DaxibotulinumtoxinA Injection for Treatment of Adductor Spasmodic Dysphonia
Phase: PHASE1
Conditions: Adductor Spasmodic Dysphonia, Voice Disorders, Spasmodic Dysphonia
Sponsor: University of California, San Francisco

 
 
 
 
 
 
 
DaxibotulinumtoxinA Injection for Treatment of Adductor Spasmodic Dysphonia 
Study Protocol and Statistical Analysis Plan 
NCT05158166 
Document Date: 11/23/2022 

Dr. Clark Rosen 
Confidential 
 
 
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 UCSF DEPARTMENT OF OTOLARYNGOLOGY 
“DAXI” Clinical Research Protocol 
A single-arm, open-label, dose-escalation clinical trial of DaxibotulinumtoxinA for 
treatment of adductor laryngeal dystonia 
Protocol Number: 
1.0 
Version Date: 
11.23.2022 
Investigational 
Product: 
DaxibotulinumtoxinA, “DAXI” 
IND Number: 
 
Development Phase: 
Phase 4 
Sponsor: 
Clark Rosen, MD 
UCSF Voice and Swallowing Center 
2230 Post St #500 
San Francisco, CA 94115 
Funding Organization: 
UCSF Department of Otolaryngology 
 Investigator: 
Name: 
 Clark Rosen, MD 
Telephone: (415)-885-7700 
E-mail: clark.rosen@ucsf.edu 
Medical Monitor: 
Name: 
Clark Rosen, MD 
 
Telephone: (415)-885-7700 
E-mail: clark.rosen@ucsf.edu 
Coordinating Center: 
N/A 
 
Approval: 
Clark Rosen, MD; Lewis Francis Morrison, MD 
Endowed Chair in Laryngology, Chief Division of 
Laryngology 
 
 
PI or Sponsor Signature (Name and Title)  
 
Date  


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The information in this document may not be disclosed unless federal or state law or regulations 
require such disclosure.  Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information.    
 
 

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PROTOCOL AGREEMENT – single center 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study, enrolled under my supervision and providing with 
complete and timely information, as outlined in the protocol.  It is understood that all 
information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the study 
in accordance with accepted GCP principles and to abide by the terms of this protocol. 
Protocol Number:  1.0 
Protocol Title:  A single-arm, open-label, dose-escalation clinical trial of 
DaxibotulinumtoxinA for treatment of adductor laryngeal dystonia 
Protocol Date:  11.23.22 
 
 
Investigator Signature  
 
Date 
Clark Rosen, MD; Lewis Francis Morrison, MD Endowed Chair in Laryngology, 
Chief Division of Laryngology 
Print Name and Title 
Site Name 
UCSF Voice and Swallowing Center 
Address 
2330 Post St # 500 
 
San Francisco, CA 94115 
Phone 
Number 
(415) 885-7700 
 
 


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TABLE OF CONTENTS 
1 
BACKGROUND 
1.1 .................................................................................. Overview of Non-Clinical Studies 
1.2 .......................................................................................... Overview of Clinical Studies 
2 
STUDY RATIONALE 
2.1 ............................................................................................... Risk / Benefit Assessment 
3 
STUDY OBJECTIVES 
3.1 ........................................................................................................... Primary Objective 
3.2 ...................................................................................................... Secondary Objectives 
4 
STUDY DESIGN 
4.1 .............................................................................................................. Study Overview 
5 
CRITERIA FOR EVALUATION 
5.1 .............................................................................................. Primary Efficacy Endpoint 
5.2 ........................................................................................ Secondary Efficacy Endpoints 
5.3 .......................................................................................................... Safety Evaluations 
5.4 ............................................................................................................ Other Evaluations 
SUBJECT SELECTION 
5.5 ............................................................................................................. Study Population 
5.6 ............................................................................................................ Inclusion Criteria 

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5.7 ........................................................................................................... Exclusion Criteria 
6 
CONCURRENT MEDICATIONS 
6.1 ............................................................................ Allowed Medications and Treatments 
7 
STUDY TREATMENTS 
7.1 ...................................................... Method of Assigning Subjects to Treatment Groups 
7.2 .......................................................................................................................... Blinding 
7.3 ...................................................................... Formulation of Test and Control Products 
7.3.1 ............................................................................ Formulation of Test Product 
7.3.2 ....................................................................... Formulation of Control Product 
7.3.3 ................................................................................... Packaging and Labeling 
7.4 ..................................................................................... Supply of Study Drug at the Site 
7.4.1 ................................................................................. Dosage/Dosage Regimen 
7.4.2 ....................................................................................................... Dispensing 
7.4.3 .............................................................................. Administration Instructions 
7.5 ..................................................................................... Supply of Study Drug at the Site 
7.5.1 ............................................................................................................. Storage 
7.6 ............................................................................................. Study Drug Accountability 
7.7 ............................................................................... Measures of Treatment Compliance 
8 
STUDY PROCEDURES AND GUIDELINES 
8.1 ...................................................................................................... Clinical Assessments 

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8.1.1 ................................................................................ Concomitant Medications 
8.1.2 .................................................................................................. Demographics 
8.1.3 ............................................................................................... Medical History 
8.1.4 ....................................................................................... Physical Examination 
8.1.5 ........................................................................................................ Vital Signs 
8.1.6 .......................................................................................................... Oximetry 
8.1.7 ....................................................................................................... Spirometry 
8.1.8 ................................................................................ Other Clinical Procedures 
8.1.9 ................................................................................................ Adverse Events 
8.2 ................................................................................. Clinical Laboratory Measurements 
8.2.1 ...................................................................................................... Hematology 
8.2.2 .................................................................................. Blood Chemistry Profile 
8.2.3 ................................................................................................. Pregnancy Test 
8.2.4 ......................................................................................................... Urinalysis 
8.3 ...................................................................................... Pharmacokinetic Measurements 
8.4 ............................................................................... Research Laboratory Measurements 
8.4.1 .............................................................................. Cell Count and Differential 
8.4.2 ..................................................................... Sputum Cytokine Measurements 
9 
EVALUATIONS BY VISIT 
9.1 ............................................................................................................. Phone Screening 

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9.2 .............................................................................................................................. Visit 1 
9.3 .............................................................................................................................. Visit 2 
9.4 .............................................................................................................................. Visit 3 
9.5 .............................................................................................................................. Visit 4 
9.6 ....................................................................................................................... Visits 5-10 
9.7 ................................................................................................... Early Withdrawal Visit 
10 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1 ............................................................................................................. Adverse Events 
10.1.1 ............................................................................................... AE Severity 
10.2 ............................................................................. Serious Adverse Experiences (SAE) 
10.2.1 .......................................................... Serious Adverse Experience Reporting 
10.3 .......... Protocol Defined Important Medical Findings Requiring Real Time Reporting 
10.4 ...................................................................................................... Medical Monitoring 
11 
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
12 
PROTOCOL VIOLATIONS 
13 
DATA SAFETY MONITORING 
14 
STATISTICAL METHODS AND CONSIDERATIONS 
14.1 ....................................................................................................... Data Sets Analyzed 
14.2 ................................................................... Demographic and Baseline Characteristics 
14.3 ....................................................................................... Analysis of Primary Endpoint 

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14.4 ................................................................................. Analysis of Secondary Endpoints 
14.5 ............................................................................................................ Interim Analysis 
14.6 ................................................................................... Sample Size and Randomization 
15 
DATA COLLECTION, RETENTION AND MONITORING 
15.1 .......................................................................................... Data Collection Instruments 
15.2 ...................................................................................... Data Management Procedures 
15.3 ............................................................................. Data Quality Control and Reporting 
15.4 ............................................................................................................ Archival of Data 
15.5 ................................................. Availability and Retention of Investigational Records 
15.6 .................................................................................................................... Monitoring 
15.7 ................................................................................................. Subject Confidentiality 
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
16.1 ................................................................................................... Protocol Amendments 
16.2 ............................... Institutional Review Boards and Independent Ethics Committees 
16.3 ................................................................................................ Informed Consent Form 
16.4 ................................................................................................................... Publications 
16.5 ......................................................................................... Investigator Responsibilities 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADLD 
Adductor laryngeal dystonia 
Botox 
OnabotulinumtoxinA 
CAPE-V 
Consensus Auditory-Perceptual Evaluation of Voice 
CFR 
Code of Federal Regulations 
CPIB-10 
Communicative Participation Item Bank-10 
CRF 
Case report form 
DAXI 
DaxibotulinumtoxinA 
DMC 
Data Monitoring Committee 
EAT-10 
Eating Assessment Tool-10 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LD 
Laryngeal dystonia 
OMNI-VES 
OMNI Vocal Effort Scale 
PI 
Principal Investigator  
PROMs 
Patient Reported Outcome Measures 
SAE 
Serious adverse experience 

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VAS 
Visual Analog Scale  
VHI-10 
Voice Handicap Index-10 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
TITLE 
A single-arm, open-label, dose-escalation clinical trial of 
DaxibotulinumtoxinA for treatment of adductor laryngeal dystonia 
 
 
SPONSOR 
Clark Rosen M.D. 
 
 
FUNDING 
ORGANIZATION 
Departmental funding from the UCSF Department of 
Otolaryngology 
NUMBER OF 
SITES 
1 
 
 
RATIONALE 
Laryngeal dystonia (LD) is a neurologic condition causing aberrant 
contraction of the laryngeal musculature, leading to abnormal 
voicing during speech. The three types (adductor, abductor,and 
mixed) affect varying muscle groups which produce characteristic 
voice patterns. The vast majority of patients with SD have 
adductor type, which impacts the lateral cricoarytenoid and 
thyroarytenoid muscle complex. While many treatment modalities 
have been investigated, the most efficacious treatment is botulism 
toxin injection to these muscle groups, performed transcervically 
with or without electromyography (EMG) guidance. Patients 
undergoing this treatment typically require re-injection every three 
months. Due to its specialized nature, the laryngeal injections are 
not performed routinely outside of academic medical centers; thus, 
patients may come from a distance to receive this treatment. Both 
due to the significant impact on voice quality when the injections 

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wear off and the sometimes challenging access to treatment, a 
longer acting agent is desire. 
 
Injectible daxibotulinumtoxinA (DAXI, Revance Therapeutics 
Inc., Newark, CA) is a FDA-approved botulinum toxin type A 
indicated for the treatment of glabellar lines. It has been shown in 
large clinical trials to provide safe, effective treatment for cervical 
dystonia and may offer longer-lasting results when compared with 
onabotulinumtoxinA. 
 
Thus, a study examining the effect of DAXI for patients with 
adductor laryngeal dystonia (ADLD) is proposed. This study aims 
to assess the efficacy of DAXI for transcervical laryngeal injection 
in patients with adductor laryngeal dystonia. 
 
 
STUDY DESIGN 
A single-arm, open-label, dose-escalation phase 4 study. 
 
 
PRIMARY 
OBJECTIVE 
Determine the efficacy of DAXI for treatment of ADLD.  
 
 
 
SECONDARY 
OBJECTIVES 
Compare duration of benefit between DAXI and BotoxA. 
 
 
NUMBER OF 
SUBJECTS 
20 
 
 

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SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
 Age ≥18 
 Diagnosis of adductor laryngeal dystonia (ADLD) 
 Previous successful treatment with BotoxA and stabilized dose for 
the last 3 treatments 
 Acceptable form of birth control for females of childbearing 
potential. 
 Women of childbearing age must have a negative pregnancy test 
 Female participants of childbearing potential may be enrolled in 
the study if the participant fulfills all the inclusion criteria listed in 
the subject selection section below. 
Exclusion Criteria: 
 Age <18 
 Other neurologic conditions (ALS, Parkinson’s disease, essential 
tremor, Meige syndrome, etc.) 
 Pregnant, breastfeeding, or unwilling to practice birth control 
during participation in the study. 
 Presence of a condition or abnormality that in the opinion of the 
Investigator would compromise the safety of the patient or the 
quality of the data. 
 Naive from other types of Botox for 6 months including BotoxA 
 
 
TEST PRODUCT, 
DOSE, AND 
ROUTE OF 
ADMINISTRATION 
Open-label dose of DAXI injected at either 0.625, 1.25, or 2.5 
units. Dosage will be determined by subject’s previous stabilized 
Botox dosage. 
 
 

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CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
N/A 
 
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION 
OF STUDY 
Subjects will be in the study for up to 36 weeks. Total time for 
recruitment and completion of the study will be up to 2 years. 
 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: all 
Prohibited: Other forms of Botox 
 
 
EFFICACY 
EVALUATIONS 
Validated laryngology PROMs, voice analysis via mobile app 
(voice recording sample), duration of effect 
PRIMARY 
ENDPOINT 
Efficacy, measured quantitively through VHI-10 questionnaires 
SECONDARY 
ENDPOINTS 
Duration of benefit, assessed qualitatively through phone call 
surveys 
OTHER 
EVALUATIONS 
 Participant Questionnaires 
o CPIB-10 
o OMNI-VES 
o EAT-10 

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 Clinician Scales 
o Unified spasmodic dysphonia rating scale (USDRS)  
o Phonalyze 
SAFETY 
EVALUATIONS 
Incidence of adverse events 
PLANNED 
INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study’s 
initial injection, an interim analysis for safety will be conducted. 
 
 
STATISTICS 
Primary Analysis 
Plan 
Safety profile including AE and SAEs will be reported. Simple 
descriptive statistics will be used to summarize toxicities in terms 
of type, severity and minimum or maximum values for laboratory 
measures, time of onset, duration, and reversibility or outcome. 
Tables will be created to summarize these toxicities and side 
effects. Safety Analyses will be performed on Safety Analysis Set. 
Rationale for 
Number of Subjects 
A sample size of 20 will provide 80% power to detect a difference 
of 6.6 at a significance threshold (alpha) of 0.05. 
 
 

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1 BACKGROUND 
Approximately 50,000 people in North America have a diagnosis of adductor laryngeal 
dystonia (ADLD). Laryngeal dystonia (LD) is a neurologic condition causing aberrant 
contraction of the laryngeal musculature, leading to abnormal voicing during speech. 
The three types (adductor, abductor, and mixed) affect varying muscle groups which 
produce characteristic voice patterns. The vast majority of patients with SD have 
adductor type, which impacts the lateral cricoarytenoid and thyroarytenoid muscle 
complex. While many treatment modalities have been investigated, the most efficacious 
treatment is botulism toxin injection to these muscle groups, performed transcervically 
with or without electromyography (EMG) guidance. Patients undergoing this treatment 
typically require re-injection every three months. Due to its specialized nature, the 
laryngeal injections are not performed routinely outside of academic medical centers; 
thus, patients may come from a distance to receive this treatment. Both due to the 
significant impact on voice quality when the injections wear off and the sometimes 
challenging access to treatment, a longer acting agent is desire. 
1.1 
Overview of Non-Clinical Studies 
An animal model has demonstrated reduced diffusion of the neurotoxin with this 
formulation which may account for its longer duration of effect. DAXI can be 
formulated without the use of human serum albumin ensuring its stability at 
room temperature before reconstitution. 
1.2 
Overview of Clinical Studies 
Injectible daxibotulinumtoxinA (DAXI, Revance Therapeutics Inc., Newark, 
CA) has received FDA approval for treatment of glabellar lines and has been 
shown in large clinical trials to provide safe, effective treatment for cervical 
dystonia. DAXI may offer a longer-lasting result when compared with 
onabotulinumtoxin. 
2 STUDY RATIONALE 
This study aims to assess the efficacy of DAXI for transcervical laryngeal injection in 
patients with adductor laryngeal dystonia. Secondly, this study aims to assess whether 
DAXI provides longer clinical benefit than BotoxA for treatment of ADLD. 

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2.1 
Risk / Benefit Assessment 
Risks are mitigated through the use of fellowship-trained laryngologists who are 
experts at this type of injection. 
Possible Risks: There are risks to taking part in any research study. Some of 
the most likely risks of participation in this study include:  
• Having no effect on voice  
• Requiring multiple injections  
• Injection site pain or discomfort 
There are also rare but serious risks of participation, like:  
• Difficulty swallowing, possibly requiring a temporary feeding tube  
• Difficulty breathing, possibly requiring hospitalization  
Possible Benefits:  
• Participants may benefit from participating in the study, but this cannot be 
guaranteed. When looking at previous trials with a different indication, 
DAXI provided a longer-lasting effect than traditional Botox.  
The potential benefits may outweigh the risks as DAXI may ultimately 
decrease frequency of injection, while maintaining similar risk to Botox 
injection.  
3 STUDY OBJECTIVES 
3.1 
Primary Objective 
Evaluate efficacy of botulinum toxin A neurotoxin, daxibotulinumtoxinA (DAXI) 
among ADLD subject population 
3.2 
Secondary Objectives 
Determine duration of clinical benefit to assess whether DAXI may provide 
longer clinical benefit than BotoxA for treatment of ADLD  
 

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4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single-center, open-label, dose-escalation trial. 20 subjects are 
planned.  Each subject will be administered a single dose of DAXI. If the 
subject does not achieve the desired self-reported voice improvement, at 1 
week post injection an additional dose of DAXI will be administered. 
Screening data will be reviewed to determine subject eligibility.  Subjects 
who meet all inclusion criteria and none of the exclusion criteria will be 
entered into the study.  
The following treatment regimens will be used: 
● Injection of DAXI at the following doses: 0.625, 1.25, 2.5 units depending on 
subject’s current standard dose of Botox. 
Total duration of subject participation will be 36 weeks. Total duration of 
recruitment and completion of all procedures of the study is expected to be up 
to 2 years. 
5 CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference in VHI-10 scores at 8 weeks after 
injection with DAXI. VHI-10 questionnaires will be given at baseline, day 14, 
then monthly. 
5.2 
Secondary Efficacy Endpoints 
The secondary endpoint is duration of benefit, assessed by median time to 
baseline VHI-10 after treatment with DAXI and via phone call surveys. VHI-10 
questionnaires will be given at baseline, day 14, then monthly until loss of benefit. 
Phone calls will be conducted at day 5, day 14, then monthly until loss of benefit. 
5.3 
Safety Evaluations 
In the event of an adverse event, the study team will notify the medical monitor. 

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5.4 
Other Evaluations  
Participant Questionnaires 
• CPIB-10 
• OMNI-VES 
• EAT-10 
Clinician scales 
• USDRS 
• Phonalyze 
SUBJECT SELECTION 
5.5 
Study Population 
Participants with a diagnosis of adductor laryngeal dystonia who meet the 
inclusion and none of the exclusion criteria will be eligible for participation in this 
study.  Participants will be recruited from the UCSF Voice and Swallowing 
Center and the National Spasmodic Dysphonia Association community.  
5.6 
Inclusion Criteria 
o Age ≥18 
o Diagnosis of adductor laryngeal dystonia 
o Previous successful treatment with BotoxA and stabilized dose for the last 3 
treatments 
o Female participants of childbearing potential may be enrolled in the study if 
the participant fulfills all the following criteria: 
§ Has a negative pregnancy test at Visit 1, Day 0. 
§ Has practiced adequate contraception or has abstained from all activities 
that could result in pregnancy for at least 30 days prior to the injection 
(Day 1). 
§ Has agreed to continue adequate contraception through 3 months 
following the injection (Day 90). 
§ Is not currently breastfeeding. 

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§ Adequate female contraception is defined as consistent and correct use of 
a Food and Drug Administration (FDA) approved contraceptive method in 
accordance with the product label. For example: 
• Barrier method (such as condoms, diaphragm, or cervical cap) 
used in conjunction with spermicide 
• Intrauterine device 
• Prescription hormonal contraceptive taken or administered via oral 
(pill), transdermal (patch), subdermal, or IM route 
• Sterilization of a female participant’s monogamous male partner 
prior to entry into the study 
• Note: periodic abstinence (e.g. calendar, ovulation, post-ovulation 
methods) and withdrawal are not acceptable methods of 
contraception. 
5.7 
Exclusion Criteria 
o Age <18 
o Other neurologic conditions (ALS, Parkinson’s disease, essential tremor, Meige 
syndrome, etc.) 
o Pregnant, breastfeeding, or unwilling to practice birth control during participation 
in the study. 
o Presence of a condition or abnormality that in the opinion of the Investigator 
would compromise the safety of the patient or the quality of the data. 
o Naive from other types of Botox for 6 months including BotoxA 
6 CONCURRENT MEDICATIONS 
All currently prescribed medications are allowed 
6.1 
Allowed Medications and Treatments 
Standard therapy for other conditions is allowed except for treatments noted in the 
exclusion criteria described above and as noted in the prohibited medications 
section below. 
6.2 
Prohibited Medications and Treatments 

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The following medications are prohibited during the study and administration will 
be considered a protocol violation. 
• Naive from other types of Botox for 6 months including BotoxA 
7 STUDY TREATMENTS 
7.1 
Method of Assigning Subjects to Treatment Groups 
N/A (open-label study). 
7.2 
Blinding 
N/A (open-label study). 
7.3 
Formulation of Test and Control Products 
7.3.1 
Formulation of Test Product 
Injectible daxibotulinumtoxinA (DAXI, Revance Therapeutics Inc., Newark, CA) 
is a FDA-approved botulinum toxin type A indicated for the treatment of glabellar 
lines. It has been shown in large clinical trials to provide safe, effective treatment 
for cervical dystonia and may offer longer-lasting results when compared with 
onabotulinumtoxinA. DAXI will be reconstituted using sterile saline into 1mL 
syringes at the desired dosage similar to clinical care for Botox. 
7.3.2 
Formulation of Control Product 
N/A (open-label study). 
7.3.3 
Packaging and Labeling 
Refer to DAXXIFY Package Insert. 
7.4 
Supply of Study Drug at the Site 
7.4.1 
Dosage/Dosage Regimen 
Subject’s Current* 
BotoxA Dose 
DAXI Dose 1 
DAXI Dose 2 

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0.625 units unilateral 
0.625 unit 
0.625 unit 
1.25 units unilateral 
1.25 units 
1.25 units 
2.5 units unilateral 
2.5 units 
2.5 units 
0.625 units bilateral 
0.625 unit 
0.625 unit (contralateral) 
1.25 units bilateral 
1.25 units 
1.25 units (contralateral) 
2.5 units bilateral 
2.5 units 
2.5 units (contralateral) 
*Current is defined as the average of subject’s last 3 injections 
7.4.2 
Dispensing 
DAXI will be received at the UCSF Voice and Swallowing Center. DAXI will be 
kept in a locked cabinet and refrigerator at the UCSF Voice and Swallowing 
Center with a log kept for usage. 
7.4.3 
Administration Instructions  
DAXI will be reconstituted using sterile unpreserved saline into 1mL syringes 
within 2 hours of injection by a trained preparer. It will then be injected into the 
unilateral or bilateral thyroarytenoid/lateral cricoarytenoid (TA-LCA) complex 
using electromyographic (EMG) guidance. 
 
Laterality of injection with DAXI will be dependent on the subject’s usual 
injection pattern. If the patient has traditionally been injected on one side, DAXI 
will be injected on the same side. If the patient has traditionally been injected 
unilaterally but with alternating sides, DAXI injection will follow the alternating 
pattern. If the patient has traditionally received bilateral injections, DAXI will 
first be injected on the left side, and if a second dose is required, it will be injected 
on the right. 
Laterality Rules 

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Traditionally unilateral 
DAXI same side 
Traditionally unilateral/alternating 
DAXI continues in sequence 
Traditionally bilateral 
1st DAXI left 
2nd DAXI right 
7.5 
Supply of Study Drug at the Site 
The study drug is supplied by the research team. 
7.5.1 
Storage 
Refer to DAXXIFY Package Insert. 
7.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for 
each subject will be maintained on an ongoing basis by a member of the study site 
staff. 
7.7 
Measures of Treatment Compliance 
There is no treatment compliance because DAXI is an injectable medication. No 
DAXI goes home with participants. 
8 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for 
the duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative. 
8.1 
Clinical Assessments 
8.1.1 
Concomitant Medications 
No concomitant medications. 

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8.1.2 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at 
Screening. 
8.1.3 
Medical History  
Relevant medical history, including history of current disease, other pertinent 
respiratory history, and information regarding underlying diseases will be 
recorded at Screening. 
8.1.4 
Physical Examination 
A physical examination will be performed by either the investigator or a sub-
investigator who is a physician at Visit # 1.  New abnormal physical exam 
findings must be documented. 
8.1.5 
Vital Signs 
 
N/A 
8.1.6 
Oximetry 
 
N/A 
8.1.7 
Spirometry 
 
N/A 
8.1.8 
Other Clinical Procedures 
 
N/A 
8.1.9 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout 
the study. Duration (start and stop dates), severity/grade, outcome, treatment and 
relation to study drug will be recorded on the case report form (CRF). 

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8.2 
Clinical Laboratory Measurements 
8.2.1 
Hematology 
 
N/A 
8.2.2 
Blood Chemistry Profile 
 
N/A 
8.2.3 
Pregnancy Test 
A urine pregnancy test will be obtained from female participants who are of 
childbearing age prior to their participation in the study at Visit 1.  
8.2.4 
Urinalysis 
 
N/A 
8.3 
Pharmacokinetic Measurements 
  
N/A 
8.4 
Research Laboratory Measurements 
  
N/A 
8.4.1 
Cell Count and Differential 
 
N/A 
8.4.2 
Sputum Cytokine Measurements 
 
N/A 
 

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9 EVALUATIONS BY VISIT 
9.1 
Phone Screening (7 Days prior to injection) 
1. 
Confirmation participants meet all inclusion criteria and no exclusion 
criteria review 
2. 
If they have provided consent to contact, reach out and explain the study to 
them. 
3. 
Review the study with the subject (subject’s legal representative) and obtain 
written informed consent and HIPAA authorization via DocuSign. 
4. 
Assign the subject a unique screening number. 
5. 
Record demographics data. 
6. 
Record medical history, including history of ADLD, diagnosis date, and 
prior Botox treatments. 
7. 
Patient fills out baseline PROMs electronically through Qualtrics (VHI-10, 
CPIB-10, OMNI-VES, EAT-10) 
8. 
Patient records their voice in Phonalyze for CPP and CAPE-V analysis 
9.2 
Visit 1 (Clinic Visit, Day 0) 
1. 
Review of birth control history with female participants of childbearing 
potential. 
2. 
For women of childbearing potential, counsel participants to use adequate 
birth control methods required during the trial to avoid pregnancy. 
3. 
For women of childbearing potential, urine pregnancy test will be checked 
prior to injection. 
4. 
Perform a complete physical examination. 
5. 
Perform DAXI injection. Laterality of injection with DAXI will be 
dependent on the subject’s usual injection pattern. If the patient has 
traditionally been injected on one side, DAXI will be injected on that same 

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side. If the patient has traditionally been injected unilaterally but with 
alternating sides, DAXI injection will follow the alternating pattern. If the 
patient has traditionally received bilateral injections, DAXI will first be 
injected on the LEFT side, and if a second dose is required, it will be 
injected on the right. 
6. 
Record any Adverse Experiences during injection 
7. 
Schedule participant for remote follow-up visit in 5 days. 
9.3 
Visit 2 (Phone Call, Day 5) 
1. 
Phone call to assess clinical improvement 
2. 
Ensure there is absence of dysphagia (using EAT-10 questionnaire), no 
injection site issue, or other adverse events using safety survey 
9.4 
Visit 3 (Optional Clinic Visit, Day 7-14) 
1. Additional DAXI can be administered in office if the 1st injection does not 
have desired clinical effect 
2. Injection occurs on same side if normally unilateral, or on opposite side if 
bilateral 
9.5 
Visit 4 (Phone call, Day 14*) 
1. Phone call to assess clinical improvement 
2. Ensure there is absence of dysphagia (using EAT-10 questionnaire), no 
injection site issue, or other adverse event 
*Day 14 after most recent DAXI injection 
9.6 
Visits 5-10 (Remote Survey, every month starting 1 month after most recent 
injection) 
1. Phone call to assess duration of benefit 
2. Patient fills out PROMs electronically through Qualtrics to assess our primary 
(VHI-10) and secondary outcome measures 

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• VHI-10 
• CPIB-10 
• OMNI-VES 
• EAT-10 
3. Patient records their voice in Phonalyze for CPP and CAPE-V analysis 
4. Patient will record whether DAXI still has desired effect 
Data is collected monthly until loss of benefit. 
For every instance when all PROMs and Phonalyze recordings are 
completed, patients will be paid $10, up to $150. After the completion of the 
study the number of entries will be tabulated and patient will be given a Visa 
gift card in the allotted amount. Patients who withdraw from the study will 
still be compensated for all instances when PROMs and Phonalyze 
recordings were completed. 
9.7 
Early Withdrawal Visit 
  
N/A 
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation of a patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with the treatment. An AE is therefore any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the administration of drug 
product, whether or not related to that product. An unexpected AE is one of a type 
not identified in nature, severity, or frequency in the current Package Insert or of 
greater severity or frequency than expected based on the information in the 
Package Insert. 
The Investigator will probe, via discussion with the subject, for the occurrence of 
AEs during each subject visit and record the information in the site’s source 
documents.  Adverse events will be recorded in the patient CRF.  Adverse events 

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will be described by duration (start and stop dates and times), severity, outcome, 
treatment and relation to study drug, or if unrelated, the cause. 
 
10.1.1 AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE) Version 3.0 should be used to assess and grade AE severity, 
including laboratory abnormalities judged to be clinically significant. The 
modified criteria can be found in the study manual.  If the experience is not 
covered in the modified criteria, the guidelines shown in Table 1 below should be 
used to grade severity.  It should be pointed out that the term “severe” is a 
measure of intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity 
(Toxicity 
Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may 
be aware of the sign or symptom but tolerates it reasonably 
well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal 
medical intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-
threatening (4) 
The subject is at risk of death due to the adverse experience 
as it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more 
severe. 
 

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10.1.2 AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the 
following the guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relation
ship 
to Drug 
Comment 
Definitel
y 
Previously known toxicity of agent; or an event that follows a 
reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the 
dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is unlikely 
to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to that suspected drug; but that could readily 
have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no 
relationship to the study drug. 
10.2 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the 
following outcomes: 

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● death 
● a life-threatening adverse experience 
● inpatient hospitalization or prolongation of existing hospitalization 
● a persistent or significant disability/incapacity 
● a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention 
to prevent one of the outcomes listed.  
 
10.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study 
drug) per UCSF HRPP Guidelines.  The collection period for all SAEs will begin 
after informed consent is obtained and end after procedures for the final study 
visit have been completed. 
In accordance with the standard operating procedures and policies of the UCSF 
Institutional Review Board (IRB), the site investigator will report SAEs 
immediately to the UCSF IRB and sponsor.   
 
10.3 
Protocol Defined Important Medical Findings Requiring Real Time 
Reporting 
  
N/A 
10.4 
Medical Monitoring 
Dr. Clark Rosen should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 
 
Phone: (415) 885-7700 
 

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11 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
11.1 
Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.  The following is a list of possible reasons for study treatment 
discontinuation:  
● Subject withdrawal of consent 
● Subject is not compliant with study procedures 
● Adverse event that in the opinion of the investigator would be in the best 
interest of the subject to discontinue study treatment 
● Protocol violation (falsifying eligibility criteria) requiring discontinuation of 
study treatment 
● Lost to follow-up 
● Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will 
be followed and treated by the Investigator until the abnormal parameter or 
symptom has resolved or stabilized.   
All participants who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to 
complete all remaining scheduled visits and procedures. 
All participants are free to withdraw from participation at any time, for any 
reason, specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will 
be specified in the subject’s source documents. 
11.2 
Withdrawal of Participants from the Study 
A subject may be withdrawn from the study at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to 
continue.   

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All participants are free to withdraw from participation at any time, for any 
reason, specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
subject withdrawals.  The reason for the subject’s withdrawal from the study will 
be specified in the subject’s source documents. 
11.3 
Replacement of Participants 
N/A 
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
● 
Failure to meet inclusion/exclusion criteria 
● 
Failure to report an AE 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Investigator will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
13 DATA SAFETY MONITORING 
A Data Monitoring Committee (DMC) to review data relating to safety and efficacy, 
to conduct and review interim analyses, and to ensure the continued scientific validity 
and merit of the study, according the UCSF IRB. The DMC will be made up of the 
investigator team (PI, other study clinicians, and research assistants) will be meeting at 
least every 2 weeks to review preliminary data. At this time, the following will be 
reviewed: 
o Enrollment (number of participants) 

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o Adverse events 
o Any unexpected voice/swallow/breathing problems based on the survey data 
collected 
o Any phone calls by participants to the Voice and Swallowing Center 
o Breaches of confidentiality 
o Unanticipated problems 
This information will be shared with the UCSF IRB every 6 weeks. If there are any 
adverse events or unanticipated problems, this will be communicated immediately. An 
interim analysis will be conducted and reported three months after the study start date, or 
after the 10th subject is recruited, whichever comes first. Any participants whose 
confidentiality has been breached will be notified as soon as possible. 
A study subject’s participation in the trial will be withdrawn immediately for any the 
following criteria: 
o The patient wishes to end participation 
o The patient undergoes an additional laryngeal Botox injection (at UCSF or 
elsewhere) 
o 
Unrelated medical event/condition which impacts 
voice/swallowing  
o The trial will be halted immediately for any of the following 
events: 
o If a pattern of poor clinical outcomes is seen 
o For multiple adverse events 
o At UCSF IRB discretion 
Based on UCSF IRB guidelines, this trial does not meet criteria for a Data Safety 
Monitoring Board, although one would be assembled if requested by the UCSF IRB. 
The study has none of the following features: 
• 
There is a significant likelihood of a serious adverse event to participants 
• 
The study is conducted at multiple sites and the level of risk is greater than 
minimal 
• 
The study generates data that are blinded or randomized 
• 
The study involves a large number of patients randomized to one of two or more 
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• 
A study for which the performance of an interim analysis is crucial for the 
protection of the participants 
• 
First use in humans 
• 
First use in children 
• 
The study involves gene therapy, stem cell therapy, or other novel interventions 
for which long-term outcome data are not known or available 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  Discuss with statistician 
14.1 
Data Sets Analyzed 
All eligible patients who are in study and receive at least one dose of DAXI will 
be included in the safety analysis. 
14.2 
Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, 
gender, age, duration of ADLD.  
14.3 
Analysis of Primary Endpoint 
Our primary outcome is the difference in VHI-10 score at 8 weeks after injection 
with DAXI. This will be determined using a paired t-test with subjects pre-
treatment VHI-10 scores as a control. Our second primary outcome measure is the 
duration of effect of DAXI, assessed qualitatively through phone calls, compared 
to patients' prior Botox treatment. We will produce a Kaplan-Meier curve to 
illustrate the duration of clinical benefit after treatment with DAXI. 
14.4 
Analysis of Secondary Endpoints 
A secondary outcome will be comparing the duration of effect of DAXI with 
patients’ prior Botox treatment. Specifically, we will determine the median time 
to baseline VHI-10 after treatment with DAXI and produce a Kaplan-Meier curve 
to illustrate the duration of clinical benefit. 

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14.5 
Interim Analysis 
Every 6 weeks:  
• Information will be shared with the UCSF IRB. 
Every 3 months: 
• An interim analysis will be conducted and reported or after the 10th subject is 
recruited 
 
14.6 
Sample Size and Randomization 
One primary outcome is the difference in VHI-10 score at 6 weeks after 
injection with DAXI. The normative values of the VHI-10 have been 
established, with a normal value of 2.83 and standard deviation of 3.93. One 
prospective study for Botox in SD determined a pretreatment VHI-10 score 
of 22.58 +/- 7.09 and 6-week post-treatment 20.86 +/- 7.24. The difference 
had a standard deviation of approximately 10. A sample size of 20 will 
provide 80% power to detect a difference of 6.6 at a significance threshold 
(alpha) of 0.05. 
 
A secondary outcome will be comparing the duration of effect of DAXI with 
patients’ prior Botox treatment. Specifically, we will determine the median 
time to baseline VHI-10 after treatment with DAXI and produce a Kaplan-
Meier curve to illustrate the duration of clinical benefit. A large retrospective 
study from Blitzer et al from described the average duration of benefit to be 
about 15.1 weeks with a standard deviation of 12.3 weeks [10]. Unpublished 
data from our institution revealed an average duration of 18.9 weeks with a 
standard deviation of 7.2 weeks. Using the data from our institution, a sample 
size of 20 will provide 80% power to detect a difference in average duration 
of 2.4 weeks. (This calculation assumed a with-subject correlation 
coefficient of 0.875.) 

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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 
Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated 
with the study drug.   
Study personnel at each site will enter data from source documents corresponding 
to a subject’s visit into the protocol-specific electronic Case Report Form (eCRF) 
into a REDCap database when the information corresponding to that visit is 
available.  Participants will not be identified by name in the study database or on 
any study documents to be collected by the Sponsor (or designee), but will be 
identified by subject number and initials. 
If a correction is required for an eCRF, the time and date stamps track the person 
entering or updating eCRF data and creates an electronic audit trail.   
The Investigator is responsible for all information collected on participants 
enrolled in this study.  All data collected during the course of this study must be 
reviewed and verified for completeness and accuracy by the Investigator. 
15.2 
Data Management Procedures 
The data will be entered into a validated database.  The Data Management group 
will be responsible for data processing, in accordance with procedural 
documentation.  Database lock will occur once quality assurance procedures have 
been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data 
for clinical trials. 
15.3 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized 
data validation checks will be implemented and applied to the database on a 
regular basis. Queries are entered, tracked, and resolved through the REDCap and 
Qualtrics system directly.  The study database will be updated in accordance with 
the resolved queries.  All changes to the study database will be documented. 

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15.4 
Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files 
will be maintained.  Databases are backed up by the database administrator in 
conjunction with any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final 
reports), data for analysis is locked and cleaned per established procedures. 
15.5 
Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency 
(e.g., FDA) inspectors upon request.  A file for each subject must be maintained 
that includes the signed Informed Consent & HIPAA Authorization Form and 
copies of all source documentation related to that subject.  The Investigator must 
ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of 
CRFs, Study File Notebook, etc.) must be kept secured for a period of two years 
following marketing of the investigational product or for two years after centers 
have been notified that the IND has been discontinued.  There may be other 
circumstances for which the Sponsor is required to maintain study records and, 
therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
15.6 
Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor-Investigator 
according to the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for 
GCP (E6).    By signing this protocol, the Investigator grants permission to the 
Sponsor (or designee), and appropriate regulatory authorities to conduct on-site 
monitoring and/or auditing of all appropriate study documentation. 
15.7 
Subject Confidentiality 
In order to maintain subject confidentiality, only subject number and subject 
initials will identify all study participants on CRFs and other documentation 

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submitted to the Sponsor.  Additional subject confidentiality issues (if applicable) 
are covered in the Clinical Study Agreement. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
16.1 
Protocol Amendments 
Any amendment to the protocol will be written by the Investigator.  Protocol 
amendments cannot be implemented without prior written IRB/IEC approval 
except as necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may 
be implemented immediately, provided the IRBs are notified within five working 
days. 
16.2 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of 
each participating center prior to study initiation.  Serious adverse experiences 
regardless of causality will be reported to the IRB/IEC in accordance with the 
standard operating procedures and policies of the IRB/IEC, and the Investigator 
will keep the IRB/IEC informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as 
protocol, protocol amendments, Package Insert, consent forms, information 
concerning patient recruitment, payment or compensation procedures, or other 
pertinent information) will be submitted to the IRB/IEC.  The IRB/IECs written 

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unconditional approval of the study protocol and the informed consent form will 
be in the possession of the Investigator before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the 
Investigator to the Sponsor prior to the shipment of study supplies to the site.  
This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated 
without prior written IRB/IEC approval except when necessary to eliminate 
immediate hazards to the patients or when the change(s) involves only logistical 
or administrative aspects of the study.  Such modifications will be submitted to 
the IRB/IEC and written verification that the modification was submitted and 
subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally 
submitted for review; serious and/or unexpected adverse experiences occurring 
during the study in accordance with the standard operating procedures and 
policies of the IRB; new information that may affect adversely the safety of the 
patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed. 
16.3 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 
CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance 
Portability and Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form and HIPAA 
authorization and provide the documents to the Sponsor or designee for approval 
prior to submission to the IRB/IEC.  The consent form generated by the 
Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC.  
The written consent document will embody the elements of informed consent as 
described in the International Conference on Harmonisation and will also comply 
with local regulations. The Investigator will send an IRB/IEC-approved copy of 
the Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each 
subject prior to entering the subject into the trial.  Information should be given in 
both oral and written form and subjects (or their legal representatives) must be 

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given ample opportunity to inquire about details of the study.  If a subject is 
unable to sign the informed consent form (ICF) and the HIPAA authorization, a 
legal representative may sign for the subject.   A copy of the signed consent form 
will be given to the subject or legal representative of the subject and the original 
will be maintained with the subject’s records. 
16.4 
Publications  
The preparation and submittal for publication of manuscripts containing the study 
results shall be in accordance with a process determined by mutual written 
agreement among the study Sponsor and participating institutions.  The 
publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
16.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 
56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, 
in accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and 
to make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will 
be responsible for initial and continuing review and approval of the clinical study. 

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8. Promptly report to the IRB and the Sponsor (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or 
others (to include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements listed in § 21 CFR part 312. 

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APPENDIX 1.  STUDY VISITS 
 
SCREENING 
VISIT 1 
(CLINIC 
VISIT, 
DAY 0)a 
VISIT 2 
(PHONE 
CALL, 
DAY 5)a 
VISIT 3 
(OPTIO
NAL 
CLINIC 
VISIT, 
DAY 7-
14)a 
VISIT 4 
(PHONE 
CALL, 
DAY 14) 
a 
VISIT 5-10 
(STARTING 
1 MONTH 
AFTER 
LAST DAXI 
INJECTION, 
MONTHLY 
UNTIL LOSS 
OF 
BENEFIT) 
Informed 
Consent 
X 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
Urine 
pregnancy 
test (if 
applicable) 
 
X 
 
 
 
 
Physical 
Exam 
 
X 
 
 
 
 
DAXI 
Injection 
 
X 
 
X 
 
 
USDRS 
 
X 
 
X 
 
 
Phone call to 
assess 
duration of 
benefit 
 
 
X 
 
X 
X 
EAT-10 
X 
 
X 
 
X 
 
VHI-10 
X 
 
 
 
X 
X 
OMNI-VES 
X 
 
 
 
X 
X 
CPIB-10 
X 
 
 
 
X 
X 
Phonalyze 
recording 
X 
 
 
 
X 
X 
a  ±2 days 

Dr. Clark Rosen 
Confidential 
 
 
Version #: 1.0 
Version Date: 11/23/2022 
Page 44 of 45 
Protocol Template Effective: 10 May 2016  
APPENDIX 2.  INVESTIGATORS 
Clark Rosen, MD 
VyVy Young, MD 
Yue Ma, MD 
Aviva Fliker, MD 
Sarah Schneider, MS, CCC-SLP 
 
APPENDIX 3. FINANCIAL CONSIDERATIONS 
Participants will be compensated for participation in the study. For every completed survey and 
VoiceEvalu8 entry, they will be paid $10, up to $150. At the completion of the study, the number 
of entries will be tabulated and the patient will be given a Visa gift card in the allotted amount. 
 
APPENDIX 4. SAFETY SURVEY 
● Pain, swelling or bruising at the injection site 
● Headache 
● Flu-like symptoms 
● Trouble speaking or swallowing 
● Breathing problems 
● Cough 
● Hoarseness 
  
APPENDIX 5.  REFERENCES 
1. 
Carruthers, J., et al., Injectable DaxibotulinumtoxinA for the Treatment of 
Glabellar Lines: A Phase 2, Randomized, Dose-Ranging, Double-Blind, 
Multicenter Comparison With OnabotulinumtoxinA and Placebo. Dermatol Surg, 
2017. 43(11): p. 1321-1331. 
2. 
Jankovic, J., et al., Injectable DaxibotulinumtoxinA in Cervical Dystonia: A Phase 2 
Dose- Escalation Multicenter Study. Mov Disord Clin Pract, 2018. 5(3): p. 273-282. 

Dr. Clark Rosen 
Confidential 
 
 
Version #: 1.0 
Version Date: 11/23/2022 
Page 45 of 45 
Protocol Template Effective: 10 May 2016  
3. 
Carruthers, J.D., et al., DaxibotulinumtoxinA for Injection for the Treatment of 
Glabellar Lines: Results from Each of Two Multicenter, Randomized, Double-Blind, 
Placebo- Controlled, Phase 3 Studies (SAKURA 1 and SAKURA 2). Plast Reconstr 
Surg, 2020. 145(1): p. 45-58. 
4. 
Stone, H.F., et al., Characterization of diffusion and duration of action of a 
new botulinum toxin type A formulation. Toxicon, 2011. 58(2): p. 159-67. 
5. 
Rumbach, A., P. Aiken, and D. Novakovic, Outcome Measurement in the Treatment of 
Laryngeal dystonia: A Systematic Review of the Literature. J Voice, 2019. 33(5): p. 810 
e13-810 e39. 
6. 
Yiu, Y., et al., Validation of the Communicative Participation Item Bank as an 
Outcome Measure for Laryngeal dystonia. Laryngoscope, 2020. 
7. 
Shoffel-Havakuk, H., et al., Validation of the OMNI vocal effort scale in the treatment 
of adductor laryngeal dystonia. Laryngoscope, 2019. 129(2): p. 448-453. 
8. 
Belafsky, P.C., et al., Validity and reliability of the Eating Assessment Tool (EAT-10). 
Ann Otol Rhinol Laryngol, 2008. 117(12): p. 919-24. 
9. 
Arffa, R.E., et al., Normative values for the Voice Handicap Index-10. J Voice, 2012. 
26(4): p. 462-5. 
10. 
Blitzer, A., M.F. Brin, and C.F. Stewart, Botulinum toxin management of 
laryngeal dystonia (laryngeal dystonia): a 12-year experience in more than 900 
patients. Laryngoscope, 1998. 108(10): p. 1435-41. 
11. 
Simonyan, K et al. https://pubmed.ncbi.nlm.nih.gov/33858994/