Conditions: Dystonia, Primary
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a single-center, open-label study of AUSTEDO in study subjects with dystonia. The study will provide preliminary experience of the safety, tolerability, and clinical activity of AUSTEDO in study subjects with dystonia. Study duration will be up to 13 weeks from screening (Visit 1) to the post treatment evaluation (Visit 5). Treatment period from drug initiation to final on-treatment Visit will be 12 weeks, or less, as follows: during the ramp-up period, study drug will start at 12 mg/day (6 mg twice daily) and will be titrated weekly by 6 mg/day increments until either 1) the maximal allowable dose (48 mg/day) is reached, or 2) dose-limiting side-effects occur. In study subjects receiving a strong CYP2D6 inhibitor, the maximum allowed dose of AUSTEDO will be 36 mg/day, reducing study duration (due to a reduction in the ramp-up period) to 11 weeks. Study subjects who experience dose-limiting side effects will be maintained on their maximum tolerated dose. Once the maximal dose is established for each participant, they will complete 6 continuous weeks on this dose (maintenance period), followed by a 1-week washout. For study subjects unable to titrate up to 48 mg/day due to side effects, the 6 weeks of maintenance will start once they reduce the study drug back to the maximum well-tolerated dose. Adverse events will be monitored throughout the study and will be reported after drug initiation. Dose reductions, suspensions, and withdrawals due to adverse events will be recorded. ECG readings will be measured at screening, during week 2, during the first week of the maintenance period (whenever this is established to be, typically week 7 for subjects able to titrate up to 48 mg/day), immediately before washout (week 12 for those study subjects who are able to titrate up to 48 mg/day) and during week 13. Assessment of Columbia Suicide Severity Rating Scale and Epworth Sleepiness Scale scores will occur at screening and all clinic Visits. The Mini Mental (MMSE) Scale will be performed at screening and at the final on-treatment Visit (week 12). A video examination of the study subjects will be made at screening (right before initiation of the study drug), and after 6 weeks on AUSTEDO at a steady dose (right before drug cessation). Part III of the MDS-UPDRS will be performed at both of these Visits as well to screen for the appearance of drug-induced parkinsonism. Videos will be sent to raters blinded to treatment, Visit number and recording date.

Detailed description:

Arms:
arm 1: This is the only arm for this trial. All subjects will receive oral Deutetrabanazine.

Interventions: intervention 1: Deutetrabenazine 6 MG
Intervention descriptions: intervention 1: Increasing doses of Deutetrabenazine

Protocol document:
Prot_SAP_002.pdf: 
1 
 
Amendment 1.1 – 20Jan2021 
 
 
CLINICAL PROTOCOL 
 
 
 
The AUDYT trial: An open-label Study to Define the Safety, Tolerability and Clinical Activity of 
deutetrabenazine (AUstedo) in Adult Study subjects with DysTonia (NCT04173260) 
 
 
 
Compound name: 
 
Deutetrabenazine (AUSTEDOTM) 
Auspex Pharmaceuticals Inc. 
AUS-001  
U.S. Patent No: 8,524,733 
 
 
 
Sponsor: 
 
Teva Pharmaceuticals USA, Inc.  
North Wales, PA 19454 
United States 
 
 
 
Document date: 
 
January 20, 2021 
 
 
 
Version: 
 
1 
 
 
 
Principal Investigator: 
 
Andres Deik, MD, MSEd 
University of Pennsylvania 
Parkinson’s Disease and Movement Disorders 
Center 
Philadelphia, Pennsylvania, United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Amendment 1.1 – 20Jan2021 
 
Table 1 
ABBREVIATIONS AND DEFINITIONS 
 
AE 
 
Adverse event 
AUC Area under the plasma concentration-time curve 
BP Blood pressure 
CGI-I   Clinical Global Impression of Improvement Scale 
Cmax Peak plasma concentration of a drug 
CS Clinically significant 
C-SSRS Columbia Suicide Severity Rating Scale 
CYP2D6 Cytochrome P450 family 2 subfamily D member 6 
DA Dopamine 
DD Day (numeric) 
DYT Dystonia 
ECG Electrocardiogram 
FDA Food and Drug Administration 
GCP Good Clinical Practices 
GDS Global Dystonia Rating Scale 
HD Huntington’s Disease 
HR Heart rate 
HTBZ Active deuterated dihydro metabolites 
ICF Informed consent form 
ICH International Committee on Harmonization 
Maintenance 
period 
Six-week study period during which study subjects are expected to 
remain on AUSTEDO 48 mg/day (36 mg/day in study subjects 
receiving a strong CYP2D6 inhibitor), or the highest well-tolerated 
dose. 
MDS Movement Disorders Society 
mg Milligrams 
mL Milliliters  
msec Milliseconds  
MMSE Mini Mental State Examination 
MMM Month (first three letters) 
Ng Nanograms  
NCS Non clinically significant 
PD Parkinson’s Disease 
PGI-I Patient Global Impression of Improvement 
pKa Logarithmic constant of the quantitative measure of the strength of 
an acid in solution  
 
 
 
 
 
 
 
 


3 
 
Amendment 1.1 – 20Jan2021 
QT interval The QT interval is a measure of the time between the start of the Q 
wave and the end of the T wave in the heart's electrical cycle. The 
QT interval represents electrical depolarization and repolarization of 
the ventricles. A lengthened QT interval is a marker for the potential 
of ventricular tachyarrhythmias like torsades de pointes and a risk 
factor for sudden death. 
QTc interval Heart rate-corrected QT interval 
Ramp-up period Titration period during which study subjects are expected to 
increase AUSTEDO from 12 mg/day to up to 48 mg/day.  
RR Respiratory rate 
SAE Serious adverse event 
Sec Second 
Significant QT 
prolongation 
SSS 
QTc interval of 450 (458) milliseconds in men or 460 (472) 
milliseconds in women. 
Stanford Sleepiness Scale 
TBZ Tetrabenazine 
TD Tardive Dyskinesias 
UPDRS Unified Parkinson’s Disease Rating Scale 
VMAT2 Vesicular monoamine transporter 2 
WT Weight (in pounds) 
YYYY Year (numeric) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4 
 
Amendment 1.1 – 20Jan2021 
 
SYNOPSIS 
 
Title: The AUDYT trial: An open-label Study to Define the Safety, Tolerability and Clinical Activity of 
deutetrabenazine (AUstedo) in Adult Study subjects with DYsTonia 
Investigator: Deik, Andres F 
University of Pennsylvania, Philadelphia, Pennsylvania, United States 
 
Background / Rationale 
A number of studies have demonstrated Tetrabenazine (TBZ) is effective in the symptomatic treatment of 
dystonia. Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that modulates synaptic 
dopamine. Unfortunately, the use of TBZ is often limited by its side effect profile, which includes, but is not 
limited to, depression (including suicidal depression), sedation and parkinsonism. Deutetrabenazine 
(AUSTEDOTM) is a novel, highly selective VMAT2 inhibitor that contains deuterium, a stable isotope of 
hydrogen. Deuterium attenuates the metabolism of AUSTEDO, leading to reduced fluctuations in plasmatic 
levels as compared to TBZ. This, is turn, reduces adverse events associated to peak drug concentrations. 
AUSTEDO is approved by the Food and Drug Administration (FDA) for the treatment of chorea associated 
with Huntington’s disease (HD) and Tardive Dyskinesias in adults, but not for the treatment of dystonia. 
Given its shared mechanism of action with TBZ, an opportunity exists to establish the safety, tolerability and 
clinical activity of AUSTEDO in subjects with dystonia. 
 
Primary Study Objective 
To explore the safety and tolerability of the daily oral administration of AUSTEDO in adult study subjects 
with dystonia. 
 
Secondary Study Objectives 
1. To establish the degree of symptomatic effect of AUSTEDO as measured by the Clinical Global Impression 
of Improvement Scale (CGI-I) after 6 weeks of AUSTEDO 48 mg daily, or at the highest tolerated dose.  
2. To establish the degree of symptomatic effect of AUSTEDO as measured by the Patient Global Impression 
of Improvement Scale (PGI-I) after 6 weeks of AUSTEDO 48 mg daily, or at the highest tolerated dose.  
3. To establish the degree of symptomatic effect of AUSTEDO as measured by the change in the Global 
Dystonia Rating Scale between baseline and after 6 weeks of AUSTEDO 48 mg daily, or at the highest 
tolerated dose. 
 
Design 
This is a single-center, open-label study of AUSTEDO in study subjects with dystonia. The study will provide 
preliminary experience of the safety, tolerability, and clinical activity of AUSTEDO in study subjects with 
dystonia. Study duration will be up to 13 weeks from screening (Visit 1) to the post treatment evaluation 
(Visit 5). Treatment period from drug initiation to final on-treatment Visit will be 12 weeks, or less, as 
follows: during the ramp-up period, study drug will start at 12 mg/day (6 mg twice daily) and will be titrated 
weekly by 6 mg/day increments until either 1) the maximal allowable dose (48 mg/day) is reached, or 2) 
dose-limiting side-effects occur. In study subjects receiving a strong CYP2D6 inhibitor, the maximum allowed 
dose of AUSTEDO will be 36 mg/day, reducing study duration (due to a reduction in the ramp-up period) to 
11 weeks. Study subjects who experience dose-limiting side effects will be maintained on their maximum 
tolerated dose. Once the maximal dose is established for each participant, they will complete 6 continuous 
weeks on this dose (maintenance period), followed by a 1-week washout. For study subjects unable to 
titrate up to 48 mg/day due to side effects, the 6 weeks of maintenance will start once they reduce the 
study drug back to the maximum well-tolerated dose. Adverse events will be monitored throughout the 


5 
 
Amendment 1.1 – 20Jan2021 
study and will be reported after drug initiation. Dose reductions, suspensions, and withdrawals due to 
adverse events will be recorded. ECG readings will be measured at screening, during week 2, during the first 
week of the maintenance period (whenever this is established to be, typically week 7 for subjects able to 
titrate up to 48 mg/day), immediately before washout (week 12 for those study subjects who are able to 
titrate up to 48 mg/day) and during week 13. Assessment of Columbia Suicide Severity Rating Scale and 
Stanford Sleepiness Scale scores will occur at screening and all clinic Visits. The Mini Mental (MMSE) Scale 
will be performed at screening and at the final on-treatment Visit (week 12). A video examination of the 
study subjects will be made at screening (right before initiation of the study drug), and after 6 weeks on 
AUSTEDO at a steady dose (right before drug cessation). Part III of the MDS-UPDRS will be performed at 
both of these Visits as well to screen for the appearance of drug-induced parkinsonism. Videos will be sent 
to raters blinded to treatment, Visit number and recording date. 
 
Inclusion Criteria 
1. Study subjects with definite dystonia (e.g. focal, segmental, multifocal and generalized), as established by 
a movement disorder specialist.  
2. Study subjects of any race and either gender, age 18 or more on the date the informed consent form (ICF) 
is signed and with the capacity to provide voluntary informed consent.  
3. Study subjects able to read and understand English and the ICF and are willing to comply with all study 
procedures, treatment and follow-up.  
4. Study subjects who are taking any central nervous system acting medications (e.g., benzodiazepines, 
antidepressants, hypnotics), including medications for the treatment of dystonia, will be on a stable regimen 
for at least 30 days prior to the screening Visit, and will willing to remain on the same dose for the duration 
of the study.  
5. Female of child-bearing potential will not be pregnant and will be using an acceptable method of 
contraception. 
6. Study subjects with an MMSE >24. 
 
Exclusion Criteria 
1. Exposure to dopamine blockers prior to the onset of dystonia that could, in the investigator’s opinion, 
have caused dystonia.  
2. Study subjects with genetically-confirmed dopa-responsive dystonia.  
3. Study subjects with a diagnosis of Parkinson’s or an atypical parkinsonian syndrome.  
4. Study subjects with a history of bipolar disorder or major depression, or the presence of active 
depression.  
5. Study subjects with a history of a suicide attempt or suicidal ideations, as well as the presence of active 
suicidal ideation as detailed on the C-SSRS administered during Visit 1.  
6. Study subjects with a history of schizophrenia or schizophrenia spectrum disorders. 
7. Treatment with tetrabenazine, reserpine, valbenazine, a monoamino oxidase inhibitor, a-methyl-p-
tyrosine, strong anticholinergic medications, metoclopramide, antipsychotics, dopamine agonists, levodopa, 
and/or stimulants within 30 days of screening.  
8. Treatment with botulinum toxin less than 11 weeks prior to screening (Visit 1); subjects receiving 
injections sooner than every 12 weeks will be excluded if their next injection is scheduled farther than 6 
days from screening.  
9. Presence of a neurologic condition that could confound dystonia assessments.  
10. Study subjects with a history of clinically relevant hepatic disease.  
11. Study subjects with a history of renal insufficiency.  
12. Any unstable medical illness.  


6 
 
Amendment 1.1 – 20Jan2021 
13. A corrected QT (Bazett) interval of 450 (458) milliseconds in men or 460 (472) milliseconds in women on 
12-lead ECG at screening, or a history of cardiac arrhythmias.  
14. Study subjects participating in any drug or device clinical investigation concurrently or within 30 days 
prior to screening for this study.  
15. Study subjects with a known hypersensitivity or contraindication to the study drug or its components. 
 
Population 
Subjects with dystonia being managed at the University of Pennsylvania, or referred to this center for the 
purpose of participation in the trial. 
 
Primary Efficacy Variables 
Tolerability will be assessed based on the proportion of study subjects able to titrate up to 48 mg/d (or up to 
36 mg/d if receiving a strong CYP2D6 inhibitor) and able to complete the study at this dosage. 
 
Secondary Efficacy Variables 
The following Scales will be assessed:  
1. Patient Global Impression of Improvement Scale (PGI-I).  
2. Clinical Global Impression of Improvement Scale (CGI-I).  
3. Global Dystonia Rating Scale. 
 
Safety Variables 
Safety will be assessed by the documentation of all adverse events. In addition, the following Scales will be 
assessed:  
1. Columbia Suicide Severity Rating Scale.  
2. Stanford Sleepiness Scale.  
3. Mini Mental Scale.  
4. MDS-Unified Parkinson's Disease Rating Scale. 
 
Statistical Methods 
Within subjects paired t-tests will be used to assess significance of change in the different Scales used. 
 
Sample Size Calculation 
A number of 15 study subjects was selected to guarantee recruitment. This is a pilot feasibility study to 
evaluate for common side effects. The study will support the development of future larger clinical trials. The 
study design is not powered to detect significant effects, but rather to determine feasibility of administering 
Austedo for 6 weeks in this population. 
 
Planned Number of Sites: One (1). Parkinson's Disease and Movement Disorders Center at the University of 
Pennsylvania. Philadelphia, PA. 
Number of Subjects: 15 
Study Duration per Subject/Visit Schedule: Thirteen (13) weeks, or less, if unable to titrate up to 48 mg/day 
of AUSTEDO. 
Expected rate of enrollment (subjects/month): Two (2). 
 
Study Start/FPFV: 02/01/2018; Study End/LPLV: 12/31/2018; Final Report: 05/31/2019 
 
Publication Plan:  


7 
 
Amendment 1.1 – 20Jan2021 
Once the data is analyzed, manuscript submission is planned in a scientific journal relevant to the field of 
movement disorders. The following is a list of journals in descending order of preference:  
1. Movement Disorders (Wiley).  
2. Parkinsonism & related disorders (Elsevier).  
3. Tremor and other hyperkinetic movements (Columbia University Libraries). 
 
 
 
 
TABLE OF CONTENTS 
 
 
 
 TITLE PAGE ………………………………………………………………………………………………………………………………. 
1 
 
 
 Table 1: ABBREVIATIONS AND DEFINITIONS ……………………………….……………………………………………. 2 
 
 
 SYNOPSIS ………………………………………………………………………………………………………………….……………… 
4 
 
 
 TABLE OF CONTENTS …………………………………………………………………………………….…………………………. 
7 
 
 
1. INTRODUCTION ............................................................................................................................. 
11 
1.1 Overview of dystonia and its treatments …………........................................................................... 
11 
1.2 Background ................................................................................................................................... 
11 
1.2.1 Overview on AUSTEDO .................................................................................................................. 11 
1.2.2 Clinical studies with AUSTEDO....................................................................................................... 
12 
1.3 Study Rationale ............................................................................................................................. 
13 
1.3.1 Selection of AUSTEDO Dose and Schedule of Administration ....................................................... 
 
14 
2. TRIAL OBJECTIVES ………………………….............................................................................................. 
15 
2.1 Primary Objective .......................................................................................................................... 15 
2.2 Secondary Objectives .................................................................................................................... 
15 
2.3 Safety Outcome Assessments ....................................................................................................... 
15 
2.4 Efficacy Outcome Assessments ..................................................................................................... 
16 
 
 
3. STUDY METHODS........................................................................................................................... 
17 
3.1 Study Design .................................................................................................................................. 17 
3.2 Site ................................................................................................................................................ 
17 
3.3 Number of Subjects........................................................................................................................ 17 
3.4 Study Population ........................................................................................................................... 
18 
3.4.1 Inclusion Criteria............................................................................................................................ 
18 
3.4.2 Exclusion Criteria............................................................................................................................ 18 
3.4.3 Duration of Subject Participation .................................................................................................. 
19 
3.4.4 Estimated Study Duration ............................................................................................................. 
20 
3.5 Study Visit and Assessment Schedule ........................................................................................... 
20 
3.5.1 Schedule for subjects able to increase to and maintain maximum AUSTEDO dose ……………...….. 
20 
3.5.1.1 Visit 1: Screening (Week 1) …......................................................................................................... 20 
3.5.1.2 Visit 2: Ramp-up period (Week 2 +/- 2 Days) ……………………………………………………………………….…… 20 


8 
 
Amendment 1.1 – 20Jan2021 
3.5.1.3 Visit 3: Maintenance dose starts ………………………………….………………………………………………………….. 
21 
3.5.1.4 Visit 4: Maintenance dose ends ………………………………….……………………………………………………….…… 21 
3.5.1.5 Visit 5: Post treatment evaluation ……………………………………………………………………………………………. 22 
3.5.2 Special situations that could cause changes in Study Visit Schedule ……………………………………..…. 
22 
3.5.2.1 Shortened Ramp-up Period ........................................................................................................... 22 
3.5.2.2 Early Termination …………............................................................................................................... 
22 
3.5.2.3 Unscheduled Visit.......................................................................................................................... 
22 
3.5.2.4 Dose Adjustment ........................................................................................................................... 23 
3.5.2.5 Subject Withdrawal ………………...................................................................................................... 
23 
3.6 Study Procedures and Assessments............................................................................................... 24 
3.6.1 Safety assessments ……………………………………………….…………………………………………………………………. 24 
3.6.1.1 Adverse Events .............................................................................................................................. 
24 
3.6.1.2 ECG ................................................................................................................................................ 
26 
3.6.1.3 Physical Examination ..................................................................................................................... 26 
3.6.1.4 Vital Signs and Weight .................................................................................................................. 
29 
3.6.1.5 Columbia Suicide Severity Rating Scale …………………………………………………………………..……………… 
 
31 
3.6.1.6 Stanford Sleepiness Scale ………………………………………………………………………………………………………… 
35 
3.6.1.7 Mini Mental State Examination ……………………………………………………………………………………………….. 
37 
3.6.1.8 MDS-UPDRS (Part III) ………………….……………………………………………………………………………………………. 
39 
3.6.2 Efficacy assessments ……………………………………………………………………………………………………………….. 
41 
3.6.2.1 Video of dystonia examination ………………………………………………………………………………………………… 
41 
3.6.2.2 Patient Global Impression of Improvement Scale…………………………………………………………………….. 
45 
3.6.2.3 Clinical Global Impression of Improvement Scale …………………………………………………………………….. 47 
3.6.2.4 Global Dystonia Rating Scale ……………………………………………………………………………………………….…… 
49 
3.7 Study Endpoints ............................................................................................................................ 
51 
3.7.1 Safety Endpoints............................................................................................................................ 
51 
3.7.1.1 Primary Safety Endpoint ............................................................................................................... 
51 
3.7.1.2 Secondary Safety Endpoints .......................................................................................................... 51 
3.7.2 Efficacy Endpoints ......................................................................................................................... 
51 
3.7.2.1 Primary Efficacy Endpoint ............................................................................................................. 
51 
3.7.2.2 Secondary Efficacy Endpoints ....................................................................................................... 
51 
3.8 Criteria for Study Termination ...................................................................................................... 
51 
 
 
4. STUDY DRUG MATERIALS AND MANAGEMENT ............................................................................ 
53 
4.1 Study Drug ..................................................................................................................................... 53 
4.1.1 Description …................................................................................................................................. 
53 
4.1.2 Mechanism of action ……………………………………………………………………………………………………………….. 
53 
4.1.3 Pharmacodynamics …………………………………………………………………………………………………………………. 
53 
4.1.4 Pharmacokinetics …………………………………………………………………………………………………………………….. 54 
4.2 Study Drug Packaging and Labeling .............................................................................................. 
55 
4.3 Study Drug Storage ....................................................................................................................... 
55 
4.4 Administration .............................................................................................................................. 
55 
4.4.1 Route of Administration and Dose Schedule................................................................................. 
55 


9 
 
Amendment 1.1 – 20Jan2021 
4.4.2 Dose Increase / Dose Reduction ................................................................................................... 
57 
4.5 Study Drug Accountability ............................................................................................................. 57 
4.6 Study Drug Handling and Disposal ................................................................................................ 
57 
4.7 Prohibited Medications and Restrictions ...................................................................................... 
58 
4.8 Concomitant Medications ............................................................................................................. 
58 
4.9 Overdose …………………………………………………………………………………………………………………………………. 
59 
4.10 Treatment Compliance .................................................................................................................. 60 
 
 
5. ADVERSE EVENTS........................................................................................................................... 
61 
5.1 Definitions..................................................................................................................................... 
61 
5.1.1 Adverse Event Definitions.............................................................................................................. 
61 
5.1.1.1 Common Adverse Events............................................................................................................... 
62 
5.1.1.2 Serious Adverse Events ................................................................................................................. 
62 
5.1.2 Adverse Event Assessment Definitions ......................................................................................... 
64 
5.1.2.1 Assessment of Severity ................................................................................................................. 
64 
5.1.2.2 Assessment of Causal Relationship................................................................................................ 
64 
5.1.2.3 Assessment of Outcome ............................................................................................................... 
64 
5.2 Pregnancy...................................................................................................................................... 
65 
5.3 Recording Adverse Events ............................................................................................................. 
65 
5.4 Reporting Serious Adverse Events................................................................................................. 
65 
5.5 Treatment and Follow-Up of Adverse Events................................................................................ 
66 
5.6 Stopping Rule…………………………………………………………………………………………………………………………… 
66 
 
 
6. DATA ANALYSIS / STATISTICAL METHODS..................................................................................... 
67 
6.1 Data Summary................................................................................................................................ 67 
6.1.1 Summary of Safety Data................................................................................................................ 
67 
6.1.2 Summary of Efficacy Data.............................................................................................................. 
67 
6.2 Protocol Deviations ....................................................................................................................... 
67 
 
 
7. STUDY DOCUMENTATION AND RECORD KEEPING ........................................................................ 68 
7.1 Investigator’s Files and Retention of Study Data .......................................................................... 
68 
7.2 Background Data ........................................................................................................................... 
68 
7.3 Monitoring, Verification of Data, Audit, and Inspection ............................................................... 
68 
 
 
8. ADMINISTRATIVE PROCEDURES .................................................................................................... 
70 
8.1 Compliance with Good Clinical Practice and Ethical Considerations............................................. 
70 
8.2 Informed Consent.......................................................................................................................... 
70 
8.3 Confidentiality of Patient Information .......................................................................................... 
71 
8.4 Conditions For Modification of the Protocol ................................................................................. 71 
8.5 Clinical Study Report and Publications .......................................................................................... 71 
8.5.1 Data Ownership ............................................................................................................................ 
71 
8.5.2 Publications................................................................................................................................... 
71 
 
 


10 
 
Amendment 1.1 – 20Jan2021 
9. LIST OF TABLES ………………………………………………………………………………………………………………………… 
72 
9.1 Table 1: ABBREVIATIONS AND DEFINITIONS.................................................................................. 
2 
9.2 Table 2: Recommended AUSTEDO titration ………………………......................................................... 
14 
9.3 Table 3: Expected study drug titration for subjects able to increase AUSTEDO to 48 mg/day ….. 
56 
9.4 Table 4: Expected study drug titration for subjects able to increase AUSTEDO to 36 mg/day ….. 
56 
9.5 Table 5: Strong CYP2D6 inhibitors ………………………………………………………………………………………….... 58 
9.6 Table 6: Drugs causing QTc prolongation ……………………………………………………………………………….... 59 
 
 
10. LIST OF FIGURES ………………………………………………………………………………………………………………………. 
73 
10.1 Figure 1: Adverse Event Documentation Form …………………………………………………………………………. 25 
10.2 Figure 2: Physical Exam Form …………………………………………………………………………………………………… 
27 
10.3 Figure 3: Vital signs Form …………………………………………………………………………………………………………. 30 
10.4 Figure 4: Columbia Suicide Severity Rating Scale ……………………………………………………………………… 
32 
10.5 Figure 5: Stanford Sleepiness Scale ………………………………………………………………………………………….. 
36 
10.6 Figure 6: Mini Mental Status Examination ……………………………………………………………………………….. 
38 
10.7 Figure 7: MDS-UPDRS (Part III) …………………………………………………………………………………………………. 40 
10.8 Figure 8: VIDEO PROTOCOL – WORKSHEET ……………………………………………………………………………… 
44 
10.9 Figure 9: Patient Global Impression of Improvement ……………………………………………………………… 
46 
10.10 Figure 10: Clinical Global Impression of Improvement Scale ……………......................................... 
48 
10.11 Figure 11: Global Dystonia Rating Scale …………………………………………………………………………………… 
50 
 
 
11. APPENDICES ………………………………………………………………………………………………………………………….... 
74 
11.1 Appendix 1: Subject Visit schedule ............................................................................................... 
74 
 
 
12. REFERENCES .................................................................................................................................. 
75 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


11 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
1. INTRODUCTION  
 
1.1 Overview of dystonia and its treatments  
 
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle 
contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements 
are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by 
voluntary action and associated with overflow muscle activation. Dystonia is classified along two axes: 
clinical characteristics, including age at onset, body distribution, temporal pattern and associated 
features (additional movement disorders or neurological features); and etiology, which includes nervous 
system pathology and inheritance. The clinical characteristics fall into several specific dystonia 
syndromes that help to guide diagnosis and treatment.1 
 
Whenever a cause for the dystonia is identified, it opens the door to specific, etiology-based treatments. 
However, in the majority of cases, a cause cannot be recognized, and treatments are based on 
symptoms. Treatment options include counseling and education, oral medications, botulinum toxin 
injections, and several surgical procedures.2 Of note, none of the oral medications commonly used to 
treat dystonia has been subject to large-Scale, double-blinded, placebo-controlled trials, and there is no 
FDA-approved oral medication for treatment of dystonia. Much of the evidence supporting their use 
comes from small controlled trials, non-blinded trials, retrospective reviews, and anecdotal experience.2 
 
Different classes of medications are often used to treat dystonia.2 These include: 
• 
Anticholinergics:  These drugs are thought to work by blocking muscarinic acetylcholine 
receptors in the basal ganglia. Examples include trihexyphenidyl, benztropine, biperidin, 
ethopropazine, orphenadrine and procyclidine. 
• 
Benzodiazepines: Benzodiazepines amplify transmission through GABA receptors. Commonly 
used benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, and diazepam.  
• 
Dopaminergics: Augmenting dopamine transmission with levodopa is dramatically effective in 
dopa-responsive dystonia, which is most often caused by mutations in the GCH1 gene encoding 
the enzyme GTP-cyclohydrolase.  
• 
Dopamine depleters: Tetrabenazine, a reversible vesicular monoamine transporter 2 (VMAT2) 
inhibitor for oral administration, may be useful for some subjects with dystonia, particularly 
those with tardive dystonia.  
 
1.2 Background  
 
1.2.1 Overview on AUSTEDO  
 
As described in the drug’s package insert,3 deutetrabenazine (which will be referred to by its trade name 
“AUSTEDO” in this protocol) is a novel VMAT2 inhibitor for oral administration. It is believed to deplete 
monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. It is 
closely related to Tetrabenazine (TBZ), which has been approved for the treatment of Huntington’s 
disease chorea. However, its high affinity for VMAT2 makes AUSTEDO better tolerated than TBZ. 
AUSTEDO has been FDA approved for the treatment of Huntington’s disease chorea and, more recently, 
 


12 
 
Amendment 1.1 – 20Jan2021 
for the treatment of Tardive Dyskinesias (TD). AUSTEDO has not been studied yet for the treatment of 
dystonia.  
1.2.2 Clinical studies with AUSTEDO 
 
Double-Blind, Placebo-Controlled Study – Chorea associated with HD 
The efficacy of AUSTEDO as a treatment for chorea associated with Huntington's disease was 
established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial 
conducted in 90 ambulatory subjects with manifest chorea associated with Huntington’s disease. The 
diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. 
Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance 
period, followed by a 1-week washout. Subjects were not blinded to discontinuation. AUSTEDO was 
started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory 
treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg 
per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the 
Unified Huntington's Disease Rating Scale (UHDRS). On this Scale, chorea is rated from 0 to 4 (with 0 
representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28. Of the 90 
subjects enrolled, 87 subjects completed the study. The mean age was 54 (range 23 to 74). Subjects 
were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Total Maximal 
Chorea Scores for subjects receiving AUSTEDO improved by approximately 4.4 units from baseline to the 
maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the 
placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The 
Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 
Visits. At the Week 13 follow-up Visit (1 week after discontinuation of the study medication), the Total 
Maximal Chorea Scores of subjects who had received AUSTEDO returned to baseline. A patient-rated 
global impression of change assessed how subjects rated their overall Huntington’s disease symptoms. 
Fifty-one percent of subjects treated with AUSTEDO rated their symptoms as “Much Improved” or “Very 
Much Improved” at the end of treatment, compared to 20% of placebo-treated subjects. In a physician-
rated clinical global impression of change, 42% percent of subjects treated with AUSTEDO rated their 
symptoms as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of 
placebo-treated subjects.3 
 
Double-Blind, Placebo-Controlled Study – Tardive dyskinesia 
Double-blind, randomized, placebo-controlled, phase 3 trial at 75 centers in the USA and Europe. 
Subjects aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned 
centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of AUSTEDO 
(12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomization was stratified by baseline 
use of dopamine receptor antagonists. Subjects were started on oral AUSTEDO 12 mg/day, and this dose 
was increased through week 4 until the randomized dose was achieved, then maintained over 8 weeks. 
During the treatment period, subjects, investigators, their site personnel, and sponsor were masked to 
group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale 
(AIMS) score from baseline to week 12 in subjects with at least one post-baseline rating. The primary 
efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at 
least one post-baseline rating). The safety analysis was done in subjects who received any study drug. 
AUSTEDO 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with 
favorable safety and tolerability. These findings suggest that dosing regimens could be individualized 
and tailored for subjects on the basis of dyskinesia control and tolerability.4 
 
Double-Blind Study – Tardive dyskinesia 
 


13 
 
Amendment 1.1 – 20Jan2021 
One hundred seventeen subjects with moderate to severe TD received AUSTEDO or placebo in this 
randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary 
Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, 
and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from 
baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global 
Impression of Change (CGIC) and Patient Global Impression of Change. For the primary endpoint, 
AUSTEDO significantly reduced AIMS scores from baseline to week 12 vs. placebo (least-squares mean 
[standard error] -3.0 [0.45] vs. -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs. 40.4%) 
favored AUSTEDO but was not significant. AUSTEDO and placebo groups showed low rates of psychiatric 
adverse events: anxiety (3.4% vs. 6.8%), depressed mood/depression (1.7% vs. 1.7%), and suicidal 
ideation (0% vs. 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the 
Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either 
group.5 
 
Open label Study – Tardive dyskinesia 
In this open-label study of 12-18-year-old subjects with TS-related tics, AUSTEDO was titrated up to 36 
mg/day over 6 weeks to adequately suppress tics without bothersome adverse effects (AEs), followed by 
maintenance at optimal dose for 2 weeks. An independent blinded rater assessed tic severity using the 
Yale Global Tic Severity Scale (YGTSS), which was the primary outcome measure. Secondary outcome 
measures included the TS Clinical Global Impression (TS-CGI) and TS Patient Global Impression of Change 
(TS-PGIC). Twenty-three enrolled subjects received AUSTEDO and had at least 1 post-baseline YGTSS 
assessment. The mean (SD [standard deviation]) baseline YGTSS Total Tic Severity Score (TTS) was 31.6 
(7.9) and had decreased by 11.6 (8.2) points at week 8, a 37.6% reduction in tic severity (p<0.0001). The 
TS-CGI score improved by 1.2 (0.81) points (p<0.0001) and the TS-PGIC results at week 8 indicated that 
76% of subjects were much improved or very much improved compared with baseline. The mean (SD) 
daily AUSTEDO dose at week 8 was 32.1 (6.6) mg (range 18-36 mg). One week after withdrawal of 
AUSTEDO, the TTS scores increased by 5.6 (8.4) points, providing confirmation of the drug effect. No 
serious or severe adverse events were reported.6 
1.3 Study Rationale  
 
Clinicians have a limited armamentarium in terms of oral medications that are effective in the treatment 
of dystonia. None of these are FDA-approved for this indication, and their efficacy is limited by their side 
effect profile and dystonia severity. A number of studies have demonstrated Tetrabenazine (TBZ) is 
effective in the symptomatic treatment of dystonia.7-14 Tetrabenazine is a vesicular monoamine 
transporter 2 (VMAT2) inhibitor that modulates synaptic dopamine.15 As with other medications used 
for the treatment of dystonia, the use of TBZ is often limited by its side effect profile, which includes, 
but is not limited to, depression (including suicidal depression), sedation and parkinsonism. AUSTEDO is 
a novel, highly selective VMAT2 inhibitor that contains deuterium, a stable isotope of hydrogen. 
Deuterium attenuates the metabolism of AUSTEDO, leading to reduced fluctuations in plasmatic levels 
as compared to TBZ. This, in turn, reduces adverse events associated to peak drug concentrations.16 
AUSTEDO is approved by the Food and Drug Administration (FDA) for the treatment of chorea 
associated with Huntington’s disease (HD) and Tardive Dyskinesias in adults, but not for the treatment 
of dystonia. Given its shared mechanism of action with TBZ, and its more favorable safety profile, an 
opportunity exists to establish the safety, tolerability and clinical activity of AUSTEDO in subjects with 
dystonia. 
 
1.3.1 Selection of AUSTEDO Dose and Schedule of Administration  
 
 


14 
 
Amendment 1.1 – 20Jan2021 
AUSTEDO is available in 6, 9 and 12 mg tablets. To allow a precise dose titration among study subjects, 
only 6 mg tablets will be used in the AUDYT trial. As this is an open label trial, all subjects will receive the 
study drug; there is no placebo arm. All subjects will be instructed to take AUSTEDO with food, and not 
to chew, crush or break the tablets. The trial will consist of 3 periods: 
 
1. Ramp-up period: During this titration period, AUSTEDO will be started at 12 mg/day and 
increased up to 48 mg/day for most study subjects, up to 36 mg/day for study subjects receiving 
a strong CYP2D6 inhibitor, or up to the maximum, well-tolerated dose for those subjects unable 
to tolerate the maximum recommended dose of AUSTEDO. Dose-limiting toxicity will be defined 
in this protocol as the development of any of the following during the titration period: a) new or 
worsening depression, b) worsening of dystonic symptoms, c) QTc increase of >39 but <60 
milliseconds from baseline, or d) any other sign or symptom that, at the PI's discretion, would 
preclude further safe titration of the study drug. AUSTEDO will be increased by 6 mg/week as 
recommended in the package insert,3 as shown in Table 2 below: 
 
Table 2 
Recommended AUSTEDO 
titration 
 
 
Total daily dose (mg) 
Week 1 
12 
Week 2 
18 
Week 3 
24 
Week 4 
30 
Week 5 
36 
Week 6 
42 
Week 7 
48 
 
2. Maintenance period: Once on the maximum dose, subjects will complete 6 weeks of treatment 
on that dose, unless a side effects ensues. If so, it will remain at the investigator’s discretion 
whether to discontinue the study drug, or to reduce the dose to a new, maximum, well-
tolerated dose, on which the study subject will complete 6 weeks of treatment. Details on dose 
reduction will be discussed further elsewhere in this protocol. 
3. Post treatment period: Following 6 weeks of treatment with AUSTEDO, the medication will be 
discontinued and a final safety evaluation will be performed once the subject has been 1 week 
off study drug.  
 
 
2. TRIAL OBJECTIVES  
 
2.1 Primary Objective  
 
To explore the safety and tolerability of the daily oral administration of AUSTEDO in adult study subjects 
with dystonia. 
 
2.2 Secondary Objectives  
 
1. To establish the degree of symptomatic effect of AUSTEDO as measured by the Clinical Global 
Impression of Improvement Scale (CGI-I) after 6 weeks of AUSTEDO 48 mg daily, or at the 
highest tolerated dose.  
 


15 
 
Amendment 1.1 – 20Jan2021 
2. To establish the degree of symptomatic effect of AUSTEDO as measured by the Patient Global 
Impression of Improvement Scale (PGI-I) after 6 weeks of AUSTEDO 48 mg daily, or at the 
highest tolerated dose.  
3. To establish the degree of symptomatic effect of AUSTEDO as measured by the change in the 
Global Dystonia Rating Scale between baseline and after 6 weeks of AUSTEDO 48 mg daily, or at 
the highest tolerated dose. 
2.3 Safety Outcome Assessments  
 
The following assessments will establish the safety and tolerability of AUSTEDO during the AUDYT trial: 
 
• 
Tolerability will be established by the proportion of study subjects able to titrate up to 48 mg/d 
(or up to 36 mg/d if receiving a strong CYP2D6 inhibitor) and able to complete the study at this 
dosage. 
• 
Adverse events will be surveyed during all study Visits and during weekly telephone 
communications with the study subjects that will happen during the ramp-up period. 
• 
AUSTEDO may prolong the QT interval. QT interval prolongation is associated with the 
development of tachyarrhythmias and Torsades de Pointes. To screen for the development of 
significant QT prolongation (defined as a corrected QT –Bazett– interval of 450 (458) 
milliseconds –or higher– in men or 460 (472) milliseconds –or higher– in women), a 12-lead 
electrocardiogram (ECG) will be performed during all scheduled study Visits, including the early 
termination Visit, if such a Visit happens. Should there be evidence of QT prolongation, it will 
remain at the investigator’s discretion whether to discontinue the study drug, or to reduce the 
dose to a new, maximum, well-tolerated dose. A follow up ECG will be performed 1 week after 
the dose reduction (during an unscheduled Visit) to ensure the QTc is no longer significantly 
prolonged.  
• 
A complete physical examination will be performed at the time of the initial and final study Visit, 
as well as during the early termination Visit, if applicable. Any and all changes in the 
examination happening during the trial will be recorded, and reported when appropriate.  
• 
Vital Signs (including weight) will be measured and recorded during all scheduled study Visits, 
including the early termination Visit, if such a Visit happens. Any and all gross abnormalities or 
significant changes will be reported. 
• 
Suicidal thoughts or actions are a possible side effect of AUSTEDO use. The Columbia Suicide 
Severity Rating Scale (C-SSRS) will be administered during all scheduled study Visits, including 
the early termination Visit, if such a Visit happens. Development of suicidality as determined by 
this instrument at any point during the trial will warrant the immediate discontinuation of the 
study drug, as well as psychiatric care as determined necessary by the investigator. Subjects 
with any signs or suicidality during Visit 1 as detected by the scale will be immediately excluded 
from participating in the trial. 
• 
Somnolence is a possible side effect of AUSTEDO use. The Stanford Sleepiness Scale (SSS) will be 
administered during all scheduled study Visits, including the early termination Visit, if such a 
Visit happens. Should this side effect develop, the investigator will decided whether to continue 
AUSTEDO at the current dose, to discontinue the study drug, or to reduce the dose to a new, 
maximum, well-tolerated dose.  
• 
To assess the impact AUSTEDO may have on cognitive function, if any, the Mini Mental State 
Examination (MMSE) will be administered during Visits 1, 4 and during the early termination 
Visit, if such a Visit happens. It will remain at the investigator’s discretion to either discontinue 
the study drug, or to reduce the dose to a new, maximum, well-tolerated dose if clinically-
 


16 
 
Amendment 1.1 – 20Jan2021 
significant, new-onset cognitive impairment is identified at any point during the course of the 
trial, even if detected during Visits during which the MMSE is not administered. 
• 
To screen for the development of drug-induced parkinsonism, a possible side effect of AUSTEDO 
use, the MDS-UPDRS (Part III) will be administered during Visits 1, 4 and during the early 
termination Visit, if such a Visit happens. It will remain at the investigator’s discretion to either 
discontinue the study drug, or to reduce the dose to a new, maximum, well-tolerated dose if 
clinically-significant, new-onset drug-induced parkinsonism is identified at any point during the 
course of the trial, even if detected during Visits during which the MDS-UPDRS (Part III) is not 
administered.  
2.4 Efficacy Outcome Assessments  
 
Although the AUDYT trial is not powered to accurately establish efficacy of AUSTEDO, the following 
assessments will be performed: 
 
• 
Patient Global Impression of Improvement: During Visit 4, subjects will be asked to rate the 
change in their dystonic symptoms using this Scale.  
 
• 
Clinical Global Impression of Improvement Scale: A video will be made of each subject’s 
movement disorder examination during Visits 1 and 4. Videos will be sent to raters blinded to 
Visit number and recording date. Raters will be asked to compare the videos looking for any 
change in the subjects’ dystonic symptoms. Their impressions will be recorded using this Scale.  
• 
Global Dystonia Rating Scale: Blinded video raters will also be asked to rate the severity of the 
subjects’ dystonia in all videos using this Scale. 
 
 
 
 
 
 
3. STUDY METHODS 
 
3.1 Study Design  
 
This is a single-center, open-label study of AUSTEDO in study subjects with dystonia. The study will 
provide preliminary experience of the safety, tolerability, and clinical activity of AUSTEDO in study 
subjects with dystonia. Study duration will be up to 13 weeks from screening (Visit 1) to the post 
treatment evaluation (Visit 5) for study subjects able to titrate up to 48 mg/day. Treatment period from 
drug initiation to final on-treatment Visit will be 12 weeks, or less, as follows: during the ramp-up 
period, study drug will start at 12 mg/day (6 mg twice daily) and will be titrated weekly by 6 mg/day 
increments until either 1) the maximal allowable dose (48 mg/day) is reached, or 2) dose-limiting side-
effects occur. Dose-limiting toxicity will be defined in this protocol as the development of any of the 
following during the titration period: a) new or worsening depression, b) worsening of dystonic 
symptoms, c) QTc increase of >39 but <60 milliseconds from baseline, or d) any other sign or symptom 
that, at the PI's discretion, would preclude further safe titration of the study drug. In study subjects 
receiving a strong CYP2D6 inhibitor, the maximum allowed dose of AUSTEDO will be 36 mg/day, 
reducing study duration to 11 weeks (given a shortening in the ramp-up period). Study subjects who 
experience dose-limiting side effects will be maintained on their maximum tolerated dose. Once the 
maximal dose is established for each participant, they will complete 6 continuous weeks on this dose 
(maintenance period), followed by a 1-week washout. For study subjects unable to titrate up to 48 
mg/day due to side effects, the 6 weeks of maintenance will start once they reduce the study drug to 
the maximum dose they can tolerate well.  
 


17 
 
Amendment 1.1 – 20Jan2021 
 
Adverse events will be monitored throughout the study and will be reported after drug initiation. Dose 
reductions, suspensions, and withdrawals due to adverse events will be recorded. ECG readings, the 
Columbia Suicide Severity Rating Scale and the Stanford Sleepiness Scale will be assessed at all 
scheduled study Visits. The Mini Mental (MMSE) Scale will be performed at screening and at the final 
on-treatment Visit (Visit 4, usually during week 12). A video examination of the study subjects will be 
made at screening (right before initiation of the study drug), and after 6 weeks on AUSTEDO at a steady 
dose (right before drug cessation). Part III of the MDS-UPDRS will be performed at both of these Visits as 
well to screen for the appearance of drug-induced parkinsonism. Videos will be sent to raters blinded to 
Visit number and recording date, who will assess changes in the subjects’ dystonic symptoms. Patients 
will be contacted on a weekly basis via telephone during the ramp-up. 
3.2 Site  
 
The AUDYT trial will be a single-center trial to be conducted at the University of Pennsylvania’s 
Parkinson’s Disease and Movement Disorders Center. This Center has ample experience in conducting 
clinical trials, and has the necessary infrastructure and qualified research staff to do so.  
 
3.3 Number of Subjects 
 
Given this is a pilot, single-center, open-label trial, a number of 15 study subjects was selected to 
guarantee recruitment (it is expected that 2 subjects will be recruited/month). 
 
3.4 Study Population  
 
Study subjects for the AUDYT trial will be subjects with dystonia being managed at the University of 
Pennsylvania, or referred to this center for the purpose of participation in the trial.  
 
Subjects undergoing botulinum toxin injections for the treatment of dystonia will be eligible to 
participate in the study as long as they are willing to keep their upcoming injection paradigm identical to 
their latest injections, and as long as they are having suboptimal dystonia control with their current 
injection paradigm, as verified by their treating movement disorders specialist. Subjects receiving 
botulinum toxin injections will only be eligible to enroll in the AUDYT trial if their last injections were at 
least 11 weeks prior to screening (Visit 1). Subjects receiving injections sooner than every 12 weeks will 
be eligible to participate in the study as long as their upcoming injections are scheduled 6 days, or less, 
from the time of screening. It will be allowed for study subjects to undergo Visit 1 on the same day as 
their regularly-scheduled botulinum toxin injections, as long as Visit 1 (in its entirety) happens BEFORE 
the injections. 
 
Subjects who have undergone Deep Brain Stimulation surgery for the treatment of dystonia will be 
eligible to participate in the study if their stimulation settings have remained unchanged for at least 3 
months prior to study enrollment, and as long as they continue to have suboptimal dystonia control 
despite neurostimulation, as verified by their treating movement disorders specialist.  
 
3.4.1 Inclusion Criteria 
 
1. Study subjects with definite dystonia (e.g. focal, segmental, multifocal and generalized), as 
established by a movement disorder specialist. 
2. Study subjects of any race and either gender, age 18 or more on the date the informed consent form 
(ICF) is signed and with the capacity to provide voluntary informed consent.  
3. Study subjects able to read and understand English and the ICF and are willing to comply with all 
study procedures, treatment and follow-up.  
 


18 
 
Amendment 1.1 – 20Jan2021 
4. Study subjects who are taking any central nervous system acting medications (e.g., benzodiazepines, 
antidepressants, hypnotics), including medications for the treatment of dystonia, will be on a stable 
regimen for at least 30 days prior to the screening Visit, and will willing to remain on the same dose 
for the duration of the study.  
5. Female of child-bearing potential will not be pregnant and will be using an acceptable method of 
contraception.  
6. Study subjects with an MMSE >24. 
3.4.2 Exclusion Criteria 
 
1. Exposure to dopamine blockers prior to the onset of dystonia that could, in the investigator’s 
opinion, have caused dystonia.  
2. Study subjects with genetically-confirmed dopa-responsive dystonia.  
3. Study subjects with a diagnosis of Parkinson’s or an atypical parkinsonian syndrome.  
4. Study subjects with a history of bipolar disorder or major depression, or the presence of active 
depression.  
5. Study subjects with a history of a suicide attempt or suicidal ideations, as well as the presence of 
active suicidal ideation as detailed on the C-SSRS administered during Visit 1.  
6. Study subjects with a history of schizophrenia or schizophrenia spectrum disorders.  
7. Treatment with tetrabenazine, reserpine, valbenazine, a monoamino oxidase inhibitor, a-methyl-p-
tyrosine, strong anticholinergic medications, metoclopramide, antipsychotics, dopamine agonists, 
levodopa, and/or stimulants within 30 days of screening. 
8. Treatment with botulinum toxin less than 11 weeks prior to screening (Visit 1); subjects receiving 
injections sooner than every 12 weeks will be excluded if their next injection is scheduled farther 
than 6 days from screening. 
9. Presence of a neurologic condition that could confound dystonia assessments.  
10. Study subjects with a history of clinically relevant hepatic disease. 
11. Study subjects with a history of renal insufficiency. 
12. Any unstable medical illness.  
13. A corrected QT (Bazett) interval of 450 (458) milliseconds in men or 460 (472) milliseconds in 
women on 12-lead ECG at screening, or a history of cardiac arrhythmias.  
14. Study subjects participating in any drug or device clinical investigation concurrently or within 30 
days prior to screening for this study.  
15. Study subjects with a known hypersensitivity or contraindication to the study drug or its 
components. 
 
3.4.3 Duration of Subject Participation  
 
The duration of study participation will be 13 weeks from screening (Week 1) to the post treatment 
evaluation (Week 13). Treatment period from drug initiation to final on-treatment Visit will be 12 weeks, 
or less, as follows:  
 
• 
Study subjects able to titrate up to 48 mg/day will have 6 weeks of ramp-up and 6 weeks of 
maintenance. 
• 
Study subjects receiving a strong CYP2D6 inhibitor will only be allowed to titrate AUSTEDO up to 
a dose of 36 mg/day. They will have will have 4 weeks of ramp-up and 6 weeks of maintenance, 
for a total of 10 weeks on treatment. The total study duration for these subjects will be 11 
weeks, when the final post treatment evaluation is included. 
• 
Study subjects who experience dose-limiting side effects will be maintained on their maximum 
tolerated dose. Once the maximal dose is established for a study subject, they will complete 6 
 


19 
 
Amendment 1.1 – 20Jan2021 
continuous weeks on this dose (maintenance period), followed by a 1-week washout. For these 
study subjects, the 6 weeks of maintenance will start once they reduce the study drug to the 
maximum well-tolerated dose, independent of the duration of the ramp-up period. 
• 
The duration of the trial for study subjects who experience dose-limiting side effects that arise 
during the ramp-up period will depend on the dose at which the side effects appear. For these 
subjects, maintenance will continue to last 6 weeks, and they will also have a 1 week washout.  
• 
Premature, unexpected withdrawal from the trial will shorten study duration for that subject in 
unpredictable ways; subjects will be asked to undergo an early termination safety Visit, 
whenever possible. 
3.4.4 Estimated Study Duration  
 
As mentioned in the previous section, the AUDYT trial will have a maximal duration of 13 weeks/subject, 
which includes a 6-week ramp-up period, a 6-week maintenance period, and a 1 week washout.  It is 
expected that 2 subjects will be recruited per month, on average. Thus, recruitment of all study subjects 
should take 8 months. If the last study subject (recruited during month 8) participates in the study for 13 
weeks (the longest possible study duration per subject), this would bring complete study duration from 
the time of recruitment of the first study subject (Visit 1) to Visit 5 of the last study subject to about 11 
months.  
 
3.5 Study Visit and Assessment Schedule  
 
3.5.1 Schedule for subjects able to increase to and maintain maximum AUSTEDO dose  
 
A diagram summarizing all study visits can be found in the Appendix section (Appendix 1). Details on 
each of the individual study visits are depicted below.  
 
3.5.1.1 Visit 1: Screening (Week 1)  
 
This will be the first study Visit. During this Visit, subjects will sign the informed consent form, their 
eligibility for study participation will be confirmed, and study drug will be dispensed. Demographic and 
baseline characteristics (age at screening, gender, weight, height, BMI, race, ethnicity, medical history, 
physical examination) will be listed for individual subjects. The activities to be performed during Visit 1 
include: 
 
• 
Informed consent 
• 
Medical history will be obtained 
• 
Medication history will be obtained. All prior medications will be assigned a generic name based 
on the World Health Organization (WHO) Dictionary.  
• 
Concomitant medications will be reviewed (subjects receiving a strong CYP2D6 inhibitor will be 
instructed to titrate up to 36 mg during the ramp-up period, not to 48 mg, once study drug is 
dispensed). All concomitant medications will be assigned a generic name based on the World 
Health Organization (WHO) Dictionary. When applicable, date of last and next botulinum toxin 
injections will be recorded, as well as the date of the last DBS setting changes.  
• 
Complete physical exam 
• 
Vital signs 
• 
12-lead ECG 
• 
C-SSRS 
• 
SSS 
• 
MMSE 
• 
First video of the movement disorder examination 
 


20 
 
Amendment 1.1 – 20Jan2021 
• 
MDS-UPDRS Part III 
• 
Revision of eligibility criteria (inclusion/exclusion criteria will be reviewed) 
• 
Dispense study drug (if eligible for participation) 
3.5.1.2 Visit 2: Ramp-up period (Week 2 +/- 2 Days)  
 
Visit 2 will be the first one on study drug. This is a safety Visit, which will happen 5-9 days after study 
drug initiation. The activities to be performed during Visit 2 include: 
 
• 
Adverse events will be assessed 
• 
Vital signs 
• 
12-lead ECG 
• 
C-SSRS 
• 
SSS 
 
Patients will be contacted on a weekly basis via telephone during the ramp-up period to assess study 
drug tolerability. Dose reductions will be allowed in this period at the discretion of the investigator, but 
also during the maintenance period. A dose reduction during the ramp-up period will determine the 
start of the maintenance period, as it will be assumed that the new, lower AUSTEDO dose is the 
maximum well-tolerated dose of AUSTEDO for that study subject. Similarly, subjects will remain on the 
new, maximum well-tolerated dose of AUSTEDO for the remainder of the trial once a dose reduction is 
done during the maintenance period.  
 
 
3.5.1.3 Visit 3: Maintenance dose starts  
 
This is a safety Visit. The time during which this Visit will happen may vary depending on the duration of 
the ramp-up period, as follows: 
 
• 
For subjects able to titrate up to 48 mg/day, Visit 3 will be scheduled during week 7. 
• 
For subjects receiving a strong CYP2D6 inhibitor and, hence, able to titrate only up to 36 
mg/day, Visit 3 will happen during week 5. 
• 
For subjects with dose-limiting side effects during the ramp-up period, Visit 3 will be scheduled 
up to 3 days after the maximal, well-tolerated dose is established (this landmark will determine 
when the maintenance period has started).  
 
 The activities to be performed during Visit 3 include: 
 
• 
Adverse events will be assessed 
• 
Vital signs 
• 
12-lead ECG 
• 
C-SSRS 
• 
SSS 
 
3.5.1.4 Visit 4: Maintenance dose ends  
 
Visit 4 will happen during the last week of the maintenance period: during week 12 for subjects on 48 
mg/day of AUSTEDO, during week 10 for those subjects receiving a strong CYP2D6 inhibitor, and 6 
weeks after the initiation of the maintenance period for subjects who experienced dose-limiting side 
effects during the ramp-up period. This will be the last visit while on study drug, and at this time 
 


21 
 
Amendment 1.1 – 20Jan2021 
subjects will be instructed on when to stop AUSTEDO. According to the package insert,3 treatment with 
AUSTEDO can be discontinued without tapering. The activities to be performed during Visit 4 include: 
 
• 
Adverse events will be assessed 
• 
Vital signs 
• 
12-lead ECG 
• 
C-SSRS 
• 
SSS 
• 
MMSE 
• 
Second video of the movement disorder examination 
• 
MDS-UPDRS Part III 
• 
Patient Global Impression of Improvement 
3.5.1.5 Visit 5: Post treatment evaluation  
 
Visit 5 will be scheduled 1 week (or up to 9 days, if necessary) after study drug cessation. This is a safety 
Visit. The activities to be performed during Visit 5 include: 
 
• 
Adverse events will be assessed 
• 
Complete physical exam 
• 
Vital signs 
• 
12-lead ECG 
• 
C-SSRS 
• 
SSS 
• 
Returned bottles will be collected and compliance will be assessed 
 
3.5.2 Special situations that could cause changes in Study Visit Schedule  
 
3.5.2.1 Shortened Ramp-up Period  
 
There are three scenarios that could shorten the duration of the ramp-up period: 
 
1. Study subjects taking a strong CYP2D6 inhibitor: The maximum dose of AUSTEDO allowed for 
subjects taking a strong CYP2D6 inhibitor will be 36 mg/day. These study subjects will start 
AUSTEDO at 12 mg/day and increase at weekly intervals in increments of 6 mg per day up to 36 
mg/day, if tolerated, as instructed in the package insert.3 For these subjects, the maximum 
length of the ramp-up period will be 4 weeks.  
2. Subjects unable to titrate up to the maximum recommended dose: Whether it is 48 mg/day or 
36 mg/day, study subjects may experience dose-limiting side effects that do not allow them to 
titrate up to their individual, maximal recommended dose. Any side effects encountered during 
the ramp-up period will be recorded and reported as appropriate. Study subjects who encounter 
these side effects will be instructed to reduce the total daily AUSTEDO dose by 6 mg (1 tablet) 
every day until a new, maximum well-tolerated dose of AUSTEDO is established. A faster dose 
reduction will be allowed if deemed necessary by the investigator. Once this new dose is 
determined, the maintenance period will be considered initiated and subjects will be asked to 
complete Visit 3 at the study site within 3 days. 
3. Subjects unable to tolerate 12 mg/day of AUSTEDO: Subjects who are unable to tolerate the 
starting dose of the study drug will be withdrawn from the trial. Side effects encountered will be 
recorded and reported as appropriate. 
 
3.5.2.2 Early Termination  
 


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Amendment 1.1 – 20Jan2021 
 
If at any time during the study a patient requests to withdraw from treatment, or if a decision is made to 
withdraw the patient from the study, the patient will be requested to return for an Early Termination 
Visit. 
3.5.2.3 Unscheduled Visit 
 
A patient may return for an unscheduled Visit at any time at the Investigator’s discretion (for example, 
when a one week post dose-reduction ECG is required). The procedures conducted at the unscheduled 
Visit may be limited, depending on the reason for the Visit (for example, for dispensing of new study 
drug to replace a lost bottle of study drug would only require those specific procedures relevant to the 
reason for the unscheduled Visit to be done). 
 
3.5.2.4 Dose Adjustment  
 
Adjustments in the dose of AUSTEDO will be allowed throughout the study. If a reduction in the dose of 
AUSTEDO is required during the ramp-up period due to dose-limiting side effects, study subjects will be 
instructed to reduce the total daily AUSTEDO dose by 6 mg (1 tablet) every day until a new, maximum 
well-tolerated dose of AUSTEDO is established. A faster dose reduction will be allowed if deemed 
necessary by the investigator. Once this new dose is determined, the maintenance period will be 
considered initiated, and subjects will be instructed to complete Visit 3 and to remain on this dose for 6 
weeks. Any side effects encountered will be recorded and reported as appropriate. 
 
Dose-limiting toxicity will be defined in this protocol as the development of any of the following during 
the titration period: a) new or worsening depression, b) worsening of dystonic symptoms, c) QTc 
increase of >39 but <60 milliseconds from baseline, or d) any other sign or symptom that, at the PI's 
discretion, would preclude further safe titration of the study drug. 
 
If a reduction in the dose of AUSTEDO is required during the maintenance period due to dose-limiting 
side effects, study subjects will be instructed to reduce the total daily AUSTEDO dose by 6 mg (1 tablet) 
every day until a new, maximum well-tolerated dose of AUSTEDO is established. A faster dose reduction 
will be allowed if deemed necessary by the investigator. Once this new dose is determined, subjects will 
be instructed to remain on this dose until the 6 weeks of the maintenance period are completed. A new 
maintenance period will NOT start every time a dose reduction is performed. Any side effects 
encountered will be recorded and reported as appropriate. 
 
Increments in the total daily dose of AUSTEDO will not exceed 6 mg/week, as recommended by the 
package insert.3 Treatment interruptions will be discouraged unless necessary. In these cases, resuming 
AUSTEDO at the previous maintenance dose without titration will be allowed as long as the subject has 
been off study drug for 6 days or less. Subjects who require drug cessation for a week or more will be 
consider withdrawn from the trial, and will be asked to complete an early termination Visit. 
 
3.5.2.5 Subject Withdrawal  
 
Subjects will be advised that they are free to withdraw from the study at any time. Reasons that subjects 
may be withdrawn from the study include the following:  
 
• 
Subject discontinued study medication: according to the package insert,3 following treatment 
interruption of greater than one week, AUSTEDO therapy would need to be re-titrated when 
resumed, and, thus, subjects who require drug cessation for a week or more will be considered 
 


23 
 
Amendment 1.1 – 20Jan2021 
withdrawn from the trial. For treatment interruption of less than one week, treatment can be 
resumed at the previous maintenance dose without titration, as per the package insert.3 
• 
Subject consent is withdrawn 
• 
QTc changes: A study subject will be asked to discontinue study drug if at any point during the 
trial he or she is found on ECG to have developed a QTc> 500 milliseconds or a QTc increase of 
>60 milliseconds from baseline.  
• 
Sponsor decision, after discussion with the Investigator 
 
If a subject is withdrawn from the study, all efforts will be made to complete the early termination Visit 
that includes efficacy assessments and safety follow-up. In addition, women of childbearing potential 
will have a pregnancy test performed at the early termination Visit. All information, including the reason 
for withdrawal, will be reported. For subjects who are lost to follow-up, three recorded attempts will be 
made to contact the subject for follow-up information, including reason for discontinuation and follow-
up of AEs. Subjects who withdraw from the study will not be replaced. 
3.6 Study Procedures and Assessments 
 
3.6.1 Safety assessments  
 
3.6.1.1 Adverse Events  
 
During the study, the Investigator or study site personnel will be responsible for querying and recording 
adverse events (AEs) and serious adverse events (SAEs). In this study AEs and SAEs will be reported from 
the time of study drug administration until Visit 5 or death, whichever occurs first.  
 
An adverse event (AE) is any untoward medical occurrence that occurs in conjunction with the use of a 
medicinal product in humans, whether or not considered to have a causal relationship to the medicinal 
product. According to the package insert,3 adverse reactions experienced by at least 4% of subjects on 
AUSTEDO and with a greater incidence than on placebo include somnolence, diarrhea, dry mouth, 
fatigue, urinary tract infection, insomnia, anxiety, constipation and contusion.  
 
All AEs will be recorded regardless of the severity or relationship to study medication. All AEs that result 
in permanent discontinuation of the study drug being studied, whether serious or nonserious, will be 
reported. Figure 1 below shows the form that will capture this data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 


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Amendment 1.1 – 20Jan2021 
 
Visit Number (circle one): 1 2 3 4 5 Early termination Visit Other ____________ 
 
 
 
 
 
 
The AUDYT Trial 
Adverse Event Documentation Form 
 
 
 
Description of the AE: __________________________________________________ 
 
 
 
Diagnosis (if known): __________________________________________________ 
 
 
 
If AE is an overdose: Medication error _____   Accidental overdose _____ 
 
Intentional overdose _____ N/A _____ 
 
 
 
Serious adverse event: Yes ______ No ______ 
  
Date/Time of Onset: __________________________________________________ 
 
 
 
Date/Time of Resolution: __________________________________________________ 
 
 
 
Relationship to drug: Probable ______ Possible ______ Not related ______ 
 
 
 
Severity: Mild ______ Moderate ______ Severe ______ 
 
 
 
Outcome: Recovered _____ 
Recovering _____ 
 
 
 
 
Recovered with sequelae ____ 
Not recovered __________ 
  
 
Death ____ 
 
 
 
 
Action taken: No action taken _____ 
Study drug stopped _____ 
 
 
 
 
Study drug discontinued _____ Other _________________ 
 
 
 
 
 
 
 
 
 
 
3.6.1.2 ECG  
 
AUSTEDO may prolong the QT interval. QT interval prolongation is associated with the development of 
tachyarrhythmias and Torsades de Pointes. To screen for the development of significant QT 
 


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Amendment 1.1 – 20Jan2021 
prolongation (defined as a corrected QT –Bazett– interval of 450 (458) milliseconds in men or 460 (472) 
milliseconds in women), a 12-lead electrocardiogram (ECG) will be performed during all scheduled study 
Visits, including the early termination Visit, if such a Visit happens. Should there be evidence of QT 
prolongation, it will remain at the investigator’s discretion to either discontinue the study drug, or to 
reduce the dose to a new, maximum, well-tolerated dose. A follow up ECG will be performed 1 week 
after the dose reduction (during an unscheduled Visit) to ensure the QT prolongation is no longer 
significant.  
 
However, a study subject will be asked to discontinue study drug if at any point during the trial he or she 
is found on ECG to have developed a QTc> 500 milliseconds or a QTc increase of >60 milliseconds from 
baseline. Study subjects will be asked to come in for an Early Termination Visit within 3 business days of 
study drug discontinuation. 
3.6.1.3 Physical Examination  
 
A complete physical and neurologic examination will be performed at the time of the initial and final 
study Visit, as well as during the early termination Visit, if applicable. Abnormalities in the examination 
appreciated during Visit 1 and reflective of the subject’s known dystonia will be recorded and labeled as 
non-clinically significant. Any and all changes in the examination happening during the course of the trial 
will be recorded and reported, when appropriate. Figure 2 below shows the form that will capture this 
data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
Visit Number (circle one): 1 5 Early termination Visit 
 
 


26 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
The AUDYT Trial 
 
 
Physical Exam Form 
 
 
 
 
Vital signs: BP:         /         HR:          RR:          WT:         lbs 
 
 
 
General examination 
 
 
Skin: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Cardiovascular: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Respiratory: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Abdomen: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Extremities: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Neurologic examination 
 
 
Mental Status: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Cranial Nerves: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Motor: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Cerebellar: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
Reflexes: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 


27 
 
Amendment 1.1 – 20Jan2021 
 
 
 
Gait: Normal _____ 
Abnormal – CS _____ 
Abnormal – NCS _____ 
If abnormal, describe: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.1.4 Vital Signs and Weight  
 
Vital Signs (including weight) will be measured and recorded during all scheduled study Visits, including 
the early termination Visit, if such a Visit happens. Any and all gross abnormalities or significant changes 
will be reported. Figure 3 shown below shows the form that will capture this data. 
 
 


28 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3 
 
Date: DD – MMM – YYYY  
 
Study subject number: ____ 
 
Visit Number (circle one): 2 3 4 
 
 
 


29 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
The AUDYT Trial 
 
 
Vital signs Form 
 
 
 
 
Vital signs: BP:         /         HR:          RR:          WT:         lbs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.1.5 Columbia Suicide Severity Rating Scale  
 
Suicidal thoughts or actions are a possible side effect of AUSTEDO use. The rater/clinician-administered 
versions of the Columbia-Suicide Severity Rating Scale (C-SSRS)17 for research 
(http://cssrs.columbia.edu/the-columbia-Scale-c-ssrs/cssrs-for-research/) assess severity and intensity 
of suicidal ideation, types of suicidal behaviors, and lethality of suicide attempts at time points and over 
time periods that are typical for randomized control trials. The Columbia Suicide Severity Rating Scale 
 


30 
 
Amendment 1.1 – 20Jan2021 
will be administered during all scheduled study Visits, including the early termination Visit, if such a Visit 
happens. Development of suicidality as determined by this instrument at any point during the trial will 
warrant the immediate discontinuation of the study drug, as well as psychiatric care as determined 
necessary by the investigator. Subjects with any signs of suicidality during Visit 1 as detected by the 
scale will be immediately excluded from participating in the trial. Figure 4 shown below shows this Scale 
embedded in a data capture form: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Figure 4 
 
Date: DD – MMM – YYYY  
 
Study subject number: ____ 
 
Visit Number (circle one): 1 2 3 4 5 Early termination Visit 
 
 
 
 
 
 
The AUDYT Trial 


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Amendment 1.1 – 20Jan2021 
Columbia Suicide Severity Rating Scale 
 
 
 
 
 


32 
 
Amendment 1.1 – 20Jan2021 


33 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
3.6.1.6 Stanford Sleepiness Scale  
 


34 
 
Amendment 1.1 – 20Jan2021 
 
Somnolence is a possible side effect of AUSTEDO use. The Stanford Sleepiness Scale will be administered 
during all scheduled study Visits, including the early termination Visit, if such a Visit happens. Should this 
side effect develop, it will be at the discretion of the investigator whether to continue AUSTEDO at the 
current dose, discontinue the study drug, or to reduce the dose to a new, maximum, well-tolerated 
dose. Figure 5 shown below shows this Scale embedded in a data capture form: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5 
 


35 
 
Amendment 1.1 – 20Jan2021 
Date: DD – MMM – YYYY  
 
Study subject number: ____ 
 
Visit Number (circle one): 1 2 3 4 5 Early termination Visit 
 
 
 
 
 
 
The AUDYT Trial 
Stanford Sleepiness Scale 
 
 
 
 
 
 
 
 
 
 
3.6.1.7 Mini Mental State Examination  
 
To assess the impact AUSTEDO may have on cognitive function, if any, the Mini Mental State 
Examination (MMSE)19 will be administered during Visits 1, 4 and during the early termination Visit, if 
such a Visit happens. It will remain at the investigator’s discretion to either discontinue the study drug, 
or to reduce the dose to a new, maximum, well-tolerated dose if clinically-significant, new-onset 
cognitive impairment is identified at any point during the course of the trial, even if detected during 
Visits during which the MMSE is not administered. Figure 6 shown below shows this Scale embedded in 
a data capture form: 
 


36 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
Visit Number (circle one): 1 4 Early termination Visit 
 
 
 
 
 
 
 
The AUDYT Trial 
Mini Mental Status Examination 
 
 
 


37 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
3.6.1.8 MDS-UPDRS (Part III)  
 
To screen for the development of drug-induced parkinsonism, a possible side effect of AUSTEDO use, 
the MDS-UPDRS (Part III)20 will be administered during Visits 1, 4 and during the early termination Visit, 
if such a Visit happens. It will remain at the investigator’s discretion to either discontinue the study drug, 
or to reduce the dose to a new, maximum, well-tolerated dose if clinically-significant, new-onset drug-
induced parkinsonism is identified at any point during the course of the trial, even if detected during 
Visits during which the MDS-UPDRS (Part III) is not administered. Figure 7 shown below shows this Scale 
embedded in a data capture form: 
 
 
 


38 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 7 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
Visit Number (circle one): 1 4 Early termination Visit 
 
 
 
 
 
 
 
The AUDYT Trial 
MDS-UPDRS (Part III) 
 
 
 


39 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.2 Efficacy assessments  
 
3.6.2.1 Video of dystonia examination  
 
As part of the informed consent, all subjects will agree to have their movement disorders examination 
videotaped. The video recordings, which include sound, will show a subject’s entire body and face, in 
order to view their overall movement. The videos will be de-identified as much as possible and stored in 
a HIPAA-compliant drive. Staff will do their best to avoid saying subject’s name. Only study staff will 
have access to the videos. The video data will be kept for a minimum of 3 years prior to destruction. The 
video names will be formatted in a way that the blinded staff remain blinded. The video will not be used 
 


40 
 
Amendment 1.1 – 20Jan2021 
for any commercial, advertising, or promotional purposes. The following protocol will be followed when 
videotaping: 
 
General instructions 
• 
Remove shoes and socks, roll long pants up to see feet. Remove glasses, if applicable. Remove 
food or chewing gum from mouth. Pull long hair away from neck in a clip or rubber band.  
• 
Use a tripod. To prevent shadows, avoid strong overhead or back lighting on the subject, more 
light on face than behind. Video should be taken from straight in front of the participant, except 
where stated otherwise.  
• 
Avoid recording the participant’s name, date of birth, other identifiers, and people other than 
the subject or staff. Subjects will be identified by the number assigned to them during study 
enrollment. 
 
Part I: Participant is seated in a chair without head support. Feet are resting flat on floor and hands are 
resting flat in lap. Zoom camera in to capture head and shoulders only. Be sure to capture full face. 
1. At rest, eyes open for 10 seconds  
2. At rest, eyes closed gently for 10 seconds  
3. At rest, after opening eyes, for another 10 seconds  
4. Squeeze eyes closed, 5 times, for 1 second each, then open eyes and observe for 10 seconds  
5. Ask participant to repeat each sentence or sound below, one at a time:  
a. “We mow our lawn all year”  
b.  “We eat eggs every day”  
c. “He had half a head of hair”  
d. “The puppy bit the tape”  
e. “TaTaTa”  
f. 
“GaGaGa”  
g. “PaPaPa”  
6. Ask the participant to hold long vowel sounds: a. “AHHHHHH” (5 seconds); b. “EEEEEEE” (5 
seconds)  
7. Stick tongue out as far as possible and hold for 5 seconds  
8. Open and close mouth as wide as possible 2 times  
9. Ask: “do you have trouble swallowing?” If yes, ask: “occasional or frequent?”  
10. Ask: “do you choke?” If yes, ask: “occasional or frequent?”  
 
Part II: Participant is seated in a chair without head support. Feet are resting flat on floor and hands are 
resting flat in lap. Zoom camera out to capture upper body, including head and both upper limbs. 
11. Front view, at rest, eyes closed: instruct participant to let head drift to its most comfortable 
(dystonic) position, 10 secs  
12. Front view, at rest, eyes open: instruct participant to keep head straight at midline for 1 minute. 
Assist verbally if necessary for initial placement. Do not ask participant to reposition if the head 
drifts.  
13. Front view, with maximum range of motion, instruct participant to:  
a. Turn head to right, then left, both as far as possible, hold each position for 5 secs  
b. Tilt ear to right shoulder, then left shoulder, both as far as possible, hold each position 
for 5 secs  
c. Look up and extend neck, then look down and flex neck, both as much as possible, hold 
each position 5 secs  


41 
 
Amendment 1.1 – 20Jan2021 
14. Roll sleeves up for both arms, use a stable writing table, do not allow any tricks or 
compensations, non-active hand should rest on table without holding paper, viewing video from 
the front of the participant (participant may put glasses on at this point):  
a. Write “TODAY IS A NICE DAY” 3 times with dominant hand on associated recording form  
b. Write “TODAY IS A NICE DAY” 3 times with non-dominant hand on associated recording 
form  
c. Draw spiral with right hand, then with left hand, on recording form (active hand should 
not rest on table)  
d. Hold tip of pen over dot with right hand for 10 secs, as close as possible. Do not let pen 
or hand touch surface  
e. Hold tip of pen over dot with left hand for 10 secs, as close as possible. Do not let pen or 
hand touch surface  
f. 
Hold up written page for video  
15. Extend arms/hands supinated towards camera for 5 secs  
16. Extend arms/hands pronated towards camera for 5 secs  
17. Flex elbows and hold hands/arms steady without touching in front of chest, 5 secs eyes open  
18. Finger-to-nose test, slow enough to capture accuracy, 5 trials for each hand  
 
Part III: Participant stays seated. Zoom camera out further to capture entire body, including head and all 
limbs  
19. Finger tapping (thumb and forefinger) 10 times for each hand, as big and fast as possible  
20. Open and close both hands all the way, simultaneously and rapidly, 5 times  
21. Tap heel on floor then toe on floor in rapid alternations, 5 repeated pairs each side 
 
Part IV: Participant stands. Zoom camera out further to capture entire body, including head and all limbs  
22. Standing frontal view (5 seconds)  
23. Standing lateral (right) view (5 seconds)  
24. Standing back view (5 seconds)  
25. Walking at least 10 steps away from camera (posterior view) and at least 10 steps towards 
camera (front view)  
26. Walking on toes at least 10 steps away from camera, and on heels at least 10 steps towards 
camera  
27. Walking in toe-heel-tandem, at least 10 steps away from camera and at least 10 steps back 
towards camera 
 
Part V (perform these only if applicable):  
28. Ask if there is anything that can be done to reduce the severity of the dystonia (sensory trick), 
and demonstrate  
29. If participant has a task specific dystonia not captured in protocol above, such as playing musical 
instrument or chewing, please video record the dystonic symptoms while participant performs 
such tasks.  
30. If participant is in “Blepharospasm Tools” protocol, conduct this task: Participant seated. Zoom 
camera in to capture all of head and shoulders only: At rest, eyes open, for 2 minutes (blink as 
natural)  
 
 
 
 


42 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8 
 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
Visit Number (circle one): 1 4 Early termination Visit 
 
 
 
 
 
 
 
The AUDYT Trial 
VIDEO PROTOCOL – WORKSHEET 
 
 
 


43 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.2.2 Patient Global Impression of Improvement Scale 
 
During Visit 4, subjects will be asked to assess their dystonic symptoms using the Patient Global 
Impression of Improvement Scale (PGI-I). Figure 8 shown below shows this Scale embedded in a data 
capture form: 
 
 
 
 
 
 


44 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 9 


45 
 
Amendment 1.1 – 20Jan2021 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
Visit Number 4  
 
 
 
 
 
 
 
The AUDYT Trial 
Patient Global Impression of Improvement 
 
 
 
Please check the one number that best describes how your dystonia is now compared to 
when you started your participation in the AUDYT trial: 
 
1 
Very much better 
2 
Much better 
3 
A little better 
4 
No change 
5 
A little worse 
6 
Much worse 
7 
Very much worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.2.3 Clinical Global Impression of Improvement Scale 
 


46 
 
Amendment 1.1 – 20Jan2021 
 
Raters will be provided 2 videos for every study subject: one recorded during Visit 1, and another 
recorded during Visit 4. Videos will be randomly labeled as Video A and Video B for each subject, but the 
letter assigned will have no correlation with the order in which the videos were captured. The raters will 
be asked to make a global comparison of both videos, and to record their assessment using the form 
shown in Figure 9 below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Figure 10 


47 
 
Amendment 1.1 – 20Jan2021 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 
 
 
To be filled out by blinded video rater  
 
 
 
 
 
 
 
The AUDYT Trial 
Clinical Global Impression of Improvement Scale 
 
 
 
Please select the option that best describes the change in this subject’s dystonia between 
videos A and B: 
 
1 _____ This subject’s dystonia is very much better in Video A compared to Video B 
2 _____ This subject’s dystonia is much better in Video A compared to Video B 
3 _____ This subject’s dystonia is a little better in Video A compared to Video B 
4 _____ This subject’s dystonia is unchanged between Videos A and B 
5 _____ This subject’s dystonia is a little better in Video B compared to Video A 
6 _____ This subject’s dystonia is much better in Video B compared to Video A 
7 _____ This subject’s dystonia is very much better in Video B compared to Video A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6.2.4 Global Dystonia Rating Scale  
 


48 
 
Amendment 1.1 – 20Jan2021 
 
Besides performing CGI-I for the videos, raters will be ask to evaluate the severity of the dystonia in each 
video supplied. The Dystonia Study Group developed the Global Dystonia Rating Scale (GDS) to serve as 
an instrument to assess dystonia severity. Figure 10 shown below shows the Global Dystonia Rating 
Scale21 embedded in a data capture form: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 11 
 
Date: DD – MMM – YYYY 
 
Study subject number: ____ 


49 
 
Amendment 1.1 – 20Jan2021 
 
To be filled out by blinded video rater 
 
Please circle the video for 
which this form is used:  
Video A        Video B 
 
 
 
 
 
 
 
 
The AUDYT Trial 
Global Dystonia Rating Scale 
 
 
 
 
 
 
 
 
3.7 Study Endpoints  
 
3.7.1 Safety Endpoints 
 
3.7.1.1 Primary Safety Endpoint  
 


50 
 
Amendment 1.1 – 20Jan2021 
 
The primary safety endpoint for the AUDYT trial will be the proportion of study subjects able to titrate 
up to 48 mg/d (or up to 36 mg/d if receiving a strong CYP2D6 inhibitor) and able to complete the study 
at this dosage. The reason(s) why subjects are unable to titrate or maintain the maximal recommended 
AUSTEDO dose will be recorded and reported, when appropriate.  
3.7.1.2 Secondary Safety Endpoints  
 
Safety will be assessed by the documentation of all adverse events throughout the study. Serious 
adverse events will be reported, as appropriate. Twelve lead ECG will be performed during all scheduled 
study Visits (including an early termination Visit, if one happens) to screen for prolongation of the QT 
interval. In addition, the following Scales will be assessed:  
 
1. Columbia Suicide Severity Rating Scale.  
2. Stanford Sleepiness Scale.  
3. Mini Mental Scale.  
4. MDS-Unified Parkinson's Disease Rating Scale. 
 
3.7.2 Efficacy Endpoints  
 
3.7.2.1 Primary Efficacy Endpoint  
 
The AUDYT trial will be a patient-driven study. Accordingly, the primary efficacy endpoint will be patient-
driven as well: during Visit 4, study subjects will be administered the Patient Global Impression of 
Improvement Scale (PGI-I), with which they will quantify the degree of change (if any) in their dystonic 
symptoms that is attributable to their participation in the trial. The median of all of these assessments 
will be considered the primary efficacy endpoint. 
 
3.7.2.2 Secondary Efficacy Endpoints  
 
The secondary efficacy endpoints will be: 
• 
the median of all CGI-I  
• 
within subjects paired t-tests to assess significance of change in the GDS between Visits 1 and 4.  
 
Both the CGI-I and GDS will be extracted by blinded raters who will evaluate video examinations of the 
study subjects following an established protocol, as mentioned elsewhere in this document. 
 
3.8 Criteria for Study Termination  
 
The Sponsor reserves the right to discontinue the trial at any time; reasons will be provided in the event 
of this happening. The Principal Investigator reserves the right to discontinue participation in the study 
for safety or other reasons at any time in collaboration with the Sponsor. The Investigator will notify the 
IRB/REC/IEC in writing of the trial’s completion or early termination and provide a copy of the 
notification to the Sponsor. 
 
 
 
 
 
 
 
 
 
 


51 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. STUDY DRUG MATERIALS AND MANAGEMENT  
 
4.1 Study Drug  
 
4.1.1 Description 
 
As described in the drug’s package insert,3 AUSTEDO (AUSTEDO) is a vesicular monoamine transporter 2 
(VMAT2) inhibitor for oral administration. The molecular weight of AUSTEDO is 323.46; the pKa is 6.31. 
AUSTEDO is a hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: 
(RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)2H-benzo[a]quinolizin-2-
one. The molecular formula for AUSTEDO is C19H21D6NO3. AUSTEDO is a white to slightly yellow 
crystalline powder that is sparingly soluble in water and soluble in ethanol. 
 
 


52 
 
Amendment 1.1 – 20Jan2021 
AUSTEDO tablets contain 6 mg, 9 mg, or 12 mg AUSTEDO, and the following inactive ingredients: 
ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated 
hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, 
polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium 
dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also 
contain FD&C yellow #6 lake. Only 6 mg AUSTEDO tablets will be used in the AUDYT trial. 
4.1.2 Mechanism of action  
 
According to the package insert,3 the precise mechanism by which AUSTEDO (AUSTEDO) exerts anti-
chorea effects is unknown but is believed to be related to its effect as a reversible depletor of 
monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The 
major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of AUSTEDO, are reversible 
inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion 
of monoamine stores. 
 
4.1.3 Pharmacodynamics  
 
The following considerations are mentioned in AUSTEDO’s package insert:3 
 
Cardiac Electrophysiology  
The effect of a single 12-mg or 24-mg dose of AUSTEDO on the QT interval was studied in a randomized, 
double-blind, placebo-controlled crossover study in healthy male and female subjects with moxifloxacin 
as a positive control. At 24 mg, AUSTEDO caused an approximately 4.5 milliseconds mean increase in 
QTc (90% CI: 2.4, 6.5 msec). Effects at higher exposures to AUSTEDO or its metabolites have not been 
evaluated. The effect of a single 25-mg or 50-mg dose of tetrabenazine, a closely related VMAT2 
inhibitor, on the QT interval was studied in a randomized, double-blind, placebo-controlled crossover 
study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, 
tetrabenazine caused an approximately 8 milliseconds mean increase in QTc (90% CI: 5.0, 10.4 msec). 
Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated.  
 
Melanin Binding  
AUSTEDO or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. 
After a single oral dose of radiolabeled AUSTEDO, radioactivity was still detected in eye and fur at 35 
days following dosing. 
 
4.1.4 Pharmacokinetics  
 
As stated in the drug’s package insert,3 after oral dosing up to 25 mg, plasma concentrations of 
AUSTEDO are generally below the limit of detection because of the extensive hepatic metabolism of 
AUSTEDO to the active deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ. Linear dose 
dependence of Cmax and AUC was observed for the active metabolites following single or multiple 
doses of AUSTEDO (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily).  
 
Absorption  
Following oral administration of AUSTEDO, the extent of absorption is at least 80%. Plasma 
concentrations of AUSTEDO are generally below the limit of detection after oral dosing. Peak plasma 
concentrations (Cmax) of deuterated α-HTBZ and β-HTBZ are reached within 3 to 4 hours after dosing.  
 
Effect of Food  
 


53 
 
Amendment 1.1 – 20Jan2021 
The effects of food on the bioavailability of AUSTEDO were studied in subjects administered a single 
dose with and without food. Food had no effect on the area under the plasma concentration-time curve 
(AUC) of α-HTBZ or β-HTBZ, although Cmax was increased by approximately 50% in the presence of 
food.  
 
Distribution  
The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of AUSTEDO are 
approximately 500 L and 730 L, respectively. Results of PET-scan studies in humans show that following 
intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, radioactivity is rapidly distributed to the 
brain, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein 
binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations 
ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged 
from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.  
 
Elimination  
AUSTEDO is primarily renally eliminated in the form of metabolites. The half-life of total (α+β)-HTBZ 
from AUSTEDO is approximately 9 to 10 hours. The median clearance values (CL/F) of the α-HTBZ, and 
the β-HTBZ metabolites of AUSTEDO are approximately 47 L/hour and 70 L/hour, respectively, in the 
Huntington’s disease patient population.  
 
Metabolism  
In vitro experiments in human liver microsomes demonstrate that AUSTEDO is extensively 
biotransformed, mainly by carbonyl reductase, to its major active metabolites, α-HTBZ and βHTBZ, 
which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and 
CYP3A4/5, to form several minor metabolites.  
 
Excretion  
In a mass balance study in 6 healthy subjects, 75% to 86% of the AUSTEDO dose was excreted in the 
urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the α-HTBZ and β-
HTBZ metabolites from AUSTEDO each accounted for less than 10% of the administered dose. Sulfate 
and glucuronide conjugates of the α-HTBZ and β-HTBZ metabolites of AUSTEDO, as well as products of 
oxidative metabolism, accounted for the majority of metabolites in the urine. 
4.2 Study Drug Packaging and Labeling  
 
As mentioned in the package insert,3 AUSTEDO tablets are available in the following strengths and 
packages: 6 mg: round, purple-coated tablets, with “SD” over “6” printed in black ink on one side. 
Bottles of 60 tablets: NDC 68546-170-60. 9 mg: round, blue-coated tablets, with “SD” over “9” printed in 
black ink on one side. Bottles of 60 tablets: NDC 68546-171-60. 12 mg: round, beige-coated tablets, with 
“SD” over “12” printed in black ink on one side. Bottles of 60 tablets: NDC 68546-172-60. Only 6 mg 
AUSTEDO tablets will be used in the AUDYT trial. 
 
4.3 Study Drug Storage  
 
As per the package insert,3 AUSTEDO will be stored at 25º C (77ºF); excursions permitted to 15°C to 30ºC 
(59°F to 86ºF). It will be protected from light and moisture. 
 
4.4 Administration  
 
4.4.1 Route of Administration and Dose Schedule 
 
 


54 
 
Amendment 1.1 – 20Jan2021 
According to the package insert,3 the dose of AUSTEDO is determined individually for each patient with 
Huntington’s Disease based on reduction of chorea and tolerability. When first prescribed to subjects 
who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting 
dose of AUSTEDO is 6 mg administered orally once daily. The dose of AUSTEDO may be increased at 
weekly intervals in increments of 6 mg per day to a maximum recommended daily dosage of 48 mg. 
Total daily dosages of 12 mg or above will be administered in two divided doses. AUSTEDO will be 
administered with food. AUSTEDO will be swallowed whole. It will not be chewed, crushed or broken. 
 
Based on these recommendations (and as shown in Table 3 below), for the purpose of the AUDYT trial, 
each study subject is expected to start, increase, maintain and then discontinue AUSTEDO 6 mg tablets 
as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3 
Expected study drug titration for subjects able to increase AUSTEDO to 48 mg/day 
 
 
Number of 
morning tablets 
Number of 
afternoon 
tablets 
Total daily 
dose (mg) 
Total 
number of 
tablets per 
day 
Total 
number of 
tablets per 
week 
Week 1 
1 
1 
12 
2 
14 
Week 2 
1 
2 
18 
3 
21 
Week 3 
2 
2 
24 
4 
28 
Week 4 
2 
3 
30 
5 
35 
Week 5 
3 
3 
36 
6 
42 
Week 6 
3 
4 
42 
7 
49 
Week 7 
4 
4 
48 
8 
56 
Week 8 
4 
4 
48 
8 
56 
Week 9 
4 
4 
48 
8 
56 
Week 10 
4 
4 
48 
8 
56 
Week 11 
4 
4 
48 
8 
56 
Week 12 
4 
4 
48 
8 
56 
Week 13 
0 
0 
0 
0 
0 
 
 


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Amendment 1.1 – 20Jan2021 
Table 4 below shows how subjects receiving a strong CYP2D6 inhibitor will start, increase, maintain and 
then discontinue AUSTEDO 6 mg tablets: 
  
 
Table 4 
Expected study drug titration for subjects able to increase AUSTEDO to 36 mg/day 
 
 
Number of 
morning tablets 
Number of 
afternoon 
tablets 
Total daily 
dose (mg) 
Total 
number of 
tablets per 
day 
Total 
number of 
tablets per 
week 
Week 1 
1 
1 
12 
2 
14 
Week 2 
1 
2 
18 
3 
21 
Week 3 
2 
2 
24 
4 
28 
Week 4 
2 
3 
30 
5 
35 
Week 5 
3 
3 
36 
6 
42 
Week 6 
3 
3 
36 
6 
42 
Week 7 
3 
3 
36 
6 
42 
Week 8 
3 
3 
36 
6 
42 
Week 9 
3 
3 
36 
6 
42 
Week 10 
3 
3 
36 
6 
42 
Week 11 
0 
0 
0 
0 
0 
 
In subjects receiving a strong CYP2D6 inhibitor, the ramp-up period will be reduced to 4 weeks, reducing 
the duration of their participation in the study to 11 weeks.  
4.4.2 Dose Increase / Dose Reduction  
 
As per the package insert,3 increments in AUSTEDO dosing will be done by 6 mg/week up to a maximum 
of 48 mg/day. Study subjects who are unable to tolerate this dose will be allowed to remain on the 
maximum well-tolerated dose of AUSTEDO. If this dose has not been previously established, they will be 
instructed to reduce the total daily AUSTEDO dose by 6 mg (1 tablet) every day until the maximum well-
tolerated dose of AUSTEDO is established. A faster dose reduction will be allowed if deemed necessary 
by the investigator. In study subjects receiving a strong CYP2D6 inhibitor, the maximum allowed dose of 
AUSTEDO will be 36 mg/day. 
 
Patients will be contacted on a weekly basis via telephone during the ramp-up period to assess study 
drug tolerability. Dose reductions will be allowed in this period at the discretion of the investigator, but 
also during the maintenance period. A dose reduction during the ramp-up period will determine the 
start of the maintenance period, as it will be assumed that the new, lower AUSTEDO dose is the 
maximum well-tolerated dose of AUSTEDO for that study subject. Similarly, subjects will remain on the 
new, maximum well-tolerated dose of AUSTEDO for the remainder of the trial once a dose reduction is 
done during the maintenance period.  
 
4.5 Study Drug Accountability  
 
All study drug supplied is for use only in this clinical study and will not be used for any other purpose. 
The Investigator is responsible for the study drug accountability, reconciliation and record maintenance 
at the investigational site. In accordance with all applicable regulatory requirements, the Investigator or 
designated site staff will maintain study drug accountability records throughout the course of the study. 
 


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Amendment 1.1 – 20Jan2021 
This person will document the amount of study drug received and the amount supplied and/or 
administered to and returned by subjects, if applicable. Copies of all packing slips for the study drug 
shipments will be retained.  
 
A Study Drug Accountability Record will be kept current and will contain at a minimum the following 
information:  
• 
The identification of the subject to whom the drug was dispensed  
• 
The date(s) and quantity of the drug dispensed to the subject  
• 
Any product accidentally or deliberately destroyed  
• 
Current quantity of total study drug supply  
 
Subjects will be instructed to return all used and unused bottles (with unused capsules) of study drug for 
drug accountability purposes. All used and unused bottles (with unused capsules) will be saved for 
reconciliation by the Sponsor’s study monitor or an assigned designee. During the study, the study drug 
and all shipment, accountability and dispensing records will be available for inspection by the study 
monitor. Drug supply reconciliation is required at the end of the study.  
4.6 Study Drug Handling and Disposal  
 
After reconciliation, unused or partially used study drug may be destroyed by the Investigator only after 
authorization from Teva, and according to instructions provided by Teva, provided such disposition does 
not expose humans to risk from the drug. The Investigator or their designee will maintain records of any 
such alternative disposition of the study drug. These records will show the identification and quantity of 
each unit that has been disposed, the method of destruction, and the person who disposed of the study 
drug. Alternatively, the Investigator may elect to return unused or partially used drug supplies to Teva, 
or the sponsor’s designee, instead of destroying them on-site. 
 
4.7 Prohibited Medications and Restrictions  
 
Reserpine 
Reserpine is an irreversible VMAT2 inhibitor, and, thus, will not be used concomitantly with AUSTEDO. In 
clinical practice, at least twenty (20) days must elapse after stopping reserpine before starting 
AUSTEDO. 
 
Monoamine Oxidase Inhibitors 
AUSTEDO is contraindicated in subjects taking MAOIs. In clinical practice, AUSTEDO will not be used in 
combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI. 
 
Tetrabenazine 
AUSTEDO is contraindicated in subjects currently taking tetrabenazine. In clinical practice, AUSTEDO 
may be initiated the day following discontinuation of Tetrabenazine. 
 
AUSTEDO is also contraindicated in subjects: 
• 
Who are suicidal, or in subjects with untreated or inadequately treated depression. 
• 
With hepatic impairment. 
 
4.8 Concomitant Medications  
 
Strong CYP2D6 inhibitors 
 


57 
 
Amendment 1.1 – 20Jan2021 
As per the package insert,3 concomitant use of strong CYP2D6 inhibitors has been shown to increase the 
systemic exposure to the active dihydro-metabolites of AUSTEDO by approximately 3 fold. The daily 
dose of AUSTEDO will not exceed 36 mg per day, and the maximum single dose of AUSTEDO will not 
exceed 18 mg in subjects taking these inhibitors. 
 
Table 5 below shows a list of strong CYP2D6 inhibitors: 
 
 
Table 5 
Strong CYP2D6 inhibitors 
 
Bupropion  
Fluoxetine  
Paroxetine  
Quinidine 
Terbinafine 
 
Neuroleptics 
The risk for parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO and 
dopamine antagonists or antipsychotics. As per the inclusion/exclusion criteria, subjects with a history of 
psychiatric disease or taking an antipsychotic (even if for a non-psychiatric reason) are not eligible for 
participation in the AUDYT trial. 
 
Alcohol or other sedatives 
Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and 
somnolence. As mentioned in the exclusion criteria, no change in the dose of psychoactive medications 
will be allowed for the duration of the trial, or at least 30 days prior to screening. Subjects will be 
encouraged to abstain from alcohol for the duration of the trial.  
 
Drugs causing QTc prolongation 
Table 6 below shows a list of medications that are known to prolong the QTc. Subjects taking these 
medication will be allowed to participate in the trial as long as their ECG during visit 1 (and while already 
on one or more of these drugs at steady state) shows no QTc prolongation. Any evidence of QTc 
prolongation during subsequent ECGs will require an adjustment in the AUSTEDO dose as detailed 
elsewhere. The introduction of these medications will not be allowed for the duration of the trial. If it is 
determined that a subject requires one of these medications during their participation in the trial, 
AUSTEDO will be stopped and the subject will be considered withdrawn from the trial.  
 
 
 
Table 6 
Drugs causing QTc prolongation 
 
Moxifloxacin 
Quinidine 
Procainamide 
Amiodarone 
Sotalol 


58 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
4.9 
 
 
Overdose  
 
According to the package insert,3 overdoses ranging from 100 mg to 1 g have been reported in the 
literature with tetrabenazine, a closely related VMAT2 inhibitor. The following adverse reactions 
occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, 
hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.  
 
All overdoses will be reported to the sponsor. Minor overdoses will be managed according to the 
sponsor’s guidelines. However, suicide attempts, should they happen, will be managed in the same way 
as attempts by non-study subjects: 911 will be called to guarantee prompt access to the nearest medical 
facility. As with the management of overdosage with any central nervous system-active drug, general 
supportive and symptomatic measures will be recommended. Cardiac rhythm and vital signs should be 
monitored. In managing overdosage, the possibility of multiple drug involvement should be considered. 
The treating physician during hospitalization will consider contacting a poison control center on the 
treatment of any overdose. Telephone numbers for certified poison control centers are listed on the 
American Association of Poison Control Centers website www.aapcc.org. 
 
 
4.10 Treatment Compliance  
 
During Visit 1, the total number of tablets that each study subject will need for the duration of the trial 
will be dispensed. Compliance will be assessed during Visit 5, that is, during the 1-week post-treatment 
Visit. The number of returned tablets will be counted by the Investigator, or a designee, and recorded in 
the Drug Dispensing Log. At least 80% compliance will be defined as acceptable in this study. Compliance 
with study drug intake will be assessed verbally (subject’s report, no tablet counting) and encouraged 
during all other study Visits. 
 
 
 
 
 
 
 
 
 
 
 


59 
 
Amendment 1.1 – 20Jan2021 
 
 
 
 
 
 
 
 
 
5. ADVERSE EVENTS 
 
5.1 Definitions 
 
5.1.1 Adverse Event Definitions 
 
During the study, the Investigator or study site personnel will be responsible for querying and recording 
adverse events (AEs) and serious adverse events (SAEs), as detailed in this section of the protocol. This 
includes the weekly communications with the study subjects via telephone during the ramp-up period. 
In this study AEs and SAEs will be reported from the time of study drug administration until the last 
study Visit or death, whichever occurs first.  
 
An adverse event (AE) is any untoward medical occurrence that occurs in conjunction with the use of a 
medicinal product in humans, whether or not considered to have a causal relationship to the medicinal 
product. An AE can, therefore, be any unfavorable or unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not it is a direct consequence of study drug use.  
 
Any medical condition or clinically significant laboratory abnormality with an onset date before the first 
date of study drug administration will be considered to be pre-existing, and will not be recorded as an 
AE. Any AE (i.e., a new event or an exacerbation of a pre-existing condition) with an onset date after 
study drug administration up to and including the designated follow-up safety Visit will be recorded as 
an AE. All AEs will be recorded regardless of the severity or relationship to study medication. All AEs that 
result in permanent discontinuation of the study drug being studied, whether serious or nonserious, will 
be reported.  
 
An AE does include:  
 
• 
an exacerbation of a pre-existing illness 
• 
an increase in frequency or intensity of a pre-existing episodic event or condition 
• 
a condition detected or diagnosed after study drug administration even though it may have 
been present prior to the start of the study 
• 
persistent disease or symptoms present at baseline which worsen following the start of the 
study 
 
 


60 
 
Amendment 1.1 – 20Jan2021 
An AE does not include:  
 
• 
medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) Note: in 
this case, the condition that led to the procedure is an AE  
• 
pre-existing diseases or conditions present or detected prior to start of study drug 
administration, which do not worsen 
• 
the disease or disorder being studied or a sign or symptom associated with that disease (i.e., 
signs or symptoms associated with lack of efficacy will generally be considered to reflect 
underlying disease, rather than AEs) 
• 
situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social, and/or convenience admissions) 
• 
overdose of either study drug or concomitant medication without any signs or symptoms 
 
All AEs will be fully and completely recorded. The following attributes will be assigned: description of AE, 
dates and times of onset and resolution (or whether ongoing), severity, causality to study drug, whether 
an SAE or not, and action taken (i.e., no action taken; study medication interrupted; study medication 
discontinued; other).  
 
In the event that a subject is withdrawn from the study because of an AE, it will be recorded. The subject 
will be followed and treated by the investigator until the AE has resolved or a new chronic baseline has 
been established. The investigator will report all directly observed AEs and all spontaneously reported 
AEs. At each Visit the investigator will ask the subject a nonspecific question (e.g., “Have you noticed 
anything different since your last Visit?”) to assess whether any AEs have occurred since the last report 
or Visit. AEs will be identified and recorded in appropriate medical terminology.  
5.1.1.1 Common Adverse Events 
 
According to the package insert, 3 adverse reactions experienced by at least 4% of subjects on AUSTEDO 
and with a greater incidence than on placebo include somnolence, diarrhea, dry mouth, fatigue, urinary 
tract infection, insomnia, anxiety, constipation and contusion. 
 
5.1.1.2 Serious Adverse Events  
 
A serious adverse event (SAE) is any AE occurring at any dose that:  
 
• 
results in death 
• 
is life-threatening (subject is at immediate risk of death at the time of the event) 
• 
requires inpatient hospitalization or results in prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect in the offspring of a subject who received study drug 
• 
is a significant or important medical event, i.e., an event that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the above mentioned criteria (examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse).  
 
When a causality assessment is provided for an SAE, a rationale for the assessment will be included, so 
that a better understanding of the reported event can be compiled. The rationale will be accompanied 
by all available supporting evidence, including relevant laboratory tests, histopathology evaluations, and 
 


61 
 
Amendment 1.1 – 20Jan2021 
the results of other diagnostic procedures. The Investigator’s rationale with supporting evidence is 
valuable when the Sponsor performs a cumulative analysis of similar events.  
 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any serious adverse event that is 
considered related to the investigational product, and that is also unexpected. SUSARs qualify for 
expedited reporting to applicable Health Authorities and IRB/REB/IECs. 
 
According to the package insert,3 the following serious adverse reactions can happen with the use of 
AUSTEDO: 
 
• 
Depression and suicidality: Subjects with Huntington’s disease are at increased risk for 
depression, and suicidal ideation or behaviors (suicidality). AUSTEDO may increase the risk for 
suicidality in subjects with Huntington’s disease. In a 12-week, double-blind, placebo-controlled 
trial, suicidal ideation was reported by 2% of subjects treated with AUSTEDO, compared to no 
subjects on placebo; no suicide attempts and no completed suicides were reported. Depression 
was reported by 4% of subjects treated with AUSTEDO. 
• 
Neuroleptic malignant syndrome: A potentially fatal symptom complex sometimes referred to 
as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that 
reduce dopaminergic transmission. While NMS has not been observed in subjects receiving 
AUSTEDO, it has been observed in subjects receiving tetrabenazine (a closely related VMAT2 
inhibitor). The management of NMS will include (1) immediate discontinuation of AUSTEDO; (2) 
intensive symptomatic treatment and medical monitoring; and (3) treatment of any 
concomitant serious medical problems for which specific treatments are available. Recurrence 
of NMS has been reported with resumption of drug therapy, and, thus, any subject developing 
this will be immediately withdrawn from the trial. 
• 
Akathisia, agitation and restlessness: AUSTEDO may increase the risk of akathisia, agitation, and 
restlessness in subjects with Huntington’s disease. In a 12-week, double-blind, placebo-
controlled trial, akathisia, agitation, or restlessness was reported by 4% of subjects treated with 
AUSTEDO, compared to 2% of subjects on placebo. If a patient develops akathisia during 
treatment with AUSTEDO, the AUSTEDO dose will be reduced; some subjects may require 
discontinuation of therapy and withdrawal from the trial. 
• 
Parkinsonism: AUSTEDO may cause parkinsonism in subjects with Huntington’s disease. Drug-
induced parkinsonism has the potential to cause more functional disability than untreated 
chorea for some subjects with Huntington’s disease. If a patient develops parkinsonism during 
treatment with AUSTEDO, the AUSTEDO dose will be reduced; some subjects may require 
discontinuation of therapy. 
• 
Sedation and somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO. In 
a 12-week, double-blind, placebo-controlled trial, 11% of AUSTEDO-treated subjects reported 
somnolence compared with 4% of subjects on placebo and 9% of AUSTEDO-treated subjects 
reported fatigue compared with 4% of placebo-treated subjects. 
• 
QTc prolongation: Tetrabenazine increases the QTc by about 8 msec. A clinically relevant QT 
prolongation may occur in subjects treated with AUSTEDO who are co-administered a strong 
CYP2D6 inhibitor, which is why these subjects will not be allowed to titrate to more than 36 
mg/day.  
• 
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations, but it is unclear 
whether AUSTEDO has this effect. Caution is advised with the use of AUSTEDO in subjects with 


62 
 
Amendment 1.1 – 20Jan2021 
known or suspected hyperprolactinemia, or in subjects with breast cancer with prolactin 
receptors.  
• 
Binding to Melanin-Containing tissues: Possible accumulation of AUSTEDO in these tissues over 
time could cause long-term ophthalmologic effects. 
5.1.2 Adverse Event Assessment Definitions  
 
5.1.2.1 Assessment of Severity  
 
The severity of each AE/SAE will be classified into one of three defined categories as follows: 
 
• 
Mild: the AE is easily tolerated by the subject, causes minimal discomfort, and does not interfere 
in a significant manner with the subject’s normal functioning level or activities 
• 
Moderate: the AE is sufficiently uncomfortable to interfere with normal everyday activities, but 
is not hazardous to health 
• 
Severe: the AE produces significant impairment of functioning or incapacitation and is a definite 
hazard to the subject’s health.  
 
These three categories are based on the investigator’s clinical judgment, which in turn depends on 
consideration of various factors such as the subject’s reports, the physician’s observations, and the 
physician’s prior experience.  
 
5.1.2.2 Assessment of Causal Relationship 
 
The Investigator will assess and record the causal relationship between the AE and the study drug using 
the following definitions:  
 
• 
Probable: the AE has a strong temporal relationship to the study drug, and another etiology is 
unlikely or significantly less likely.  
• 
Possible: the AE has a suggestive temporal relationship to the study drug, and an alternative 
etiology is equally or less likely.  
• 
Not related: the AE has no temporal relationship to the study drug or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no causal relationship 
between the study drug and the adverse event).  
 
An AE will be considered causally related to the use of the study drug when the causality assessment is 
probable or possible. 
 
5.1.2.3 Assessment of Outcome  
 
The Investigator will assess and record the outcome of the AE using the following definitions:  
 
• 
Recovered: the subject has recovered completely, and no symptoms remain.  
• 
Recovering: the subject’s condition is improving, but symptoms still remain. 
• 
Recovered with sequelae: the subject has recovered, but some symptoms remain 
• 
Not recovered: the subject’s condition has not improved and the symptoms are unchanged  
• 
Death 
 
5.2 Pregnancy 
 
Risk Summary  
 


63 
 
Amendment 1.1 – 20Jan2021 
There are no adequate data on the developmental risk associated with the use of AUSTEDO in pregnant 
women. Administration of AUSTEDO to rats during organogenesis produced no clear adverse effect on 
embryofetal development. However, administration of tetrabenazine to rats throughout pregnancy and 
lactation resulted in an increase in stillbirths and postnatal offspring mortality. In the U.S. general 
population, the estimated background risk of major birth defects and miscarriage in clinically recognized 
pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and 
miscarriage for the indicated population is unknown.  
 
Data  
Animal Data  
Oral administration of AUSTEDO (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to pregnant 
rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 
6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m2) basis. 
The effects of AUSTEDO when administered during organogenesis to rabbits or during pregnancy and 
lactation to rats have not been assessed. Tetrabenazine had no effects on embryofetal development 
when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 
mg/kg/day. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) 
from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring 
postnatal mortality was observed at 15 and 30 mg/kg/day, and delayed pup maturation was observed at 
all doses. 
 
A pregnancy is not an AE. If a subject becomes pregnant while enrolled in the study following 
administration of study drug, the Sponsor or designee will be notified within 24 hours of the Investigator 
learning of the pregnancy. Administration of study drug will be discontinued immediately and the 
subject will be followed through the outcome of the pregnancy.  
5.3 Recording Adverse Events  
 
Adverse events will be recorded on an Adverse Event Documentation Form (see Figure 1). The 
investigator will provide information on the AE, preferably with a diagnosis, or at least with signs and 
symptoms; start and stop dates, start and stop time; intensity; causal relationship to study drug; action 
taken; and outcome. If the AE is an overdose, the nature of the overdose will be stated (medication 
error, accidental overdose, or intentional overdose). If the AE is serious, this will be indicated on the 
Adverse Event Form. Furthermore, the Investigator will report the SAE to Teva within 24 hours after 
becoming aware of it. 
 
5.4 Reporting Serious Adverse Events 
 
The Investigator will report SAEs to Teva immediately (within 24 hours) after becoming aware of them 
by completing a Serious Adverse Event Form. As much information as possible will be recorded. If more 
information about the patient’s condition becomes available at a later date, the Serious Adverse Event 
Form will be updated with the additional information. Teva will assume responsibility for reporting SAEs 
to the authorities in accordance with U.S. regulations.  
 
5.5 Treatment and Follow-Up of Adverse Events 
 
Subjects with AEs will be treated in accordance with usual clinical practice at the discretion of the 
investigator. At the post treatment evaluation, information on new SAEs, if any, and stop dates for 
previously reported AEs will be recorded. It is the responsibility of the Investigator to follow up on SAEs 
 


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Amendment 1.1 – 20Jan2021 
until the patient has recovered, stabilized, or recovered with sequelae. Relevant information includes 
discharge summaries, autopsy reports, and medical consultations.  
5.6 Stopping Rule 
 
A study subject will be asked to discontinue study drug if at any point during the trial he or she is found 
on ECG to have developed a QTc> 500 milliseconds or a QTc increase of >60 milliseconds from baseline. 
Study subjects will be asked to come in for an Early Termination Visit within 3 business days of study 
drug discontinuation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. DATA ANALYSIS / STATISTICAL METHODS 
 
6.1 Data Summary 
 
6.1.1 Summary of Safety Data 
 
The safety analysis population will include all enrolled subjects who receive at least one dose of study 
drug. Demographic data and key baseline characteristics will be summarized for the Safety population. 
Safety data will be summarized from the time of first dose and include all available safety data.  
 


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6.1.2 Summary of Efficacy Data 
 
The efficacy analysis population will include all enrolled subjects who receive at least one dose of study 
drug and who undergo both dystonia video examinations. Demographic data and key baseline 
characteristics will be summarized for the Efficacy population. 
  
 
6.2 Protocol Deviations  
 
Protocol deviations will be avoided whenever possible. If significant protocol deviations ensue, they will 
be listed and categorized (for example, deviations related to entry criteria, dosing, prohibited 
concomitant medications, other). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. STUDY DOCUMENTATION AND RECORD KEEPING  
 
7.1 Investigator’s Files and Retention of Study Data  
 
The Investigator will maintain adequate and accurate records to enable the conduct of the study to be 
fully recorded and the study data to be subsequently verified. These documents will be separated into 
two categories: Investigator’s study file and patient clinical source documents, as follows: 
 
1. The Investigator’s study file will contain the protocol and protocol amendments (if applicable), 
query forms, IRB and governmental regulatory approval with correspondence, informed 
consent, drug records, staff curriculum vitae and authorization forms and other appropriate 
documents and correspondence.  
 


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2. Patient clinical source documents may include patient and/or hospital clinical records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, 
pathology and special assessment reports, consultant’s letters, screening and enrollment log, 
etc.  
 
The patient’s involvement in the study will be clearly recorded in the study site’s clinical records. Details 
will include the study protocol number, the patient’s study number, the patient’s consent to take part in 
the study (including the date of consent), the dates of all study Visits, details of any treatments 
withdrawn because of study participation, the dates of dispensing study drug, details of any AEs 
(including any SAEs), and changes in concomitant medications. The documents in these two categories 
will be kept on file by the Investigator for at least 15 years after completion or termination of the study. 
Study documents will not be destroyed without prior written agreement between Teva and the 
Investigator. If the Investigator wishes to assign the study records to another party or move them to 
another location, Teva will be notified in advance. If the Investigator cannot guarantee this archiving 
requirement for any or all the documents at the investigational site, arrangements will be made 
between the Investigator and Teva to store these in a sealed container(s) outside the site. The sealed 
container(s) can therefore be returned to the Investigator in case of a regulatory audit. Where source 
documents are required for the continued care of the patient, appropriate copies will be made for 
storing outside the site. 
7.2 Background Data  
 
The Investigator will supply Teva, on request, with any required background data from the study 
documentation or clinic records. In case of special problems and/or governmental queries or requests 
for audit inspections, it is also necessary to have direct access to the completed study records, provided 
that patient confidentiality is protected. 
 
7.3 Monitoring, Verification of Data, Audit, and Inspection  
 
The Teva monitor may periodically Visit the site to discuss the progress of the study and review source 
documents with the study personnel, for accuracy of data recording, study drug accountability, and 
correspondence. The Investigator will ensure that the study participants are aware of and consent that 
personal information may be reviewed during the data verification process as part of 
monitoring/auditing by properly authorized agents of Teva or subject to inspection by regulatory 
authorities. In addition, participation and personal information is treated as strictly confidential to the 
extent the applicable law permits and not publically available.  
 
The Investigator will notify Teva of an announced inspection by a regulatory authority. During audits and 
inspections, the Investigator will allow access to all the source documents, including medical records and 
other documents pertinent to the study. During audits and inspections, the auditors and inspectors may 
copy relevant parts of medical records. No personal identification apart from the study number will 
appear on these copies. Patient data will not be disclosed to unauthorized third parties, and patient 
confidentiality will be maintained at all times. 
 
 
 
 
 
 
 
 


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8. ADMINISTRATIVE PROCEDURES  
 
8.1 Compliance with Good Clinical Practice and Ethical Considerations 
 
This study will be conducted in compliance with Institutional Review Board/Independent Ethics 
Committee (IRB) and International Committee on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines. In addition, all local regulatory requirements will be adhered to, in particular those which 
afford greater protection to the safety of the study participants. This study will be conducted in general 
according to the Declaration of Helsinki and with local laws and regulations relevant to the use of new 
therapeutic agents in the country of conduct. 
 
Before initiating a study, the Investigator/institution will have written and dated approval/favorable 
opinion from the IRB for the study protocol, written informed consent form, patient recruitment 
procedures (e.g., advertisements), and data collection instruments which will be completed by subjects. 
Protocol amendments, consent form updates, and any amendments to the documents described before 
will be approved by the IRB prior to implementation unless such changes are necessary to address 
immediate safety concerns. 
 
8.2 Informed Consent 
 
 


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The ICF documents the study-specific information the Investigator provides to the subject and the 
subject’s agreement to participate. Among other things, the Investigator or designee will fully explain in 
layman’s terms the nature of the study, along with the objectives, methods, potential risks, and any 
discomfort that participation may entail. It will be explained that the study is for research purposes only 
and may not provide any therapeutic benefit to the individual. Each subject will acknowledge receipt of 
this information by giving written informed consent for participation in the study. No study-related 
procedures, including washout of any medications, will be performed prior to obtaining written 
informed consent.  
 
The Investigator will explain that the subjects are completely free to refuse to enter the study or to 
withdraw from it at any time and for any reason. Similarly, the Investigator or Teva is free to withdraw 
the patient from the study at any time for safety reasons. Any other requirements necessary for the 
protection of the human rights of the patient will also be explained, according to current ICH GCP 
Guidelines.  
 
A sample copy of the patient information sheet and consent form will be provided by the sponsor. These 
documents may, however, be subject to country specific changes and the IRB may ask for them to be 
altered. In this case, any modifications are to be approved by Teva. A copy of the patient information 
sheet and consent form that is approved for this study by the IRB and Teva will be kept in the trial 
master file. 
 
The Informed Consent will comply with all applicable US Code of Federal Regulations and ICH Good 
Clinical Practice guidelines. It will also include any additional information required by local laws relating 
to institutional review. A statement that subject medical records must be available for investigations 
into SAEs will be included in the ICF. It will also include any additional information required by local laws 
relating to institutional review. 
8.3 Confidentiality of Patient Information  
 
All subjects who provide written informed consent will be assigned a patient number. Any information 
published as a result of the study will be such that it will not permit identification of any patient. The 
information from this study will be available within Teva and may be shared with regulatory authorities. 
It may also be the subject of an audit by a regulatory agency, such as the Food and Drug Administration 
(FDA), within the local government. The patient’s identity will remain protected except as required for 
legal or regulatory inquiries. 
 
8.4 Conditions For Modification of the Protocol  
 
Protocol modifications that could potentially adversely affect the safety of participating subjects, or that 
alter the scope of the investigation, the scientific quality of the study, the experimental design, dosages, 
duration of therapy, assessment variables, the number of subjects treated or patient selection criteria 
may be made only after consultation with appropriate representatives of Teva and the Investigator. Any 
modifications to the protocol that are made after receipt of the IRB approval must be submitted by the 
Investigator to the IRB in accordance with local procedures and regulatory requirements, before the 
changes can be implemented. Modifications to the protocol that eliminate an apparent immediate 
hazard to subjects do not require pre-approval by the IRB. 
 
8.5 Clinical Study Report and Publications  
 
8.5.1 Data Ownership  
 
The data collected in this study are the property of the Principal Investigator. 
 


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8.5.2 Publications 
 
The results of this study will be submitted for publication. The primary publication based on this study 
must be published before any secondary publications are submitted for publication. 
 
 
 
 
 
 
 
 
 
   
 
9. LIST OF TABLES 
 
9.1 Table 1: ABBREVIATIONS AND DEFINITIONS 
 
9.2 Table 2: Recommended AUSTEDO titration  
 
9.3 Table 3: Expected study drug titration for subjects able to increase AUSTEDO to 48 mg/day  
 
9.4 Table 4: Expected study drug titration for subjects able to increase AUSTEDO to 36 mg/day  
 
9.5 Table 5: Strong CYP2D6 inhibitors  
 
9.6 Table 6: Drugs causing QTc prolongation  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10. LIST OF FIGURES 
 
10.1 Figure 1: Adverse Event Documentation Form  
 
10.2 Figure 2: Physical Exam Form  
 
10.3 Figure 3: Vital signs Form  
 
10.4 Figure 4: Columbia Suicide Severity Rating Scale  
 
10.5 Figure 5: Stanford Sleepiness Scale  
 
10.6 Figure 6: Mini Mental Status Examination  
 
10.7 Figure 7: MDS-UPDRS (Part III)  
 
10.8 Figure 8: VIDEO PROTOCOL – WORKSHEET  
 
10.9 Figure 9: Patient Global Impression of Improvement  
 
10.10 Figure 10: Clinical Global Impression of Improvement Scale  
 
10.11 Figure 11: Global Dystonia Rating Scale  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. APPENDICES  
 
11.1 Appendix 1: Subject Visit schedule  
 
 
  
 
 
 
 
 
 
 
 
 
 


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12. REFERENCES 
 
 
1. 
Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a 
consensus update. Mov Disord 2013; 28:863-873. 
2. 
Jinnah HA, Factor SA. Diagnosis and treatment of dystonia. Neurol Clin 2015; 33:77-100. 
3. 
AUSTEDO Package Insert. https://www.AUSTEDO.com/pi. 
4. 
Anderson KE, Stamler D, Davis MD, et al. AUSTEDO for treatment of involuntary movements in 
subjects with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. 
Lancet Psychiatry 2017; 4:595-604. 
5. 
Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of AUSTEDO for tardive 
dyskinesia: The ARM-TD study. Neurology 2017; 88:2003-2010. 
6. 
Jankovic J, Jimenez-Shahed J, Budman C, et al. AUSTEDO in Tics Associated with Tourette 
Syndrome. Tremor Other Hyperkinet Mov (N Y) 2016; 6:422. 
7. 
Miguel R, Mendonca MD, Barbosa R, et al. Tetrabenazine in treatment of hyperkinetic 
movement disorders: an observational study. Ther Adv Neurol Disord 2017; 10:81-90. 
8. 
Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. 
Neurology 1988; 38:391-394. 
9. 
Luciano AY, Jinnah HA, Pfeiffer RF, Truong DD, Nance MA, LeDoux MS. Treatment of myoclonus-
dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 2014; 20:1423-1426. 
10. 
Asher SW, Aminoff MJ. Tetrabenazine and movement disorders. Neurology 1981; 31:1051-1054. 
11. 
Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind 
crossover study. Ann Neurol 1982; 11:41-47. 
12. 
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. 
Neurology 1997; 48:358-362. 
13. 
Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of 
hyperkinetic movement disorders. Mov Disord 2007; 22:193-197. 
14. 
Paleacu D, Giladi N, Moore O, Stern A, Honigman S, Badarny S. Tetrabenazine treatment in 
movement disorders. Clin Neuropharmacol 2004; 27:230-233. 


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15. 
Huntington Study G. Tetrabenazine as antichorea therapy in Huntington disease: a randomized 
controlled trial. Neurology 2006; 66:366-372. 
16. 
Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of AUSTEDO for tardive 
dyskinesia: The ARM-TD study. Neurology 2017. 
17. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry 2011; 168:1266-1277. 
19. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the 
cognitive state of subjects for the clinician. J Psychiatr Res 1975; 12:189-198. 
20. 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the 
Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing 
results. Mov Disord 2008; 23:2129-2170. 
21. 
Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T, Dystonia Study G. Rating Scales for 
dystonia: a multicenter assessment. Mov Disord 2003; 18:303-312. 

ICF_003.pdf: 
AUDYT PARTICIPANT INFORMED CONSENT 
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UNIVERSITY OF PENNSYLVANIA
RESEARCH SUBJECT  
INFORMED CONSENT AND HIPAA AUTHORIZATION FORM 
Protocol Title:  
The AUDYT Trial: An Open-Label Study to Define the Safety, Tolerability, and 
Clinical Activity of Deutetrabenazine (AUstedo) in Adult Study subjects with 
DYsTonia 
Principal Investigator:
Andres Deik, MD
Emergency Contact: 
On-Call Neurologist
(215) 829-3606
Sponsor
Teva Pharmaceuticals USA, Inc.
RESEARCH STUDY SUMMARY 
Purpose: This research study is being conducted to explore the safety and tolerability of deutetrabenazine, a
drug whose trade name is Austedo, for treatment of adults with dystonia.
Procedures & Activities: If you agree to join the study, you will be asked to complete 5 research visits,
physical exam, medical history, completion of questionnaires/assessments, video recording, and multiple
electrocardiograms.
Duration: Your participation will last for a maximum of 13 weeks.
You are being invited to participate in a research study. Your participation is voluntary, which means you can 
choose whether or not you want to participate. If you choose not to participate, there will be no loss of benefits 
to which you are otherwise entitled.  Before you make your decision, you will need to know what the study is 
about, the possible risks and benefits if being in this study, and what you will have to do in this study. The 
research team is going to talk to you about the research study and they will give you this informed consent form 
(ICF) to read. You may also decide to discuss it with your family, friends, or family doctor. You may find some of 
the medical language difficult to understand. Please ask the study doctor and/or research team about this form. 
Your doctor may be an investigator in this research study. As an investigator, your doctor is interested both in 
your clinical welfare and in the conduct of this study. Before entering this study or at any time during the 
research, you may want to ask for a second opinion about your care from another doctor who is not an 
investigator in this study. You do not have to participate in any research study offered by your doctor. After 
reading this consent form, if you would like to participate, you will be asked to sign this form. You will be given a 
signed copy of your consent form to take home and keep for your records. If you have any questions about your 
rights as a human research participant at any time before, during or after participation, please contact the 
Institutional Review Board (IRB) at (215) 898-2614 for assistance. 
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Risks: The most common risks of treatment with deutetrabenazine are sleepiness, diarrhea, dry mouth, fatigue, 
urinary tract infection, insomnia, anxiety, constipation, and bruising. 
Benefits: There is no guarantee that you will personally benefit from participation in this study. Information 
from this study may be used to help patients with dystonia in the future.
Alternatives: As an alternative to participation, you would continue receiving standard of care treatment for 
dystonia. Your choice to not participate would have no impact on that care.
Please note that there are other factors to consider before agreeing to participate such as additional procedures, use 
of your personal information, costs, and other possible risks not discussed here. If you are interested in 
participating, a member of the study team will review the full information with you. You are free to decline or stop 
participation at any time during or after the initial consenting process. 
Why am I being asked to volunteer?
You are being invited to participate in this research study because you have been diagnosed with dystonia by a 
physician. Dystonia is defined as a movement disorder characterized by uncontrollable muscle spasms causing 
abnormal movements or postures, or both. Dystonic movements are typically patterned and twisting, and may be 
tremulous. Many different classes of medication are used to treat dystonia. 
 
A number of studies have shown that tetrabenazine, a drug closely related to deutetrabenazine, is effective in the 
symptomatic treatment of dystonia. The safety profile of deutetrabenazine may be more favorable, and this study 
will evaluate its use in treatment of dystonia. Both drugs are approved by the U.S. Food and Drug Administration 
(FDA) for treatment of other movement disorders, but not for treatment of dystonia. For that reason, 
deutetrabenazine is considered an experimental drug in this study. 
 
What is the purpose of this research study? 
The purpose of this research study is to explore the safety and tolerability of the daily oral administration of 
deutetrabenazine, whose trade name is Austedo, in adults with dystonia.
How long will I be in the study? How many other people will be in the study?
The study is being conducted at the Parkinson’s Disease and Movement Disorders Center of the University of 
Pennsylvania. Approximately 15 men and women over the age of 18 who have been diagnosed with dystonia will 
take part in this study. Participants will be patients whose dystonia is being managed at the University of 
Pennsylvania or are referred to this center for the purpose of participating in this trial. 
Your participation in the study will last for up to 13 weeks, with the length of time depending on how long it takes 
to determine the appropriate dose of Austedo for you. 
What am I being asked to do?
There will be a total of five office visits - a screening visit (Visit 1), a ramp-up period visit (Visit 2), maintenance 
visit (Visit 3), end of maintenance visit (Visit 4), and post-treatment evaluation visit (Visit 5). 
 
During Visit 1, you will begin taking Austedo, 6 mg twice daily (12 mg a day). If the safety assessment in Visit 2 
shows that you tolerated the 12-mg daily dose, your dosage will be increased, or ramped up, by 6 mg daily per week 
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based on assessments of effectiveness and tolerability made in weekly telephone calls. Visit 3, the maintenance visit, 
will be scheduled when you reach your maximum well-tolerated dosage level. 
The maximum Austedo dose you may receive in this study is 48 mg daily – or 36 mg daily if you are receiving drugs 
known as strong CYOP2D6 inhibitors, such as fluoxetine (Prozac), bupropion (Wellbutrin), and quinidine. Dose 
reductions may be made during the ramp-up period if you experience side effects due to Austedo, and a well-
tolerated lower dose will be considered your maximum dosage level as you enter the maintenance period. 
 
Dose reductions also may be made during the maintenance period if you experience side effects. In this case, the 
time when you start a well-tolerated lower dose would mark the beginning of a restarted maintenance period. It is 
also possible that the study doctor may end your participation at any time because of side effects, if necessary to 
protect your health or safety or to meet research standards.  
 
AUSTEDO will be used as an adjunctive medication. You will be able to continue to receive other medications for 
dystonia (including botox). 
 
There are no placebo pills in this study. All subjects will be given Austedo. 
 
STUDY PROCEDURES 
You will be asked to complete a series of questionnaires at each office visit. These questionnaires will assess your 
quality of life and assess the overall severity of your dystonia. Additionally, some visits require a movement disorder 
evaluation that is video recorded, an electrocardiogram (ECG), and a complete physical exam. 
 
Visit 1: Screening Visit (Week 1) 
During this visit, once you understand the study procedures and decide to participate in the study, you will sign this 
consent form. Your eligibility for study participation will then be determined, and your demographic information 
will be recorded. Additional activities to be completed during Visit 1 include the following: 
 Review and collection of medical history
Review of medication history 
Review of current medications and dates of the last and upcoming botulinum toxin injection, and date of 
last change in setting for deep brain stimulation (DBS) (if applicable).
Complete physical exam including recording of vital signs 
A 12-lead electrocardiogram (ECG)
The Mini Mental Status Examination (MMSE)
The Stanford Sleepiness Scale (SSS)
The Columbia Suicide Severity Rating Scale (C-SSRS)
Video recording of Movement Disorder Examination 
The MDS-UPDRS Part III, an assessment of body position, involuntary movements, muscle strength, and 
muscle tone 
Dispensing of Austedo 
NOTE: This visit will take about 2 hours.
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Visit 2: Ramp-up Period Starts (Week 2) 
Visit 2 will be the first visit while you are taking Austedo. This is a safety visit, which will happen 5 to 9 days after 
you start taking the drug. You must bring your Austedo bottles to this visit. study drug initiation. The activities to be 
completed during Visit 2 include the following:   
 Review of adverse events
Collection of vital signs
A 12-lead ECG
 The Stanford Sleepiness Scale (SSS) 
The Columbia Suicide Severity Rating Scale (C-SSRS)
 Assessment of Austedo dosage compliance 
NOTE: This visit will take about 1 hour. 
Visit 3: Maintenance Period Starts (timing of this visit varies)
This is a safety visit. The time during which this visit will happen will vary depending on the duration of the ramp-
up period as follows: 
 If you are able to tolerate up to 48mg of Austedo per day, Visit 3 will be scheduled during Week 7. 
 If you are receiving a strong CYP2D6 inhibitor, and only permitted to receive up to 36 mg of Austedo per 
day, visit 3 will occur during Week 5. 
 If you experience dose-limiting side effects during the ramp-up period, visit 3 will be scheduled up to 3 days 
after the maximum, well-tolerated dose is established. 
You must bring your Austedo bottles to this visit. The activities to be completed during Visit 3 include the 
following: 
 A review of adverse events 
 Collection of vital signs 
 A 12-lead ECG 
 The Stanford Sleepiness Scale (SSS) 
 The Columbia Suicide Severity Rating Scale (C-SSRS) 
Assessment of Austedo dosage compliance 
NOTE: This visit will take about 1 hour.
Visit 4: Maintenance Period Ends (timing of this visit varies) 
Visit 4 will take place during the last week of the maintenance period; however, the timing will vary as follows: 
 If you are taking 48 mg/day of Austedo, then Visit 4 will be scheduled during Week 12. 
 If you are taking 36 mg/day of Austedo because you are receiving a strong CYP2D6 inhibitor, then Visit 4 
will be scheduled during Week 10. 
 If you experienced dose-limiting side effects, then Visit 4 will be scheduled 6 weeks after your maintenance 
dose was initiated.  
This will be the last visit while on study drug, and at this time, you will be instructed on when to stop taking 
AUSTEDO. You will not be required to taper off this medication. The activities completed during visit 4 include:  
 A review of adverse events 
 Collection of vital signs 
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A 12-lead ECG
The Stanford Sleepiness Scale (SSS)
The Columbia Suicide Severity Rating Scale (C-SSRS)
The Mini Mental Status Examination (MMSE)
 A video of Movement Disorder Examination 
 The MDS-UPDRS Part III 
 The Global Impression of Improvement 
 Assessment of Austedo dosage compliance 
NOTE: This visit will take about 2 hours. 
 
Visit 5: Post Treatment Evaluation
Visit 5 is a safety visit that will take place up to 9 days after you stop taking Austedo. The following activities will be 
completed during visit 5:  
A review of adverse events
A complete physical exam including recording of vital signs 
A 12-lead ECG
The Columbia Suicide Severity Rating Scale (C-SSRS)
The Stanford Sleepiness Scale (SSS)
NOTE: This visit will take about 2 hours 
 
Unscheduled Visits
You may return for an unscheduled visit at any time at the study doctor’s discretion. The procedures conducted at 
the unscheduled visit may be limited depending on the reason for the visit.  
Early Termination Visits
If at any time during the study you ask to withdraw from treatment or if the study doctor decides to withdraw you 
from the study due to a need for intervention, you will be required to complete an early termination visit. The 
following activities will be completed during the early termination visit:
Review of concomitant medications
 Review of adverse events 
 A complete physical exam, including vital signs 
 A 12-lead ECG 
 The Columbia Suicide Severity Rating Scale (C-SSRS)
 The Stanford Sleepiness Scale (SSS)
 The Mini Mental Status Examination (MMSE)
 A video of Movement Disorder Examination 
 The MDS-UPDRS Part III 
 The Global Impression of Improvement 
 Collection of returned Austedo bottles and assessment of dosages compliance 
NOTE: This visit will last for about 2 hours.  
 
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VIDEO RECORDING
While participating in AuDYT, you will be video recorded during the research study visits while completing specific 
assessments. The video recordings, which include sound, will show your entire body and face, in order to view your 
overall movement. The videos will be saved in a secure HIPAA-compliant study-specific file at the University of 
Pennsylvania. The video data will be kept for a minimum of 3 years prior to destruction. The video will not be used 
for any commercial, advertising, or promotional purposes. 
 
PARTICIPANT RESPONSIBILITIES 
In order for this study to provide good information on dystonia, you will be expected to do the following: 
 Fill out the questionnaires honestly. 
 Tell the study staff about any health problems you are having even if you do not think they are important 
 Notify the study staff if you wish to stop being in the study. 
 
What are the possible benefits of the study? 
There is no guarantee that you will personally benefit from participation in this study. Your dystonia may or may 
not improve, or it may get worse while you are in this study.  Information from this study may be used to help 
patients with dystonia in the future. 
 
What are the possible risks and discomforts? 
There are risks, discomforts, and inconveniences associated with participation in any research study. For this study, 
they are described below. In addition, there may be risks that are not yet known. 
Common but low risks and side effects related to taking Austedo include: 
 sleepiness 
 diarrhea 
 dry mouth 
 fatigue 
 urinary tract infection 
 insomnia 
 anxiety 
 constipation  
 bruising 
 
Possible adverse reactions that are more serious, but to occur infrequently, with the use of the AUSTEDO and in 
this study are: 
 Depression and thoughts of suicide 
 Neuroleptic malignant syndrome, a potentially 
life-threatening reaction including high fever, 
muscle stiffness, and altered mental status 
 Akathisia (a need to be in constant motion), 
agitation, and restlessness 
 Parkinsonism 
 Sedation and sleepiness 
 QTc Prolongation, a potentially life-
threatening disturbance of heart rhythm 
 Hyperprolactinemia 
 Binding to melanin-containing tissue
Signs of hyperprolactinemia include, but not limited to, infertility, irregular periods, change in menstrual flow, pause 
in menstrual cycle, loss of libido, lactation (galactorrhea), pain in breasts, and vaginal dryness for women. For men, 
signs include, but not limited to, abnormal breast growth (gynecomastia), lactation, infertility, erectile dysfunction, 
loss of sexual desire, headaches, and vision change. 
 
Clinical relevance of Austedo’s binding to melanin-containing tissue is unknown. Austedo or its metabolites can 
bind to melanin-containing tissues, which can lead to an increase of these tissues over time. This raises the 
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possibility that Austedo may cause toxicity in these tissues after extended use. However, a previous study has not 
found such findings. 
Additionally, you may be uncomfortable or experience stress while completing the questionnaires; however, you 
may skip any questions that you are uncomfortable with. There is also a potential loss of privacy for your medical 
information or personal identification. However, all possible precautions will be taken to ensure your privacy and 
the confidentiality of your information. 
 
REPRODUCTIVE RISKS 
Because of the effects of this drug, there could be serious harm to unborn children or children who are breast-
feeding. These effects could also harm the mother. It is also possible that harmful side effects that are not yet 
known could happen to both the mother and unborn or breast-feeding child. If you are currently pregnant, it is 
important that you inform the investigator because you will not be able to participate in the study. If you are able to 
become pregnant, you will be given a serum pregnancy test before entry into the study. You must also use a 
medically accepted method of birth control (e.g. IUD, hormonal oral contraceptive pill, tubal ligation) while you 
participate in the study. If you are a female of child-bearing age, you should not become pregnant while you are 
taking this drug. If you do become pregnant, you must tell the investigator and consult an obstetrician or maternal-
fetal specialist. If you are a male who is fertile and have a partner of childbearing potential, you must agree to use 
reliable contraception (e.g. condoms, vasectomy) throughout the duration of the study. 
 
OTHER RISKS 
Your condition may not get better or may get worse during this study.   
 
What other choices do I have if I do not participate in this study? 
The alternative to participating in this research study is to not participate, with no effect on the quality of your 
existing medical care. 
 
What if new information becomes available about the study? 
During the course of the study, new information may be found that could be important to you. The study doctor 
and the team will relay any and all information to you as soon as it becomes available. This includes information 
that, once learned, may cause you to change your mind about participating in this study. You may contact the study 
doctor and team at any time after your participation ends to find out if any new information about this study has 
become available.
Will I receive results of research testing?
Most tests done in research studies are only for research and have no clear meaning for health care. Research results 
from this study will not be returned to you because they would not be relevant to your health care.  
Will I have to pay for anything?
There is no cost to you for participating in this study.  You are still responsible for any deductibles or applicable co-
pays for routine office visits, scans and blood work. Please talk to your doctor and study team about putting you in 
touch with a financial counselor to determine exactly what the deductible and co-pay will be for you; this is highly 
variable depending on your type of insurance. There will be no charge for Austedo and procedures that are done 
only for the study will not be billed to you or your insurance company. 
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Will I be paid for being in the study?
You will receive $50.00 for completing each office visit, totaling $250.00 for the entire study. You will be paid in the 
form of a Greenphire ClinCard, a reloadable prepaid card. This card will be loaded while you are in clinic for your 
visit and the funds will be available immediately.
 
Please note: In order to be compensated for your participation in this study, you must provide your Social Security 
Number. Additionally, please note that the University of Pennsylvania is required to report to the IRS any 
cumulative payments for participation in research studies that exceed a total of $600.00 in a calendar year.
 
What happens if I am injure from being in the study? 
If you are injured or get sick as a result of being in this study, tell the study doctor immediately.  We will offer you 
the care needed to treat injuries directly resulting from taking part in this research. We may bill your insurance 
company or other third parties, if appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. The Sponsor will pay any charges that your insurance does not cover.  No other 
payment is routinely available from the study doctor or Sponsor. 
 
There are no plans for the University of Pennsylvania to pay you or give you other compensation for the injury.  If 
you feel this injury was caused by medical error on the part of the study doctors or others involved in the study, you 
have the legal right to seek payment, even though you are in the study. You do not give up your legal rights by 
signing this form. 
 
If you think you have been injured as a result of taking part in this research study, tell the person in charge of the 
research study as soon as possible. The researcher’s name and phone number are listed on the first page of this 
form. 
 
When is the study over? Can I leave the study before it ends?
Your decision to participate is entirely voluntary. You may refuse to participate or withdraw from the study, at any 
time, without penalty or loss of benefits to which you are otherwise entitled. Your ongoing medical care will not be 
affected by your decision to be in this study or to withdraw from the study. 
 
If you agree to participate in the study and later change your mind, call the study doctor at (215) 829-6500. 
 
This study is expected to end after all participants have completed all visits, and all information has been collected. 
This study may also be stopped at any time by your physician, the study Sponsor, or the FDA without your consent 
because: 
 The Principal Investigator (i.e. the study doctor) feels it is necessary for your health or safety. Such an action 
would not require your consent, but you will be informed if such a decision is made and the reason for this 
decision. 
 You have not followed study instructions. 
 You have withdrawn your consent. 
 The Sponsor, the study Principal Investigator, or the FDA has decided to stop the study. 
 
 
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How will my personal information be protected during the study? 
We will do our best to make sure that the personal information obtained during the course of this research study will 
be kept private. However, we cannot guarantee total privacy.  Your personal information may be given out if required 
by law. If information from this study is published or presented at scientific meetings, your name and other personal 
information will not be used. The IRB at the University of Pennsylvania will have access to your records. If this study 
is being overseen by the FDA, they may review your research records. 
 
What information may be collected, used, or shared with others? 
Your personal health information from your original medical records and all data resulting from your participation in 
this research will be collected during the course of this study. Your study doctor may ask you to sign a separate 
authorization to obtain some or all of your original medical records.  Personal health information that will be 
collected includes:  
Your name, date of birth, address, and telephone number, email address 
Demographic information including race and gender 
 Past and present medical records and research records
 Social security number
 Results from physical examinations, tests or procedures 
Results of questions you are asked by the study doctor or by filling out questionnaires. 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. Your information and results of tests 
and procedures are used to: 
do the research 
oversee the research
 to see if the research was done right
 to evaluate and manage research functions.  
 
Who may use and share information about me? 
The following individuals may use or share your information for this research study: 
 The Principal Investigator of the study and the study team  
Other authorized personnel at Penn, including offices that support research operations 
Other research personnel with access to the databases for research and/or study coordination and as 
otherwise approved by the IRB
 
Who, outside of the school of medicine, might receive my information? 
 Your health insurance company 
 The study sponsor (Teva Pharmaceuticals USA, Inc.) or sponsor representatives such as monitors and/or 
auditors 
 The U.S. Food and Drug Administration (FDA) 
 The Department of Health and Human Services (DHHS)  
 Governmental agencies in other countries
 Governmental agencies to whom certain diseases (reportable diseases) must be reported 
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Any laboratories and other individual organizations that analyze your health information in connection with 
this study in accordance with the study’s protocol 
Once your personal information is disclosed to others outside the School of Medicine, it may no longer be covered 
by federal privacy protection regulations.
 
The Principal Investigator or study staff will inform you if there are any additions to the list above during your active 
participation in the trial. Any additions will be subject to University of Pennsylvania procedures developed to protect 
your privacy.
 
What may happen to my information collected in this study? 
Your information will be de-identified, meaning that all identifiers will be removed. The information could be stored 
and shared for future research in this de-identified fashion. It would not be possible for future researchers to identify 
you because we would provide any identifiable information about you to future researchers. This sharing of 
information can be done without again seeking your consent in the future, as permitted by law. The future use of 
your information only applies to the information collected on this study. 
 
How long may the School of Medicine use or disclose my personal health information? 
Your authorization for use of your personal health information for this specific study does not expire. 
 
Your information may be held in a research database. However, the School of Medicine may not re-use or re-disclose 
information collected in this study for a purpose other than this study unless: 
 You have given written authorization 
 The University of Pennsylvania’s IRB grants permission 
 As permitted by law 
 
ELECTRONIC MEDICAL RECORDS AND RESEARCH RESULTS 
An Electronic Medical Record (EMR) is an electronic version of the record of your care within a health system. An 
EMR is simply a computerized version of a paper medical record.
A clinical trial management system (CTMS) is used to register your information as a participant in a study and to 
allow for your research data to be entered/stored for the purposes of data analysis and any other required activity for 
the purpose of the conduct of the research. 
If you are receiving care or have received care within the University of Pennsylvania Health System (UPHS) 
(outpatient or inpatient) and are participating in a University of Pennsylvania research study, information related to 
your participation in the research (i.e. laboratory tests, imaging studies and clinical procedures) may be placed in your 
existing EMR maintained by UPHS. Information related to your participation in clinical research will also be 
contained in the CTMS. 
If you have never received care within UPHS and are participating in a University of Pennsylvania research study that 
uses UPHS services, an EMR will be created for you for the purpose of maintaining any information produced from 
your participation in this research study.  The creation of this EMR is required for your participation in this study. In 
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order to create your EMR, the study team will need to obtain basic information about you that would be similar to 
the information you would provide the first time you visit a hospital or medical facility (i.e. your name, the name of 
your primary doctor, the type of insurance you have). Information related to your participation in the study (i.e. 
laboratory tests, imaging studies and clinical procedures) may be placed in this EMR. 
 
Once placed in your EMR or in the CTMS, your information may be accessible to appropriate UPHS workforce 
members that are not part of the research team.  Information within your EMR may also be shared with others who 
are determined by UPHS to be appropriate to have access to your EMR (e.g. health insurance company, disability 
provider, etc.). 
 
Can I change my mind about giving permission for use of my information? 
You may withdraw or take away your permission to use and disclose your health information at any time. If you no 
longer want to share your protected health information, you may cancel your permission by writing to the study 
doctor at the address below: 
Dr. Andres Deik, MD 
Parkinson’s Disease and Movement Disorders Center
330 S. 9th Street, 3rd Floor 
Philadelphia, PA 19107 
 
If you cancel your permission after you have started in the study, the study staff and the study doctor will stop 
providing questionnaires for you to complete and stop collecting your health information. Although they will stop 
collecting new information about you, they will need to use the information they have already collected to evaluate 
the study results. If you start the study and then cancel your permission, you will not be able to participate in the 
study at a later date.
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject Informed Consent and HIPAA Authorization Form describing 
your confidentiality and privacy rights for this study. By signing this document, you are permitting the School of 
Medicine to use and disclose personal health information collected about you for research purposes as described 
above. 
 
RIGHTS TO YOUR DATA:  
You may have the right to access, correct and make a copy of your medical records as allowed by applicable privacy 
laws.  You may ask to see your records by requesting such records from your doctor.  However, to ensure the valid 
results of the research, you agree that you may not be able to review or make a copy of some of your records related 
to the research until after the research has been completed.   
 
Who can I call with questions, complaints, or concerns about my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this research study or if you have any 
questions about your rights as a research subject, you should speak with the Principal Investigator listed on page one 
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of this form. If a member of the research team cannot be reached or you want to talk to someone other than those 
working on the study, you may contact the IRB at the Office of Regulatory Affairs: (215) 829-2614. 
 
 
 
 
When you sign this form, you are agreeing to take part in this research study. This means that you have read the 
consent form, your questions have been answered, and you have decided to volunteer.  Your signature also 
means that you are permitting the University of Pennsylvania to use your personal health information collected 
about you for research purposes within our institution. You are also allowing the University of Pennsylvania to 
disclose that personal health information to outside organizations or people involved with the operations of this 
study. 
CONSENT 
I have read this consent form (or it has been read to me).  All my questions about the study and my part in it have 
been answered.  I freely consent to be in this research study.
By signing this consent form, I have not given up any of my legal rights. 
________________________________________________ 
Subject Name (printed) 
________________________________________________            _________________________ 
Signature of Subject 
Date 
________________________________________________ 
Printed Name of Person Conducting  
Informed Consent Discussion 
________________________________________________            __________________________ 
Signature of Person Conducting                                                          Date 
Informed Consent Discussion 
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