A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging, Multi-Center Trial to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA for Injection for the Treatment of Upper Limb Spasticity in Adults After Stroke or Traumatic Brain Injury
Phase: PHASE2
Conditions: Upper Limb Spasticity
Sponsor: Revance Therapeutics, Inc.

DaxibotulinumtoxinA for Injection for Adult Upper Limb Spasticity 
 Version 6 
Protocol 1820203 Amendment 3 
29 June 2020 
Revance Therapeutics, Inc  
Confidential 
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CONFIDENTIAL 
 
Clinical Study Protocol 
 
STUDY TITLE:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group, Dose-Ranging, Multi-Center Trial to Evaluate the 
Efficacy and Safety of DaxibotulinumtoxinA for Injection for the 
Treatment of Upper Limb Spasticity in Adults After Stroke or 
Traumatic Brain Injury (JUNIPER) 
SPONSORS: 
REVANCE THERAPEUTICS, INC. 
7555 Gateway Boulevard 
Newark, California 94560, USA 
Telephone: (510) 742-3400 
STUDY NUMBER: 
1820203 
STUDY PHASE: 
Phase 2 
STUDY DRUG: 
DaxibotulinumtoxinA for Injection 
INDICATION 
Upper Limb Spasticity in Adults 
PROTOCOL 
VERSION/DATE: 
Amendment 3 / 29 June 2020  
VERSION HISTORY 
Version 1, 13 July 2018 
Version 2, 27 August 2018 
Version 3, 14 September 2018 (Original Protocol) 
Amendment 1, 29 November 2018 
Amendment 2, 04 November 2019 
 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
Confidentiality Statement 
The information contained in this document is the property of Revance Therapeutics, Inc. and is 
confidential. This information may not be disclosed, reproduced, or distributed to anyone other 
than personnel directly involved in the conduct of the study and in response to a relevant 
Institutional Review Board/Independent Ethics Committee and Review by a Regulatory Authority 
as required by the applicable laws and regulations, without the written authorization of Revance 
Therapeutics, Inc. These restrictions will continue to apply after the study has closed. 
 
 
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DaxibotulinumtoxinA for Injection for Adult Upper Limb Spasticity
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Protocol 1820203 Amendment 3
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INVESTIGATOR SIGNATURE 
 
Protocol Number: 1820203 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging, 
Multi-Center Trial to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA for Injection 
for the Treatment of Upper Limb Spasticity (ULS) in Adults After Stroke or Traumatic Brain 
Injury (JUNIPER) 
 
I have read this protocol and agree that it contains all the necessary details for performing the 
study in accordance with the Declaration of Helsinki and the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP). 
I will provide copies of the protocol and of the clinical and preclinical information on the 
investigational product, which was furnished to me by the Sponsor, to all members of the study 
team responsible to me who participate in the study. I will discuss this material with them to 
assure that they are fully informed regarding the study drug and the conduct of the study. 
I will perform the study according to specifications outlined in the protocol and agree to 
implement protocol requirements only after the protocol and patient information/Informed 
Consent form have been approved by the Institutional Review Board/Ethics Committee 
(IRB/EC). I will submit any protocol modifications (amendments) and/or any Informed Consent 
form modifications to the IRB/EC, and approval will be obtained before any modifications are 
implemented. 
I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior 
consent from the Sponsor, Revance Therapeutics, Inc. unless this requirement is superseded by a 
regulatory authority (e.g., FDA). 
 
__________________________________ 
Investigator Name (PLEASE PRINT)  
 
Signature: ________________________________ Date ______________  
 
 
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SYNOPSIS  
TITLE OF STUDY:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 
Dose-Ranging, Multi-Center Trial to Evaluate the Efficacy and Safety of DaxibotulinumtoxinA 
for Injection for the Treatment of Upper Limb Spasticity in Adults After Stroke or Traumatic 
Brain Injury (JUNIPER) 
 
NAME OF SPONSOR(S): Revance Therapeutics, Inc 
 
NAME OF INVESTIGATIONAL PRODUCT:  DaxibotulinumtoxinA for Injection 
 
STUDY CENTERS: Up to 35 study centers across the United States 
 
PLANNED NUMBER OF SUBJECTS: Approximately 128 subjects  
 
DURATION OF STUDY:   Up to 39 weeks, including 3 weeks for 
screening 
 
 
Clinical Phase: 2 
 
OBJECTIVES 
Primary Objective 
x To compare the safety and efficacy of a single treatment of DaxibotulinumtoxinA for 
Injection (DAXI for injection) at three dose levels (250 U, 375 U, 500 U) versus placebo in 
reducing muscle tone of adult subjects with upper limb spasticity after stroke or 
traumatic brain injury         
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
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STUDY DESIGN 
This randomized, double-blind, placebo-controlled trial will evaluate the dose-related efficacy 
and safety of 3 doses of DAXI for injection for the treatment of upper limb spasticity (ULS) in 
adult subjects. 
Approximately 128 adult subjects with upper limb spasticity after stroke or traumatic brain 
injury will be recruited from up to 35 study centers across the United States (US). The 
Screening period will be up to 21 days.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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d.   
 
SUBJECT REPLACEMENT STRATEGY: Subjects who discontinue from the study will not be 
replaced. 
 
 
 
 
 
 
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ELIGIBILITY CRITERIA  
Inclusion Criteria 
1. Adults, 18 to 75 years of age, inclusive. 
2. Written informed consent including authorization to release health information. 
3. Focal upper limb spasticity (ULS) after a stroke (as defined by WHO criteria) or traumatic 
brain injury (TBI), last stroke or TBI > 24 weeks prior to Screening. 
4. ULS with the primary aggregate posture (AP): flexed elbow + flexed wrist + clenched fist 
(flexed fingers) and ≥ 1 other clinical pattern(s): adducted and internally rotated shoulder, 
pronated forearm, and/or thumb-in-palm deformity.  
5. Moderate to severe ULS with a MAS score ≥ 2 at the elbow, wrist, and finger flexors; with 
the exception that the MAS score is ≥ 3 at the suprahypertonic muscle group (SMG) for 
subjects with previous injections of BoNTA in the paretic limb. 
6. Moderate to severe functional disability (DAS score ≥ 2) on the principal target of 
treatment (1 of 4 functional domains: hygiene, dressing, malposition of the 
arm/wrist/fingers, and pain). 
7. Has sufficient cognitive and communication ability to be able to give informed consent 
including authorization to release health information. 
 
Exclusion Criteria 
1. Upper limb spasticity attributable to an etiology other than stroke or TBI. 
2. Bilateral upper limb paresis or quadriplegia. 
3. Initiated in physiotherapy of the upper extremities ≤ 30 days prior to Screening or 
planned to start physiotherapy of the upper extremities during the course of the study. 
4. Previous treatment with any BoNT product for any condition ≤ 16 weeks prior to 
Screening.   
5. Botulinum neurotoxin treatment-experienced subjects who have historically required 
< 200 U of Botox/Xeomin or its equivalent to effectively treat the upper limb spasticity. 
6. Botulinum neurotoxin treatment-experienced subjects who had suboptimal or no 
treatment response to the most recent BoNTA injection for spasticity, as determined by 
the investigator; or history of primary or secondary non-response to BoNTA injections, 
known to have neutralizing antibodies to BoNTA; or have a history of botulinum toxin 
type B (rimabotulinumtoxinB [Myobloc/Neurobloc]) injection for spasticity due to non-
response or suboptimal response to BoNTA. 
7. Change in oral medications for spasticity including dosage and dosing frequency ≤ 30 days 
prior to Screening. 
8. Previous or planned treatment of the spastic upper limb with phenol, alcohol injection or 
surgery.  
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9. Profound muscular atrophy or fixed contracture (spasticity angle, per the Tardieu Scale, 
<10 degrees in the most hypertonic muscle group {elbow, wrist or finger flexors}) of the 
spastic limb leading to marked limitation on passive range of motion or any other known 
conditions of the upper limb that could confound muscle tone or functional assessment.   
10. Current or prior treatment with intrathecal baclofen pump. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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EFFICACY ASSESSMENTS 
x Modified Ashworth Scale (MAS) 
x Physician Global Impression of Change (PGIC) 
x Disability Assessment Scale (DAS)  
x Patient or Caregiver Global Impression of Change (P/CGIC) 
x Tardieu Scale (TS) 
x Active Range of Motion (AROM)  
x Fugl-Meyer Upper Extremity (FMUE) Assessment (measure of active motor function) 
x EuroQoL Five Dimension Scale (EQ-5D-5L) 
x Short Form Health Survey (SF-36) 
 
SAFETY ASSESSMENTS 
x Adverse events including 
 
 
 
x Vital signs, physical and neuro examination findings 
x Injection site evaluations 
x Spirometry (discontinued 20 March 2020 due to COVID-19) 
x Lab tests (CBC, PT, chemistry panel, UA, urine pregnancy test [WOCBP]) 
x 12-lead ECG 
x Concomitant medications 
x Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
ENDPOINTS 
Co-Primary Endpoints 
x Mean change from baseline in muscle tone measured using the MAS in the 
suprahypertonic muscle group (SMG) of the elbow, wrist, OR finger flexors at Week 6 
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x Mean score on the PGIC at Week 6  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
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PLANNED ANALYSES 
Analyses of Co-Primary Endpoints  
1) Mean change from baseline in muscle tone measured by MAS in the suprahypertonic 
muscle group (SMG: elbow flexors, wrist flexors, or finger flexors) at Week 6   
2) Mean score on the PGIC at Week 6  
The SMG is the one with the highest MAS score at baseline. In case two or three muscle 
groups have the same highest MAS scores, the selection of the SMG will be at the discretion 
of the investigator, based upon his/her clinical judgement. Change from baseline in muscle 
tone of the SMG at Week 6 and mean PGIC score at week 6 will be compared between each 
dose group and placebo beginning with DAXI 500 U vs placebo, then DAXI 375 U vs placebo, 
and DAXI 250 U vs placebo with control of the family-wise type 1 error rate using a 6-step 
hierarchical testing procedure. The significance of each comparison will be tested only if the 
previous step reached significance. 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
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STATISTICAL ANALYSIS 
Sample Size Calculations 
The treatment effect size for the primary endpoint (mean change from baseline in MAS in the 
SMG) was observed in a BoNTA product registration study (de) for the treatment of ULS. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
Analysis Populations 
x Intention-to-Treat Population:  Efficacy analysis will be performed using the intention-to-
treat analysis set. This population includes all subjects randomized, given one injection 
session of the study medication and have a MAS score in the SMG at baseline and at least 
one post-baseline MAS assessment 
 
 
 
 
 
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x Safety Population:  all randomized subjects who received a study treatment. 
x Pre-COVID-19 ITT Population: a subset of the ITT population, subjects who were enrolled 
before COVID-19 enrollment hold (20MAR2020).  
x Pre-COVID-19 PP Population: a subset of the PP population, subjects who were enrolled 
before COVID-19 enrollment hold (20MAR2020).  
Protocol Version/Date: Amendment 3/ 29 June 2020 
 
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DaxibotulinumtoxinA for Injection for Adult Upper Limb Spasticity 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................8 
TABLE OF CONTENTS ............................................................................................................23 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS ................................................................26 
1 
INTRODUCTION ................................................................................................................29 
1.1         Pathophysiology of Spasticity ...........................................................................29 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
2 
STUDY OBJECTIVES ........................................................................................................35 
2.1 
Primary Objective .............................................................................................35 
 
 
 
 
3 
INVESTIGATIONAL PLAN ..............................................................................................35 
3.1    
Overall Study Design .........................................................................................35 
3.2         Efficacy Measures ..............................................................................................37 
3.3         Safety Measures .................................................................................................38 
3.4         Endpoints ............................................................................................................38 
3.5    
Duration of Trial ................................................................................................39 
3.6    
End of Study Definition .....................................................................................39 
    
 
     
 
4 
STUDY POPULATION .......................................................................................................41 
      4.1           Diagnosis and Main Eligibility Criteria .........................................................41 
4.1.1 
Inclusion Criteria ...............................................................................................42 
4.1.2 
Exclusion Criteria ..............................................................................................42 
 
 
 
 
4.4 
Concomitant Medications .................................................................................44 
 
 
4.5 
Screen Failures ...................................................................................................45 
4.6 
Subject Discontinuation/Withdrawal Criteria ................................................45 
4.7 
Lost to Follow-Up ..............................................................................................46 
5 
STUDY VISITS AND PROCEDURES ..............................................................................46 
5.1  
Screening Visit (Day -21 to -1) ..........................................................................46 
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5.2         Baseline/Treatment Visit (Day 1) .....................................................................48 
5.3 
Follow-up Visits .................................................................................................49 
5.4 
End of Study Visit ..............................................................................................50 
6    SAFETY ASSESSMENTS ....................................................................................................50 
6.1 
Clinical Laboratory Tests .................................................................................50 
6.2 
Adverse Events ...................................................................................................51 
6.2.1 
Assessment of Adverse Events: ........................................................................51 
6.2.2 
Adverse Events and Serious Adverse Events ..................................................52 
6.2.2.1 Definition of Adverse Events ............................................................................52 
6.2.2.2    Definition of Serious Adverse Events (SAE) ..................................................52 
6.2.2.3 Classification of an Adverse Event ..................................................................53 
6.2.2.4 Time Period and Frequency for Event Assessment and Follow-Up .............53 
6.2.2.5  Adverse Event Reporting .................................................................................54 
6.2.2.6 Serious Adverse Event Reporting ....................................................................54 
6.2.2.7 Reporting Events to Participants .....................................................................55 
 
 
6.3 
Injection Site Evaluation: .................................................................................57 
 
6.4 
  Reporting of Pregnancy ………………………………………………………51 
 
6.5 
  Columbia-Suicide Severity Rating Scale (C-SSRS)…………………............58  
7 
UNANTICIPATED ADVERSE EVENTS .........................................................................58 
7.1 
Definition of Unanticipated Adverse Events ...................................................58 
7.2         Unanticipated Adverse Event Reporting .........................................................58 
7.3         Reporting Unanticipated Adverse Events to Participants .............................59 
 
         
 
         
 
         
 
        
 
 
 
 
 
 
 
 
9 
STATISTICAL PLAN..........................................................................................................62 
      9.1     Sample Size ..........................................................................................................62 
      9.2        Analysis Populations ...........................................................................................63 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..67 
10.1 
Good Clinical Practice ......................................................................................67 
10.2       Institutional Review Board/Ethics Committee Approval ..............................67 
10.3       Informed Consent ..............................................................................................67 
10.4       Recording and Collecting of Data ....................................................................68 
10.4.1 
Case Report Forms ............................................................................................68 
10.4.2 
Protocol Deviations and Compliance ...............................................................68 
10.5  
Safety Oversight .................................................................................................68 
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10.7 
Clinical Monitoring ...........................................................................................69 
11  DATA HANDLING AND RECORD KEEPING...............................................................70 
11.1  
Data Collection and Management Responsibilities ........................................70 
11.2       Study Records Retention ...................................................................................72 
11.3       Treatment of Missing Data ...............................................................................72 
       
 
       
 
11.6 
Access to Information for Monitoring and Auditing .....................................74 
11.7 
Termination of the Study ..................................................................................74 
 
 
 
     
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
   
 
      
 
     
 
 
 
List of Tables 
  
 
 
 
Table 3. 
Clinical Laboratory Parameters .............................................................................50 
 
 
Table 5. 
Injection Site Evaluation ..........................................................................................57 
 
  
 
 
List of Figures 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
AE 
adverse event 
AP 
aggregate posture 
AROM 
active range of motion 
BoNT 
botulinum neurotoxin  
BoNTA 
botulinum neurotoxin type A 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CD 
cervical dystonia 
CI 
confidence interval 
COVID-19 
Coronavirus disease 2019 
CS 
clinically significant 
DAS 
Disability Assessment Scale 
DAXI 
daxibotulinumtoxinA, RTT150 
DAXI for injection 
daxibotulinumtoxinA for injection 
DCC 
Data Coordinating Center 
DMC 
Data Monitoring Committee 
DSFS 
Drooling Severity and Frequency Scale 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
EuroQoL Five Dimension Scale (EQ-5D-5L) 
ET 
early termination 
FMUE 
Fugl-Meyer Upper Extremity 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IM 
Intramuscular 
INR 
International Normalized Ratio 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Randomization System 
kDa 
Kilodalton 
MAS 
Modified Ashworth Scale 
MMRM 
mixed model repeated measures 
NOAEL 
no observed adverse effect level 
PI 
principal investigator 
PP 
per protocol 
PT 
prothrombin time 
PTT 
principal treatment target 
QoL 
quality of life 
QT 
time from start of the ECG q wave and the end of the t wave 
Revance 
Revance Therapeutics, Inc. 
RT002 
previous name for daxibotulinumtoxinA for injection 
RTP004 
Revance proprietary stabilizing excipient 
RTT150 
previous drug substance (daxibotulinumtoxinA) name 
SAE 
serious adverse event 
SDST 
Serious Distant Spread of Toxin 
SF-36 
Short-Form 36 
SMG 
suprahypertonic muscle group 
SOA 
Schedule of Activities 
SOP 
standard operating procedure 
TS 
Tardieu Scale 
TdP 
Torsade de Pointe 
TEAE 
treatment-emergent adverse event 
U 
units (botulinum toxin) 
UP 
unanticipated problem 
UPT 
urine pregnancy test  
US 
United States 
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Abbreviation 
Definition 
WOCBP 
women of child bearing potential 
 
 
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1 
INTRODUCTION 
1.1   Pathophysiology of Spasticity 
Spasticity is a motor symptom characterized by an increase in velocity dependent stretch 
reflexes, with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex, as 
one component of the upper motor neuron syndrome (Brashear, 2016). Spasticity is one of 
several abnormalities of muscle tone, and is characterized by rigidity, muscle tightness, joint 
stiffness, involuntary jerky movements, exaggeration of reflexes, unusual posture, 
abnormal positioning of fingers, wrists, arms, or shoulders, and muscle spasms. Primary causes 
of spasticity are anoxia secondary to cerebrovascular ischemia (stroke), trauma to the brain or 
spinal cord, and neurodegenerative diseases such as multiple sclerosis. (Brashear, 2011). 
Essentially spasticity can result from a lesion or injury anywhere along the corticospinal 
(pyramidal) tracks including the motor cortex, basal ganglia, thalamus, brainstem, cerebellum, 
central white matter or spinal cord. Fatigue, impaired coordination, impaired motor control, 
impaired motor planning, and muscle weakness often accompany spasticity and contribute to 
functional motor impairment, discomfort, and pain.  
Effective treatment of spasticity is lacking. Pharmacotherapy has included baclofen (oral and 
intrathecal), benzodiazepines, dantrolene, phenol or alcohol injections, gabapentin, lamotrigine, 
cyproheptadine and cannabinoids, all with minimal success. Physical therapy, splints, casts and 
functional electrical stimulation have been useful to stimulate or stretch muscles and minimize 
soft tissue contractures.  The most affected subjects may need to undergo orthopedic or 
neurological surgery.  However, none of these methods of treating spasticity have been effective. 
Recent studies have demonstrated that intramuscular injections (IM) of botulinum toxin type A 
shows promise in effectively relieving many spastic symptoms, particularly when combined with 
physical therapy (Royal College of Physicians, 2009). By preventing acetylcholine release from 
the presynaptic nerve terminal and thus blocking cholinergic transmission at the neuromuscular 
junction, botulinum toxins (BoNTs) induce a reduction in muscle contraction and muscle tone. 
As a result, BoNTA has become the treatment of choice for multifocal spasticity (Kaku & 
Simpson, 2016). 
 
 
 
 
 
  
 
 
 
 
 
 
 
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2.1 
Primary Objective 
x 
To compare the safety and efficacy of a single treatment of DAXI for injection at three 
dose levels (250 U, 375 U, 500 U) versus placebo in reducing muscle tone of adult 
subjects with upper limb spasticity due to stroke or TBI 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
3 INVESTIGATIONAL PLAN 
3.1    Overall Study Design 
JUNIPER is a randomized, double-blind, placebo-controlled trial will evaluate the efficacy and 
safety of DAXI for injection (3 dose levels) vs placebo for the treatment of ULS after stroke or 
TBI in adult subjects. 
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Approximately 128 adult subjects with ULS after stroke or TBI will be recruited from study 
centers across the US. 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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3.2   Efficacy Measures 
x Modified Ashworth Scale (MAS) 
x Disability Assessment Scale (DAS)  
x Physician Global Impression of Change (PGIC) 
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x Patient or Caregiver Global Impression of Change (P/CGIC) 
x Spasticity per the Tardieu Scale (TS) 
x Active Range of Motion (AROM) 
x Active function via the Fugl-Meyer Upper Extremity (FMUE) Assessment   
x EuroQoL Five Dimension Scale (EQ-5D-5L) 
x Short Form Health Survey (SF-36) 
3.3    Safety Measures 
x Adverse events  
 
 
 
 
x Vital signs, physical and neuro examination findings 
x Injection site evaluations 
x Spirometry (pre-COVID-19 only) 
x Laboratory tests (CBC, PT/INR, chemistry panel, urinalysis)  
x 12-lead ECGs  
x Concomitant medications  
 
 
x Columbia-Suicide Severity Rating Scale (C-SSRS) 
3.4   Endpoints 
x Co-Primary Endpoints   
o Mean change from baseline in muscle tone measured with the MAS in the 
suprahypertonic muscle group (SMG) of the elbow, wrist, OR finger flexors at  
Week 6 
o Mean score of the PGIC at Week 6 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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3.5    Duration of Trial 
To provide a sufficient amount of time to document the duration of effect and safety profile of 
DAXI administered doses, all subjects will be prospectively followed for a minimum of 
12 weeks and a maximum of 36 weeks. With a median duration of effect of at least 24 weeks 
experienced by adult subjects with cervical dystonia given a single treatment of DAXI for 
injection in the RT002-CL005 Study and adults with glabellar lines treated with a single 
treatment of DAXI for injection from the SAKURA Studies, it is scientifically justifiable to 
follow adult subjects with upper limb spasticity treated with DAXI for injection for up to 
36 weeks.  
Due to the COVID-19 pandemic impact study enrollment, visits, and conduct, subjects enrolled 
after the 20 March 2020 screening and enrollment hold will complete the study at Week 12. 
Subject participation may be terminated early for continuing or emergent safety concerns related 
to COVID-19. Sufficient results should be available to make informed decisions for program 
development.   
3.6    End of Study Definition 
For subjects enrolled before COVID-19, the EOS visit for a given subject can occur at Week 12 
if the change in MAS score in the SMG is < 1-point reduction from baseline AND the PGIC 
score is ≤ 0.   
The EOS visit will occur after Week 12 when there is loss of muscle tone improvement in the 
SMG (i.e., a reduction from baseline in MAS score of < 1-point) AND the PGIC score is ≤ 0. 
Week 36 will be the end of study for all subjects even those who maintain the muscle tone 
improvement in the SMG (i.e., a reduction from baseline in MAS score of t 1-point) OR the 
PGIC score is t 1.  
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For subjects enrolled after the COVID-19 20 March 2020 screening and randomization hold the 
end of study will be at Week 12.   
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
STUDY POPULATION  
4.1 
Diagnosis and Main Eligibility Criteria 
Adult subjects with a diagnosis of upper limb spasticity after stroke or traumatic brain injury 
meeting the full eligibility criteria may participate in the study.  Major inclusion and exclusion 
criteria are presented below. 
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4.1.1 Inclusion Criteria  
All subjects must meet the following inclusion criteria: 
1. Adults, 18 to 75 years of age, inclusive. 
2. Written informed consent including authorization to release health information. 
3. Focal ULS after a stroke (as defined by WHO criteria) or TBI, last stroke or TBI > 24 
weeks prior to Screening. 
4. Upper limb spasticity with the primary aggregate posture (AP): flexed elbow + flexed 
wrist + clenched fist (flexed fingers) and ≥ 1 other clinical pattern(s): adducted and 
internally rotated shoulder, pronated forearm, thumb-in-palm and/or intrinsic plus hand.  
5. Moderate to severe ULS with a MAS score ≥ 2 at the elbow, wrist, and finger flexors; 
with the exception that the MAS score is ≥ 3 at the suprahypertonic muscle group (SMG) 
for subjects with previous injections of BoNTA in the paretic limb.   
6. Moderate to severe functional disability (DAS score ≥ 2) on the principal target of 
treatment (1 of 4 functional domains: hygiene, dressing, malposition of the 
arm/wrist/fingers, and pain). 
7. Has sufficient cognitive and communication ability to be able to give informed consent 
including authorization to release health information. 
4.1.2 
Exclusion Criteria    
1. Upper limb spasticity attributable to an etiology other than stroke or TBI. 
2. Bilateral upper limb paresis or quadriplegia. 
3. Initiated in physiotherapy of the upper extremities ≤ 30 days prior to Screening or 
planned to start physiotherapy of the upper extremities during the course of the study. 
4. Previous treatment with any BoNT product for any condition ≤ 16 weeks prior to 
Screening.  
5. Botulinum neurotoxin treatment-experienced subjects who have historically required 
< 200 U of Botox/Xeomin or its equivalent to effectively treat the upper limb spasticity. 
6. Botulinum neurotoxin treatment-experienced subjects who had suboptimal or no 
treatment response to the most recent BoNTA injection for spasticity, as determined by 
the investigator; or history of primary or secondary non-response to BoNTA injections, 
known to have neutralizing antibodies to BoNTA; or have a history of botulinum toxin 
type B (rimabotulinumtoxinB [Myobloc/Neurobloc]) injection for spasticity due to non-
response or suboptimal response to BoNTA. 
7. Change in oral medications for spasticity including dosage and dosing frequency ≤ 30 
days prior to Screening. 
8. Previous or planned treatment of the spastic upper limb with phenol, alcohol injection or 
surgery.  
9. Profound muscular atrophy or fixed contracture (spasticity angle, per the Tardieu Scale, 
<10 degrees in the most hypertonic muscle group [elbow, wrist or finger flexors]) of the 
spastic limb leading to marked limitation on passive range of motion or any other known 
conditions of the upper limb that could confound muscle tone or functional assessment.   
10. Prior or current treatment with intrathecal baclofen pump.  
 
 
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(e.g., amyotrophic lateral sclerosis and motor neuropathy, and neuromuscular junctional 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.4 
Concomitant Medications 
Concomitant medications are any prescription or over-the-counter preparations, including herbs, 
vitamins, or other nutritional supplements, used by subjects during participation in the study. Use 
of concomitant medications will be recorded on the Concomitant Medications electronic case 
report form (eCRF) from Screening through end of study. Subjects are allowed to be on a stable 
dose of medications (if any) used for spasticity treatment (e.g., anticholinergics, muscle 
relaxants, benzodiazepines) for at least 4 weeks prior to screening and continuing through end 
of study. 
 
 
 
 
 
 
 
 
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4.5 
Screen Failures 
A screen failure subject will be an individual from whom informed consent is obtained and is 
documented in writing (i.e., subject signs an informed consent form) but who does not meet the 
study eligibility requirements. 
Individuals who do not meet the criteria for participation in this study (screen failure) because of 
failure to meet an eligibility criterion that may requalify them after a waiting period (such as a 
clinically significant out of range clinical laboratory result, prohibited medication use, etc.), or 
because the treatment was not performed within the 21-day window after screening, may be 
rescreened once. Rescreened subjects may be assigned a different subject number from the one 
assigned at initial Screening. 
4.6 
 Subject Discontinuation/Withdrawal Criteria  
Study subjects will receive a one (1) time only treatment for this study. Discontinuation of study 
treatment is not applicable. However, subjects may choose to discontinue their participation in 
the follow-up phase at any time.  
x If the subject withdraws consent and discontinues from the trial, the Investigator will attempt 
to determine the reason for discontinuation and record the reason in the subject’s trial records 
and on the case report form (CRF). 
x 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) and 
whenever possible, the subject should be asked to return to the trial center to complete the 
assessments specified in the Week 12/Early Termination visit. Subjects who withdraw from 
the trial will not be replaced. 
x If at any time during the trial, the Investigator determines that it is not in the best interest of 
the subject to continue, the subject will be discontinued from participation.  
x The Investigator can discontinue a subject from study participation at any time if medically 
necessary or if the subject has failed to follow trial procedures or to keep follow-up 
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appointments. Appropriate documentation in the subject’s trial record and CRF 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 trial 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 trial. If a subject is unreachable by telephone after a 
minimum of two (2) documented attempts (one [1] attempt on two [2] different days), a 
registered letter will be sent requesting that contact be made with the Investigator.  
Revance can terminate or to stop the trial at any time. Should this be necessary, both Revance 
and the Investigator will ensure that proper study discontinuation procedures are completed. 
4.7 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled study 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
The site will attempt to contact the participant and reschedule the missed visit(s) and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
Before a participant is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the participant (where possible, three (3) telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record or 
study file. 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
5 
STUDY VISITS AND PROCEDURES 
5.1  
Screening Visit (Day -21 to -1) 
Subjects presenting with upper limb spasticity will be examined to verify the diagnosis of spastic 
hemiparesis. Then, subjects with upper limb spasticity will be screened to determine if they meet 
the study eligibility criteria. Prospective study participants will be informed of the study, and the 
requirements for study participation will be explained to them. Subject informed consent must be 
obtained prior to conducting screening procedures. Refer to Table 1.1. Schedule of Study 
Assessments and Procedures for activities to be performed. 
At screening, protocol-specified procedures include: 
x Physical and neurological examinations  
x Laboratory: serum chemistry, hematology, PT/INR, 
  
x Urinalysis 
 
  
x Concomitant medications 
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x Medical/surgical and neurological history  
x 12-lead electrocardiogram 
x Columbia-Suicide Severity Rating Scale (C-SSRS) – Baseline/Screening version 
x Modified Ashworth Scale (MAS) 
x Disability Assessment Scale (DAS) 
x Tardieu Scale (TS) 
x Active Range of Motion (AROM) 
 
Results from clinical laboratory tests and centrally-read ECGs must be obtained and reviewed by 
the investigator. WOCBP with a positive pregnancy test must be excluded from study entry.  
Before enrolling WOCBP in this clinical trial, investigators must review guidelines about study 
participation for WOCBP. The topics should generally include: 
x 
Informed consent document 
x 
Pregnancy prevention information 
x 
Risks to unborn children 
x 
Any drug interactions with hormonal contraceptives 
x 
Contraceptives in current use 
x 
Guidelines for the follow-up of a reported pregnancy 
 
A female is considered to be of childbearing potential UNLESS she is post-menopausal (no 
menses for 12 consecutive months) or without a uterus and/or both ovaries.  
WOCBP and male subjects must, accordingly, use an effective method of birth control such as 
oral contraceptive, injection, implant, patch, vaginal ring, intrauterine coil or device, tubal 
ligation, and female/male condom with either cap, diaphragm, or sponge with spermicide 
(double barrier methods). True abstinence (i.e. no heterosexual intercourse) when it is in line 
with preferred and usual lifestyle, or having a vasectomized partner is considered acceptable 
methods of contraception. Effective methods of contraception must be used from the start of 
study, Screening visit, to 30 days after the end of study participation. 
Prior to study enrollment, WOCBP and male subjects must be advised of the importance of 
avoiding pregnancy during participation in this clinical study from the Baseline visit to 30 days 
after the end of study participation, and the potential risk factors for an unintentional pregnancy. 
The subject must sign the informed consent document stating that the above-mentioned 
risks/consequences were discussed with her/him. 
During the study, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual cycle). The investigator must 
immediately notify the sponsor or the authorized representative of any female subject who 
becomes pregnant any time during study participation. The site will be asked to follow-up with 
the subject periodically during the pregnancy for ongoing health and safety information through 
term, as applicable. Given that this is a single treatment administration study, subjects who 
become pregnant after receiving their study treatment will not be automatically discontinued 
from the study. 
After the required screening procedures are completed and study eligibility is confirmed, the 
subject is enrolled in the study and randomized to a treatment arm. 
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5.2 Baseline/Treatment Visit (Day 1) 
The Baseline/Treatment Visit must be performed within 21 days of the Screening Visit.  
 
  
The following procedures will be completed pre-treatment on Day 1 (refer to the SOA):  
x 
Vital signs (blood pressure [BP], pulse, temperature) and weight 
 
 
 
 
 
 
 
x 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Baseline/Screening version 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
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5.3 
Follow-up Visits 
 
 
 
    
 
 
 
 
  
 
The following procedures will be completed at follow-up visits:  
 
 
x Vital signs (blood pressure [BP], pulse, temperature) and weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x Columbia- Suicide Severity Rating Scale (C-SSRS)- Since Last Visit version 
 
 
 
 
 
 
 
 
 
 
 
 
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5.4 
End of Study Visit 
A participant is considered to have completed the study when the MAS score has returned to 
baseline levels and the PGIC ≤0, or the Week 36 visit whichever comes first and has completed 
the last scheduled procedure shown in Table 1.1. Schedule of Study Assessments and 
Procedures.  
Subjects enrolled post COVID-19, after 20 March 2020 will have the EOS Visit at Week 12 as 
shown in Table 1.2. Table 1.1. Schedule of Study Assessments and Procedures. 
The EOS Visit may also occur when a subject prematurely withdraws from the study for specific 
reasons (e.g., AEs, pregnancy, or withdraws consent).    
 
6    SAFETY ASSESSMENTS 
6.1 
Clinical Laboratory Tests 
A central laboratory will be used to process all clinical specimens. The clinical laboratory 
parameters that will be evaluated in the study are listed in Table 3. 
Table 4. 
Clinical Laboratory Parameters 
Hematology 
Chemistry 
Urinalysis 
Additional Tests 
Hemoglobin 
Hematocrit 
Leukocyte count 
(total) 
Leukocyte count 
(differential) 
Red blood cell count 
Platelet count 
 
Sodium 
Potassium 
Chloride 
CO2 
Calcium 
Albumin 
Glucose 
Total bilirubin 
Alanine 
aminotransferase 
Specific gravity 
pH 
Glucose 
Protein 
Blood 
Bilirubin 
Ketones 
  
 
 
  
  
PT/INR 
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Aspartate 
aminotransferase 
Alkaline phosphatase 
Blood urea nitrogen 
Creatinine 
CO2=carbon dioxide; ET=early termination; WOCBP=women of childbearing potential. 
 
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 pre-treatment 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, and pregnancy tests) and note Not Clinically Significant 
(NCS) or Clinically Significant (CS) 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 to be assessed according to severity. Refer to Section 6.2 for further 
information. 
 
 
 
6.2 
Adverse Events 
6.2.1 
Assessment of Adverse Events:  
Adverse Events (AEs) will be graded as mild, moderate, or severe as defined in Section 6.2.2.3 
of this protocol. 
AEs will be evaluated at the Injection visit post-treatment, follow-up Weeks 2, 4, 6, 8, 12,16, 20, 
24, 28, 32 and 36/EOS, if applicable.  
Adverse events will be reported by the Sponsor in accordance with “21CRF part 312.32 and 
Guidance for Industry and Investigators: Safety Reporting Requirements.” The Investigator will 
report any serious adverse events (SAEs) to the IRB. 
Subjects should be told to seek immediate medical attention if they experience any abnormal 
symptoms after investigational product administration, especially: 
x 
Generalized loss of strength and muscle weakness 
x 
Difficulty swallowing, breathing or speaking 
x 
Extreme tiredness 
x 
Loss of bladder control  
x 
Symptoms of allergic reaction (rash, itching, etc.) 
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6.2.2  Adverse Events and Serious Adverse Events 
6.2.2.1  Definition of 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 trial 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, whether or not 
considered related to the investigational product. A treatment-emergent AE (TEAE) 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 clinically significant change in the study safety evaluations, (e.g., vital signs, 
laboratory results, ECG, injection site evaluation, physical/neurological examinations, etc.) post-
treatment must be reported as an AE. 
6.2.2.2     Definition of Serious Adverse Events (SAE)  
A serious adverse event (SAE) is any untoward medical occurrence that results in any of the 
following outcomes: 
x Death 
x 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) 
x Persistent or significant disability/incapacity or substantial disruption of the subject’s 
ability to carry out normal life functions 
x Requires in-patient hospitalization or prolongs hospitalization (i.e., a prolonged 
hospitalization beyond the expected length of stay; hospitalizations for elective 
medical/surgical procedures, scheduled treatments, or routine check-ups are not SAEs by 
this criterion) 
x 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) 
x 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 (1) of the outcomes listed above (i.e., is a significant or important medical 
event) 
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6.2.2.3    Classification of an Adverse Event 
Relationship of an AE to investigational product will be assessed as follows: 
x 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 
x 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 
x 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 
x 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, or severe according to the following definition: 
x Mild: Event may be noticeable to subject; does not influence daily activities; usually 
does not require intervention 
x Moderate: Event may be of sufficient severity to make a subject uncomfortable; 
performance of daily activities may be influenced; intervention may be needed 
x 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 
Expectedness  
The Sponsor medical monitor will be responsible for determining whether an adverse event (AE) 
is expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. Expectedness is further defined in the Investigator’s Brochure (IB) under 
Anticipated Risks and Side Effects. The list of AEs found in the IB can be considered to be 
expected AEs.   
6.2.2.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
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resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. The investigator will assess subject post-treatment and at 
each subsequent study visit for the occurrence of AEs. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The investigator should follow the SAE until it resolves or is determined by the investigator to be 
stable, or the subject is lost to follow-up. The investigator should continue to report any 
significant follow-up information to the sponsor or the authorized representative, and the IRB, up 
to the point the event has resolved, or is determined to be stable. Resolution means the subject 
has returned to the baseline state of health, and stable means 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 the sponsor or the authorized 
representative, and the IRB, as required. 
6.2.2.5    Adverse Event Reporting  
The Investigator will assess subjects for post-treatment AEs at each subsequent trial visit. In 
order 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) reported by the 
subject must be recorded on the source documents and CRFs. Adverse events related to 
COVID19 should be documented.   
6.2.2.6 Serious Adverse Event Reporting 
An Investigator must report an SAE to Revance or the designated CRO representative within 
24 hours of their awareness of the event:  
 
1. Complete and return an SAE Form with all information known to date; including the 
Investigator’s assessment of causality. 
2. A fatal or life-threatening SAE must be telephoned to Revance or the authorized 
representative as soon as the Investigator learns of the event. 
3. All pertinent medical records (discharge summary, autopsy report, etc.) should be 
obtained and judgments of all medical personnel who assisted in subject’s treatment and 
follow-up. 
4. Provide follow-up information to Revance or the authorized representative. 
 
All SAEs will be followed until satisfactory resolution or until the Investigator deems the event 
to be chronic or the participant is stable. Other supporting documentation of the event may be 
requested by the Data Coordinating Center (DCC)/study sponsor and should be provided as soon 
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as possible. The study sponsor will be responsible for notifying the FDA of any unexpected 
fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor’s initial receipt of the information. In addition, the 
sponsor must notify FDA and all participating investigators in an Investigational New Drug 
(IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting. Regulatory authorities, IRBs, and Investigators will be 
notified of SAEs in accordance with applicable regulations and requirements (e.g., GCPs, ICH 
Guidelines, national regulations and local requirements). 
6.2.2.7     Reporting Events to Participants  
Revance will disclose clinical trial data to individuals, to investigators at clinical sites, and 
publicly as aggregate summaries, in accordance to Regulatory and local legal requirements. 
Follow-up of Non-Serious Adverse Events 
Non-serious AEs that are identified during the last scheduled trial visit (or early discontinuation, 
if applicable) must be recorded on the AE CRF as ongoing. 
Any clinically significant abnormal test results, e.g., laboratory findings, at the Week 12/Early 
Termination visit 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, trial-related abnormalities at the end of the trial, 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. 
Follow-up of Post-Trial Serious Adverse Events 
SAEs that are identified on the last scheduled contact (or early discontinuation, if applicable) 
must be recorded on the AE CRF page and reported to the CRO and Revance according to the 
reporting procedures outlined in Section 6.2.2.6. This may include unresolved previously 
reported SAEs, or new SAEs. The Investigator should follow these SAEs until the events are 
resolved, or the subject is lost to follow-up. The Investigator should continue to report any 
significant follow-up information to the Medical Monitor, Revance, and the IRB 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 and the IRB. 
     
 
 
 
 
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6.3 
Injection Site Evaluation:  
The injection sites will be evaluated at Injection Visit (Day 1) pre- and post- treatment (to 
determine if there is an immediate reaction to the investigational product), follow-up visits 
(Weeks 2, 4, and 36 or Early Termination visit), if applicable. The assessment will be done as a 
global evaluation of the injection sites to be performed pre-treatment on Injection visit.  
Table 5. 
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 
 
 
Drainage 
 
 
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6.4 
Reporting of Pregnancy 
During the trial, all WOCBP should be instructed to contact the Investigator immediately (within 
24 hours) if they suspect they might be pregnant (e.g., missed or late menstrual cycle). The 
Investigator must immediately notify Revance or designated Contract Research Organization 
(CRO) of any female subject who becomes pregnant any time during study participation, record 
the information on the Pregnancy Notification Form and send the form to the CRO. The site will 
be asked to follow-up with the subject periodically during the pregnancy for ongoing health and 
safety information through term, as applicable. Subjects will remain on the trial. 
6.5  
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
Behavior using a semi-structured interview to probe subject responses (Posner, 2008) 
(APPENDIX K). The C-SSRS is to be administered at Screening and each study visit, including 
unscheduled ones. Both the Baseline/Screening and Since Last Visit versions will be utilized. All 
assessors will receive formal training in the use of this tool. 
A subject who endorses “suicidal ideation” must be referred to a mental health professional for 
further assessment and/or treatment. 
7 
UNANTICIPATED ADVERSE EVENTS 
7.1 
Definition of Unanticipated Adverse Events 
Unanticipated problems involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria: 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the 
• Characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and suggests that the research places 
subjects or others at a greater risk of harm (including physical, psychological, economic, 
or social harm) than was previously known or recognized. 
Revance will comply with these criteria for reporting Unanticipated Adverse Events. 
7.2 Unanticipated Adverse Event Reporting  
The Investigator will report unanticipated Adverse Events to the reviewing Institutional Review 
Board (IRB) and the Sponsor. The unanticipated adverse event report will include the following 
information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number. 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated adverse event;  
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• A description of any changes to the protocol by the Sponsor or other corrective actions 
that have been taken or are proposed in response to the unanticipated adverse event. 
• The Sponsor will update the IB or provide Dear Doctor letter should these actions be 
deemed required.  
To satisfy the requirement for prompt reporting, unanticipated adverse events will be reported 
using the following timeline:   
• Unanticipated adverse events that are fatal and life-threatening serious adverse events 
(SAEs) will be reported to the IRB and to the Sponsor within seven (7) days of the 
Investigator becoming aware of the event.  
• Any other unanticipated adverse events that are SAEs will be reported to the IRB and to 
the Sponsor within 15 days of the Investigator becoming aware of the problem.  
• All unanticipated adverse events that non-serious AEs are not required to be reported to 
the IRB or to the Sponsor.  
• All unanticipated serious adverse events should be reported to appropriate institutional 
officials (as required by an institution’s written reporting procedures), the supporting 
agency head (or designee), and the Office for Human Research Protections (OHRP) if 
applicable.  
7.3  Reporting Unanticipated Adverse Events to Participants  
Revance will disclose clinical trial data to individuals, to investigators at clinical sites, and 
publicly as aggregate summaries, in accordance to Regulatory and local legal requirements. 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
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9 
STATISTICAL PLAN  
This section contains a brief overview of the statistical analyses planned for this study. A formal 
statistical analysis plan (SAP) will be finalized before database lock.  
9.1 
Sample Size  
The sample size calculation is based on the effect size that was observed for the primary 
endpoint (change from baseline in MAS in the SMG) from the registration study of Dysport 
(Gracies J, 2015) for the treatment of ULS.
 
 
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9.2  Analysis Populations  
x Intent-to-Treat Population: Efficacy analysis will be performed using the intention-to-treat 
analysis set. This population includes all subjects randomized, given one injection session of 
the study medication and have a MAS score in the SMG at baseline and 6 weeks after 
treatment and a PGIC score at least one post-baseline MAS assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
x Pre-COVID-19 ITT Population: a subset of the ITT population, subjects who were enrolled 
before COVID-19 enrollment hold (20MAR2020).  
x Pre-COVID-19 PP Population: a subset of the PP population, subjects who were enrolled 
before COVID-19 enrollment hold (20MAR2020).  
 
 
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Analysis Plan 
9.2.1. Primary Analyses  
Efficacy analysis will be performed using the intention-to-treat analysis set. This population 
includes all subjects randomized, given one injection session of the study medication and have a 
MAS score in the SMG at least one post-baseline MAS assessment.  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS   
10.1 
Good Clinical Practice  
It is the responsibility of the Principal Investigator to oversee the safety of the subject at their 
site. The Investigator will ensure that this study is conducted in full compliance with the 
principles of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted. By signing the US Form FDA 1572, “Statement of Investigator”, the 
Investigator commits to adhere to applicable sections of the US 21CFR parts 50 “Protection of 
Human Subjects”, 54 “Financial Disclosure by Clinical Investigators”, 56 “Institutional Review 
Boards”, and 312 subpart D “Responsibilities of Sponsors and Investigators”. All Investigators 
will ensure adherence to ICH guidelines for GCP and Clinical Safety Data Management. 
10.2    Institutional Review Board/Ethics Committee Approval 
The institution’s IRB, or other committee functioning in a similar capacity, will review and 
approve the protocol and any protocol amendments, initial and any revised IC documents, 
protocol amendments, and safety items. After approval by the IRB, documentation of approval 
and the approved Informed Consent document will be sent to Revance/designee before any 
subject is enrolled into this study. 
10.3   Informed Consent  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Written informed 
consent will be obtained from all subjects before any study-related procedures (including any 
pre-treatment screening procedures) are performed. The investigator may discuss the study 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 study has been given a full explanation of the 
procedures and expectations for study participation. 
When applicable, the site-specific informed consent must be forwarded to the sponsor for 
approval prior to submission to an IRB that is registered with appropriate local or federal 
agencies as required. Each subject will sign the consent form that has been approved by the same 
IRB 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, Health Canada’s Food and Drug Regulations, Division 5, 
European Medicines Agency (EMA), as well as the elements required by the ICH-GCP 
guideline, and applicable national and local regulatory requirements. The consent form must also 
include a statement that the sponsor, their designees, and auditing regulatory agencies will have 
direct access to the subject’s records and medical history for study related purposes. 
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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 study, the IRB 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 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).  
10.4      Recording and Collecting of Data 
In accordance with ICH and GCP guidelines, the Investigator will maintain complete, accurate, 
legible, and easily retrievable data, and will allow personnel authorized by Revance access to all 
study data at any time. Such data shall also be secured in order to prevent loss of data. 
10.4.1  Case Report Forms 
At scheduled monitoring visits, CRFs will be verified against source documentation and 
submitted as final data.  
10.4.2  Protocol Deviations and Compliance 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations as soon as possible. All deviations must be entered in the eCRFs and must be sent to 
the reviewing IRB per their policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.  
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and well-being of the subject requires immediate intervention, 
based on the judgment of the investigator (or a responsible, appropriately trained professional 
designated by the investigator). In the event of a significant deviation from the protocol due to an 
emergency, accident, or mistake, the investigator or designee must contact the medical monitor 
and the sponsor at the earliest possible time by telephone. This will allow an early joint decision 
regarding the subject’s continuation in the study. This decision will be documented by the 
investigator and the medical monitor. 
10.5  Safety Oversight 
Safety oversight will be under the direction of an independent Data Monitoring Committee 
(DMC) composed of individuals with the appropriate expertise, including indication and/or 
neuromodulators and/or data management. The DMC will be appointed to review safety data 
during the study and will monitor quality and completeness of the safety data, as well as signals 
and outcomes (SAEs, AEs, laboratories, and other outcome data). Data will be reviewed in both 
blinded and unblinded manners, as appropriate.  
The DMC will consist of 5 members, including a chair, a biostatistician, two neurologists, a 
pulmonologist, and a cardiologist.  Details of the composition, identity of members, and scope of 
the committee’s mandate will be presented in a DMC charter document. 
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10.7 
Clinical Monitoring 
All aspects of the study will be monitored by the sponsor or authorized representatives of the 
sponsor according to GCP and Standard Operating Procedures (SOPs) for compliance with 
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applicable government regulations, (i.e., Informed Consent Regulations [US 21CFR, Part 50] 
and Institutional Review Board regulations [US 21CFR, Part 56.103]). Access to all records, 
both during the trial and after trial completion, should be made available to the sponsor at any 
time for review and audit to ensure the integrity of the data. The investigator must notify sponsor 
immediately if the responsible IRB has been disqualified or if proceedings leading to 
disqualification have begun. 
The investigator must conduct the protocol in accordance with applicable GCP regulations and 
guidelines; applicable informed consent regulations (US 21CFR, Part 50); and in compliance 
with the Declaration of Helsinki. Every attempt must be made to follow the protocol and to 
obtain and record all data requested for each subject at the specified times. If data is not recorded 
per protocol, the reasons must be clearly documented on the eCRF/records. 
Before study initiation, at a site initiation visit or at a meeting with the investigator(s), a 
representative from the sponsor will review the protocol and study eCRFs with the 
investigator(s) and their staff. During the study, the study monitor will visit the site regularly to 
check the completeness of subject records, the accuracy of entries on the eCRFs, the adherence 
to the protocol and to GCP, the progress of enrollment, and to ensure that consent is being sought 
and obtained in compliance with applicable regulations, and that the investigational product is 
being stored, dispensed and accounted for according to specifications. The investigator and key 
trial personnel must be available to assist the monitor during these visits. 
The investigator must give the monitor access to relevant hospital or clinical records, to confirm 
their consistency with the eCRF entries. No information in these records about the identity of the 
subjects will leave the study center. Monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and the recording of primary efficacy and safety variables. Additional checks of the 
consistency of the source data with the eCRFs will be performed according to the study-specific 
monitoring plan. 
The investigator must promptly complete the eCRFs after the subject’s visit. The monitor is 
responsible for reviewing them and clarifying and resolving any data queries. A copy of the 
eCRFs will be retained by the investigator who must ensure that it is stored in a secure place with 
other study documents, such as the protocol, the Investigator’s Brochure, and any protocol 
amendments.   
11  DATA HANDLING AND RECORD KEEPING 
11.1  Data Collection and Management Responsibilities  
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 sponsor’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 
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records. Subjects will be informed of the importance of increased record access and permission 
granted by signature on the informed consent document prior to Screening. 
Checks will be performed to ensure the quality, consistency, and completeness of the data. 
Instances of missing or uninterpretable data will be resolved with the investigator or study 
coordinator. Data queries, documented on data query forms, will be sent to the research facility. 
Site personnel will be responsible for providing resolutions to the data queries and for correcting 
the eCRFs, as appropriate. All unused sponsor source documents and binders must be returned to 
the sponsor 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:  
x Name 
x Contact information 
x Age 
x Sex 
x Medical history 
x Concomitant diseases 
x Concomitant therapies/medication 
x Study visit dates 
x Performed examinations, evaluations, and clinical findings 
x Investigational product administration 
x 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 study number, and 
the date of the evaluation.   
The data recorded during the course of 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 the sponsor. 
The data will then be recorded, evaluated, and stored in anonymous or coded form in accordance 
with data-protection regulations. 
Subjects will authorize the use of their protected health information during the informed consent 
process in accordance with the applicable privacy requirements. Subjects who deny permission 
to use and disclose protected health information will not be eligible to participate in the study. 
The investigator will ensure that the study documents forwarded to the sponsor, and any other 
documents, contain no mention of subject names. 
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 so 
as to avoid unnecessary follow up inquiries. 
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Regulatory authorities, the IRB and/or the sponsor’s Quality Assurance group (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. Electronic CRFs 
(eCRFs) will be kept by the sponsor or an authorized 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 the sponsor after descriptive and 
statistical analyses and reports have been generated and are complete. 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with the ICH Guidance for Industry E6 Good Clinical Practice: Consolidated 
Guidance, Section 8 – Essential Documents for the Conduct of a Clinical Trial. 
11.2 Study Records Retention 
It is a sponsor requirement that all investigators participating in clinical studies maintain detailed 
clinical data for one of the following periods: 
x Country-specific requirements, or 
x A period of at least two 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 
x A period of two years after the sponsor notifies the investigator that the data will not be 
submitted for review by any Regulatory Authority  
The investigator must not dispose of any records or essential documents relevant to this study 
without either (1) written permission from the sponsor, or (2) providing an opportunity for the 
sponsor to collect such records. The investigator shall take 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 the sponsor 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 sponsor in writing. 
It is the responsibility of the investigator to ensure that the study center file is maintained in 
accordance with the ICH Guidance for Industry E6 Good Clinical Practice: Consolidated 
Guidance, Section 8 - Essential Documents for the Conduct of a Clinical Trial. 
11.3 Treatment of Missing Data 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations as soon as possible. All deviations must be addressed in study source documents and 
must be sent to the reviewing IRB per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and well-being of the subject requires immediate intervention, 
based on the judgment of the investigator (or a responsible, appropriately trained professional 
designated by the investigator). In the event of a significant deviation from the protocol due to an 
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emergency, accident, or mistake, the investigator or designee must contact the medical monitor 
and the sponsor at the earliest possible time by telephone. This will allow an early joint decision 
regarding the subject’s continuation in the study. This decision will be documented by the 
investigator and the medical monitor. 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.6  Access to Information for Monitoring and Auditing 
In accordance with ICH GCP guidelines and 21 CFR 312, the CRA/auditor is to have direct 
access to the subject’s source documentation in order to verify the data recorded in the CRFs. 
The CRA is responsible for routine review of the CRFs at regular intervals throughout the study 
and to verify adherence to the protocol, as well as the completeness, consistency, and accuracy of 
the data being recorded. The CRA/auditor is to have access to any subject records needed to 
verify the entries on the CRFs, as well as access to all other study-related documentation and 
materials. The Investigator agrees to provide the monitor with sufficient time and facilities to 
conduct monitoring, and to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring/auditing visits are resolved. 
11.7   Termination of the Study 
For reasonable cause, either the Investigator or the Sponsor (Revance) may terminate the 
Investigator’s participation in this study, provided a written notice is submitted within the time 
period provided for in the Clinical Trial Agreement (CTA). In addition, Revance may terminate 
the study at any time upon immediate notice for any reason, including but not limited to, 
Revance’s belief that termination is necessary for the safety of subjects. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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