined by the investigator to be reasonably associated with the 
administration of investigational product should be reported to Revance or designee and the 
IRB/IEC. 
8.5.7. 
Investigational Product Causality and Severity 
Relationship of an AE to investigational product will be assessed as follows: 
 Definite: There is a clinically plausible time sequence between the onset of the AE and 
the administration of investigational product; when the event responds to withdrawal of 
investigational product and/or recurs with re-administration of investigational product 
 Probable: There is a clinically plausible time sequence between the onset of the AE and 
the administration of investigational product; the AE is unlikely to be caused by the 
concurrent/underlying illness, other drugs or procedures 
 Possible: There may or may not be a clinically plausible time sequence between the onset 
of the AE and the administration of investigational product and a cause cannot be ruled 
out 
 Unrelated: There is not a temporal or causal relationship to investigational product 
administration 
The investigator is responsible for evaluating all AEs and determining the severity of the event. 
Severity will be categorized as mild, moderate to severe according to the following definitions: 
 Mild: Event may be noticeable to subject; does not influence daily activities; usually 
does not require intervention 
 Moderate: Event may be of sufficient severity to make subject uncomfortable; 
performance of daily activities may be influenced; intervention may be needed  
 Severe: Event may cause severe discomfort; usually interferes with daily activities; 
subject may not be able to continue in the study; treatment or other intervention usually 
needed  
 

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9. 
Statistical Considerations 
9.1. 
Sample Size Determination 
The sample size is not determined by the power of any hypothesis testing.  
 
 
 
 
 
 
 
9.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined and the summary groups for 
analysis will be based on the actual dose for FHL received (which is expected to be consistent 
with the enrollment cohorts): 
Population 
Description 
Enrolled  
All subjects who receive the GL treatment 
GL-Evaluable 
All enrolled subjects who have any post-GL treatment 
assessment of IGA-FWS at maximum frown  
FHL-Evaluable 
All enrolled subjects who receive the FHL treatment and have 
any post-FHL treatment assessment of IGA-FHWS at maximum 
eyebrow elevation 
Safety 
All enrolled subjects 
Safety-FHL 
All enrolled subjects who receive the FHL treatment 
 
9.3. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the detailed methods of analysis, the subject populations to be included in the analyses, 
and procedures for accounting for missing, unused, and spurious data. This section is a summary 
of the planned statistical analyses of the primary and secondary endpoints. 
In general, descriptive summaries will include means, standard deviations, and ranges for 
continuous variables; and counts and proportions for categorical measures.  Unless otherwise 
stated, a 95% CI will be provided for means and proportions. No formal hypothesis tests are 
planned, but may be performed as exploratory analyses.  No multiplicity adjustments or 
imputation of missing data are planned. 

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9.3.1. 
Efficacy Analyses 
Unless otherwise noted, baseline for all efficacy assessments for GL refers to the last available 
assessment prior to GL treatment for those associated with GL severity and for FHL refers to the 
last available assessment prior to FHL treatment for those associated with FHL severity. 
The primary efficacy endpoint will be the proportion of subjects achieving a score of 0 or 1 
(none or mild) on the FHWS as assessed by IGA-FHWS at maximum eyebrow elevation at 
Week 6.  The dose response in the proportion of responders at 4 weeks after the FHL treatment 
(Week 6) will be explored using the logistic regression stratified by baseline FHWS severity (last 
assessment prior to GL treatment at Day 1 Visit) and study center to assess the dose-response. 
Additional measures to assess the effectiveness outcomes will include the IGA-FHWS, PFHWS, 
GAIS evaluated at maximum contraction (eyebrow elevation) and at rest at each visit. Various 
responder endpoints associated with the FHWS, such as achieving certain status or certain 
magnitude of improvement from baseline, will be derived from these effectiveness outcomes for 
each visit.  These responder endpoints will be analyzed by statistical models similar to that for 
the primary endpoint.     
Duration of response will be evaluated by various time-to-event endpoints. Kaplan-Meier curves 
will be plotted by dose group for each time-to-event endpoint and median duration with 
associated 95% CIs will be provided.  
Similar responder and time-event endpoints associated with the GL wrinkle severity defined 
based on the assessments for GL wrinkle severity such as IGA-FWS, PFWS or GAIS on GL, 
will be summarized similarly to those endpoints associated with FHWS. Efficacy outcomes will 
be summarized. Descriptive statistics will be provided for all efficacy variables at all timepoints.  
Note that exploratory analyses of the change in FHL severity from Day 1 (post-GL treatment) to 
Week 2 and from pre-FHL treatment (Week 2 pre-treatment) to post treatment will also be 
performed. 
9.3.2. 
Safety Analyses 
Adverse events (AEs) occurring during the study will be recorded and classified according to 
MedDRA terminology. Those occurred one or after treatment are considered as treatment-
emergent.  All reported TEAEs will be summarized, in terms of the number of subjects reporting 
events, system organ class, preferred term, severity, relationship to study drug, and seriousness. 
For summarization of event causality and seriousness, subjects will be counted only once within 
a system organ class or preferred term using the event with the event with the greatest 
relationship for causality and the event with the highest severity. A summary of TEAEs leading 
to discontinuation will also be provided. 
A by-subject listing of any SAEs will be provided and all SAEs will be summarized by severity 
and relationship to study treatment.  
Clinical laboratory test results will be summarized by visit and if applicable a shift table will be 
used to evaluate the shift in status from baseline at each visit. 
 

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9.4. 
Interim Analyses  
Due to the nature of the study design, data will be evaluated after each dosing cohort achieves a 
pre-specified milestone (e.g., 5 weeks after last subject’s enrollment) before a decision is made 
to move forward with the next dosing cohort. In addition, a formal interim analysis of the data 
will be performed when all subjects finish 8 weeks after receiving the FHL treatment or have 
withdrawn from the study earlier. 
9.4.1. 
Data Review Committee  
Due to the dose-escalation nature of the study design, safety data and subject photographs/videos 
will be evaluated by the DRC at Week 5 following GL treatment (3 weeks after FHL treatment) 
for each cohort before a decision is made to move forward with the next and subsequent doses. If 
the DRC elects not to proceed with the FHL injection in a given dose cohort, subjects will be 
followed for 14 weeks from the time of treatment (Day 1).   
Dose escalation for FHL may be stopped at the discretion of the DRC as outlined in the DRC 
Charter. 
The full details for the roles and responsibilities of the DRC will be detailed in the study-specific 
DRC charter. 
  

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10. 
RECORDS MANAGEMENT 
10.1. 
Data Collection 
For this study, all protocol-specified data will be recorded in the source documents, and data will 
be entered on the eCRFs from the source documents. In addition to signature confirmation that a 
subject meets the study eligibility criteria, upon each subject’s completion of the study, the 
investigator will sign a statement indicating that all pages of the subject’s case report have been 
reviewed. Signature stamps and “per signatures” are not acceptable.  
It is Revance’s policy that the study data be verifiable with the source data that necessitates 
access to all original recordings, laboratory reports, and other records for each subject. The 
investigator must, therefore, agree to allow access to subjects’ records, and source data must be 
made available for all study data. Subjects (or their legal representatives) must also allow access 
to their medical records. Subjects will be informed of the importance of increased record access 
and permission granted by signature on the informed consent document prior to any screening 
procedures. 
Checks will be performed to ensure the quality, consistency, and completeness of the data. 
Instances of missing or un-interpretable data will be resolved with the investigator or Study 
Coordinator. Data queries will be sent to the study center. Site personnel will be responsible for 
providing resolutions to the data queries and for correcting the eCRFs, as appropriate. All unused 
Revance or designee study materials and binders must be returned to Revance or designee upon 
completion of the study. 
The investigator must keep written or electronic source documents for every subject participating 
in the clinical study. The subject file that identifies the study in which the subject is participating 
must include the subject’s available demographic and medical information including:  
 Name 
 Contact information 
 Date of birth 
 Sex 
 Medical history 
 Concomitant diseases 
 Concomitant therapies/medication 
 Study visit dates 
 Performed examinations, evaluations, and clinical findings 
 Investigational product administration 
 AEs, SAEs, or pregnancy (as applicable) 
Additionally, any other documents with source data, especially original printouts of data that 
were generated by technical equipment must be included in the subject’s source document (e.g., 
laboratory value listings). All these documents must have at least the subject’s initials, study 
number, and the date of the evaluation.  

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The data recorded during the study will be documented in the eCRF and/or the study-specific 
forms. Before or at study termination, all data must be forwarded to Revance or designee. The 
data will be recorded, evaluated, and stored in anonymous form in accordance with data-
protection regulations. 
Subjects will authorize the use of their protected health information (PHI) during the informed 
consent process in accordance with the applicable privacy requirements. Subjects who deny 
permission to use and disclose PHI will not be eligible to participate in the study. The 
investigator will ensure that the study documents forwarded to Revance or their designee, and 
any other documents, contain no subject names or other PHI, such as medical record number or 
date of birth. 
Any amendments and corrections necessary will be undertaken in both the source documents and 
eCRFs (as appropriate) and countersigned by the investigator, or documented designee, stating 
the date of the amendment/correction. Errors must remain legible and may not be deleted with 
correction aids. The investigator must state his/her reason for the correction of any data. In the 
case of missing data/remarks, the entry spaces provided in the eCRF should be cancelled out to 
avoid unnecessary follow-up inquiries. 
Regulatory authorities, the IRB/IEC and/or Revance’s Quality Assurance department (or 
designee) may request access to all source documents, eCRFs, and other study documentation for 
on-site audit or inspection. The investigator must guarantee direct access to these documents. 
The eCRFs will be kept by Revance or designee in a secured area. Clinical data will be recorded 
in a computer format for subsequent statistical analyses. Data files will be stored on electronic 
media with a final master data file kept by Revance or designee after descriptive and statistical 
analyses and reports have been generated and are complete.  
10.2. 
File Management at the Study Center 
It is the responsibility of the investigator to ensure that the study center maintains all source and 
essential documents in accordance with ICH Guidance for Industry E6 (R2) Good Clinical 
Practice: Consolidated Guidance, Section 8 – Essential Documents for the Conduct of a Clinical 
Study. 
10.3. 
Records Retention at the Study Center 
It is a Revance requirement that all investigators participating in clinical studies maintain 
detailed clinical data for one of the following periods: 
 Country-specific requirements, or 
 A period of at least 2 years following the last approval of a marketing application 
approved by a Regulatory Authority in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region, or, 
 A period of 2 years after Revance notifies the investigator that the data will not be 
submitted for review by any Regulatory Authority  
Regardless of applicable retention period, the investigator must not dispose of any records or 
essential documents relevant to this study without either (1) written permission from Revance, or 
(2) providing an opportunity for Revance to collect such records. The investigator shall take 

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responsibility for maintaining adequate and accurate electronic or hard copy source documents of 
all observations and data generated during this study. Such documentation is subject to 
inspection by Revance or designee and relevant regulatory agencies. If the investigator 
withdraws from the study (e.g., relocation, retirement) all study-related records should be 
transferred to a mutually agreed upon designee. Notice of such transfer will be provided to 
Revance in writing.  
 

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12. 
ETHICS AND RESPONSIBILITY 
This study must be conducted in compliance with the protocol, the ICH Guidance for Industry 
E6 (R2) Good Clinical Practice: Consolidated Guidance and the applicable regulatory 
requirements. Investigators must submit all essential regulatory documentation, as required by 
local and national regulations (including IRB/IEC approval of the protocol and informed consent 
form) to Revance or designee before investigational product will be shipped to the study center.  

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