Clinical trial NCT02198794
Conditions: Tardive Dyskinesia
Keywords: Dyskinesias Movement Disorders Central Nervous System Diseases Nervous System Diseases Neurologic Manifestations Signs and Symptoms
Sponsor: Auspex Pharmaceuticals, Inc.
Start date: 2014-10-20; Completion date: 2020-12-14
Enrollment: 343 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the long-term safety, tolerability, and efficacy of SD-809 in reducing the severity of abnormal involuntary movements of moderate to severe tardive dyskinesia. The purpose of part B is to establish the durability of effect of SD-809 following 1-week period of randomized withdrawal (SD-809 and placebo), followed by 12 weeks of maintenance with SD-809.

Detailed description:
Participants who complete study SD-809-C-18 (NCT02195700), SD-809-C-23 (NCT02291861), or any other SD-809 study will be enrolled in this study. This study include a screening period (Part A), a titration period (Part A), a long-term treatment period (Part A), a double-blind, randomized withdrawal period (Part B), treatment after completion of the randomized withdrawal period (Part B), and a post-treatment safety follow-up period (Part A and Part B). EU participants who complete Part B will be invited to participate in Part C.

Arms: arm 1: Participants will receive SD-809 orally twice daily (BID) starting at 12 mg/day, which will be titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who decline to participate in Part B, will continue at their stable dose of SD-809 BID up to Week 158. arm 2: Participants will receive placebo matched to SD-809 for 1 week in randomized withdrawal period and thereafter will receive SD-809 (stable dose) for 12 weeks. arm 3: Participants will receive SD-809 (stable dose) for 1 week in randomized withdrawal period and will continue to receive the same dose of SD-809 for an additional 12 weeks. arm 4: EU participants who complete Part B and willing to continue in the study will continue treatment with SD-809 for 52 weeks at the dose administered during the 12-week open-label period of Part B.
Interventions: intervention 1: SD-809 intervention 2: Placebo
Intervention descriptions: intervention 1: SD-809 will be administered per dose and schedule specified in the arm. intervention 2: Placebo matching to SD-809 will be administered per schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
AN OPEN-LABEL, LONG-TERM SAFETY STUDY OF SD-809 
(DEUTETRABENAZINE) FOR THE TREATMENT OF MODERATE TO 
SEVERE TARDIVE DYSKINESIA 
 
 
Study Number SD-809-C-20 
 
 
NCT02198794 
 
 
Protocol with Amendment 07 Approval Date: 02 May 2018 


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Protocol SD-809-C-20 Amendment 07
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CONFIDENTIAL
The following contains confidential, proprietary information, which is the property of 
Auspex Pharmaceuticals, Inc.
PROTOCOL NUMBER: SD-809-C-20
AN OPEN-LABEL, LONG-TERM SAFETY STUDY OF SD-809 
(DEUTETRABENAZINE) FOR THE TREATMENT OF 
MODERATE TO SEVERE TARDIVE DYSKINESIA
EUDRACT No.: 2014-001891-73
Amendment 07 (Part C Study)
(Specific to Investigators in EU Countries)
02 May 2018
Development Phase: 3


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STUDY CONTACTS
SPONSOR:
Auspex Pharmaceuticals, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
USA
Vice President, TA Head, Specialty R&D
Tel: 
E-mail: 
Sr Mgr, Global Clinical Project Mgmt
Global Clinical Operations, CNS & Pain
Tel: 
 
E-mail
Study SD-809-C-20 Phone: 
MEDICAL MONITOR (US)
MEDICAL MONITOR (EU)
E-mail: 
E-mail: 
Email: 


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PROTOCOL SYNOPSIS
PROTOCOL
SD-809-C-20
TITLE
An Open-Label, Long-Term Safety Study of SD-809 (deutetrabenazine) for the 
Treatment of Moderate to Severe Tardive Dyskinesia
PHASE
3 (Safety)
INDICATION
Treatment of drug-induced tardive dyskinesia (TD)
NO. SITES
Approximately 80
OBJECTIVES

To evaluate the safety and tolerability of long-term maintenance therapy with 
SD-809

To evaluate the efficacy of long-term maintenance therapy of SD-809 to reduce 
the severity of abnormal involuntary movements of TD

To evaluate the persistence of the therapeutic effect of SD-809
STUDY 
POPULATION
Male and female adult subjects with moderate to severe drug-induced TD who have 
successfully completed a previous placebo-controlled efficacy study of SD-809 for 
the treatment of TD with the Sponsor will be enrolled.
STUDY 
DESIGN
This is an open-label, single-arm study in which subjects with moderate to severe TD 
who have successfully completed a parent study (Study SD-809-C-18, Study 
SD-809-C-23, or any other controlled study of SD-809 for the treatment of moderate 
to severe TD) will be invited to participate.
Informed consent/assent (Part A) will be obtained before any study procedures are 
performed. Subjects may have informed consent/assent obtained up to 30 days in 
advance of the subject’s parent study Week 13 Visit/TD-Long Term Safety (LTS) 
Baseline Visit. 
Informed consent/assent for Part B will be obtained after Amendment 06 
implementation and before any study procedures related to Part B are performed.
Informed consent/assent for Part C will be obtained after Amendment 07 
implementation and before any study procedures related to Part C are performed. 
Subjects who do not sign the informed consent/assent for Part C will complete the 
study at Part B Follow-up Call. 
Subjects who have successfully completed a parent study may be eligible to enroll 
into this study after they complete a 1-week washout period and the final evaluation 
in the parent study. To reduce subject burden, after obtaining informed 
consent/assent, some data collected in the parent study will be used in Study 
SD-809-C-20 and will provide some of the baseline data for Study SD-809-C-20 (see 
Schedule of Events). For example, in addition to assessments completed for the 
SD-809-C-18 Week 13 visit, evaluations required as part of the SD-809-C-20 study 
will be completed on the same day as the Week 13 visit. 
Part A:
Titration Period (up to 6 weeks): As subjects will have discontinued study drug 
(SD-809 or placebo) for 1 week at completion of the parent study, they will undergo 
SD-809 dose titration in this study. During titration, the Investigator, in consultation 
with the subject, will determine when an adequate level of dyskinesia control has 
been achieved. The dose of SD-809 should be adjusted (upward or downward), in 


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STUDY 
DESIGN 
(continued)
increments of 6 mg per day (up to once per week), until there is adequate control of 
dyskinesia, the subject experiences a protocol-defined clinically significant adverse 
event (defined as related to study drug and either a) moderate or severe in intensity or 
b) meets the criteria for a serious adverse event), or the maximal allowable dose is 
reached. If a subject experiences a clinically significant adverse event attributable to 
SD-809, the Investigator will determine if a dose reduction, dose suspension, or 
withdrawal from the study is necessary. 
Subjects will have a telephone contact at Week 1 and a clinic visit at Week 2 to 
evaluate safety and establish a dose of study drug that adequately controls dyskinesia 
and is well tolerated. Although subjects will enter the Long-Term Treatment Period 
after Week 2, titration should continue through Week 6 to optimize dose.
Long-Term Treatment Period (Week 3 until the last dose in Part A): During 
long-term treatment, subjects will continue titration through Week 6. During titration, 
all subjects will be contacted by telephone at Week 3 (the first week of the Long-
Term Treatment Period) and Week 5 and will return to the clinic at Week 4 and Week 
6 for evaluation of safety and dyskinesia control. Subjects who have not achieved a 
dose level that adequately controls dyskinesia and is well tolerated by the Week 6 
visit should have unscheduled visits or telephone contacts to further adjust their dose 
upward or downward. Interactions with the clinical site for dose adjustment should 
alternate between telephone contacts and clinic visits. During the remainder of the 
Long-Term Treatment Period, subjects will return to the clinic for evaluation of safety 
and dyskinesia once every 13 weeks, starting at Week 15 and ending at the last dose
of Part A (completion of Part A=Week 158 or beginning of Part B after Amendment 
06 implementation). During long-term treatment, further dose adjustments of SD-809 
may be made, if necessary, but not more often than weekly and only in increments of 
6 mg per day. Dose adjustments should be based on all available information, 
including the subject’s and caregiver’s (if appropriate) reports of adverse events and 
dyskinesia control, as well as information from rating scales and safety evaluations, 
when available. If warranted, study sites are encouraged to conduct periodic phone 
calls with subjects to ensure adherence to the treatment regimen and retention of 
unused drug containers.
Subjects who have been on a stable dose of SD-809 and any concomitant dopamine 
receptor antagonist (DRA) for a minimum of 4 weeks will be invited to participate in 
the Randomized Withdrawal Period (Part B) at the next routine visit at the site after 
approvals from IRB/Ethics Committee and as required by country regulations. If the 
subject chooses to participate in Part B, then participation in Part A will end. Subjects 
who decline to participate in Part B will continue in Part A until Week 158. Subjects 
who decline participation in Part B will be given an ongoing option to participate at 
subsequent study visits.
Part B:
Part B will consist of a double-blind, randomized withdrawal period; treatment with 
SD-809; and post-treatment safety follow-up. The Randomized Withdrawal Period 
will be 1 week (+3 days maximum) in duration and will consist of 2 visits, the 
Pre-withdrawal Visit and the Post-withdrawal Visit. After the Randomized 
Withdrawal Period, the subject will resume treatment with SD-809 on the prior 
established dose for an additional 12 weeks until end of treatment (EOT). A follow-up 
telephone call will occur 4 weeks after EOT.
At the beginning of the Randomized Withdrawal Period, subjects will be randomized 


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in a blinded fashion to either SD-809 (current dose) or placebo in a 1:1 ratio stratified 
by DRA usage. Up to 194 subjects (active subjects as of the approval date of 
Amendment 06) will be randomized (SD-809 or placebo). Subjects will be required to 
sign a written informed consent. 
Subjects will need to be on a stable dose of SD-809 and any concomitant DRA for a 
minimum of 4 weeks before starting the Randomized Withdrawal Period.
Subjects will be scheduled to return 1 week (+3 days maximum) after the 
Pre-withdrawal Visit of the Randomized Withdrawal Period for efficacy and safety
assessments. 
At the end of this period, subjects will continue treatment with SD-809 at the previous
dose administered before the Randomized Withdrawal Period (last dose in Part A). 
Treatment with SD-809 will continue for 12 weeks until the EOT visit.
Video ratings of the Abnormal Involuntary Movement Scale (AIMS) will occur at the 
Pre-withdrawal Visit, the Post-withdrawal Visit, and the EOT/early termination (ET) 
visit.
Part C:
Part C will consist of a 52-week period of reduced burden safety assessments, for 
subjects in the EU countries. Subjects can only enter Part C once they have entered 
and completed Part B. The Part B EOT will coincide with Part C Visit 1 for those 
subjects who are willing to continue with the 52-week reduced burden safety 
assessment period.
Post-Treatment Safety Follow-up:
Part A:
Subjects who do not participate in Part B will continue in Part A, discontinue study 
drug at the Week 158 visit, and return for their final clinic visit at Week 159 for 
evaluation of safety, dyskinesia control, and motor function. During this 1-week 
follow-up period, subjects should continue to not take prohibited concomitant 
medications. Subjects will also have a follow-up telephone contact at Week 162, 
4 weeks after their last dose of study drug, to evaluate adverse events and 
concomitant medication usage.
Subjects who discontinue study drug in Part A will complete an ET visit; a follow-up 
clinic visit 1 week later to evaluate safety, dyskinesia, and motor function; and a 
follow-up telephone contact 4 weeks after the last dose of study drug to evaluate the 
adverse events and concomitant medication use since ET.
Part B:
Subjects who complete the Randomized Withdrawal Period and subsequent 12 weeks 
of treatment will complete an EOT visit and a follow-up telephone contact 4 weeks 
after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since EOT. Subjects in EU countries may choose to enroll in Part C, 
in which case Part B EOT will coincide with Part C Visit 1.
Subjects who discontinue study drug in Part B will complete an ET visit; a follow-up 
clinic visit 1 week later to evaluate safety, dyskinesia, and motor function; and a 
follow-up telephone contact 4 weeks after the last dose of study drug to evaluate the 
adverse events and concomitant medication use since ET.
Part C:
Subjects who complete the 52 weeks of reduced burden safety assessments period 


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will complete a Part C EOT Visit and a follow-up telephone contact 4 weeks after the 
last dose of study drug to evaluate the adverse events and concomitant medication use 
since Part C EOT. Subjects who discontinue study drug in Part C will complete an ET 
visit, a follow-up clinic visit 1 week later for safety evaluation, and a follow-up 
telephone contact 4 weeks after the last dose of study drug to evaluate the adverse 
events and concomitant medication use since ET.
FORMULATION SD-809 tablets will be provided in dosage strengths of 6, 9, 12, 15, and 18 mg. 
During dose adjustment/titration in Part A, SD-809 will be supplied in weekly blister 
cards. During long-term treatment, SD-809 will be supplied in 30-count bottles. 
During the blinded Randomized Withdrawal Period, SD-809 will be supplied in 
20-count bottles, all of which are identical in size, shape, and color (white), whereas 
during long-term treatment, SD-809 will be supplied in 30-count bottles. Placebo 
tablets are identical in appearance to the SD-809 tablets and contain the same inactive 
ingredients as the SD-809 tablets. During Part C, SD-809 will be supplied in 30-count 
bottles.
DOSE 
REGIMEN
Study drug will be administered as follows:

All treatment regimens will be administered twice daily (BID) with meals, 
approximately 10 hours apart during the day.

The starting dose will be SD-809 12 mg/day (6 mg BID) regardless of previous 
treatment in the parent trial. Prior treatment assignment from the parent trial will 
remain blinded.

The maximum total daily dose of SD-809 is based on body weight:
o
If body weight <100 kg, the maximum daily dose is 48 mg/day (24 mg 
BID) unless the subject is on a strong CYP2D6 inhibitor (paroxetine, 
fluoxetine, or bupropion), in which case the maximum total daily dose is 
36 mg/day. 
o
If body weight ≥100 kg the maximum daily dose is 60 mg/day (30 mg 
BID) unless the subject is on a strong CYP2D6 inhibitor (paroxetine, 
fluoxetine, or bupropion), in which case the maximum daily dose is 
42 mg/day

Daily doses will be administered according to instructions provided in the 
Pharmacy Manual.

During the titration period, the dose of SD-809 should be increased on a weekly 
basis in increments of 6 mg per day until:
o
There is adequate control of dyskinesia; 
o
The subject experiences a protocol defined clinically significant adverse 
event (defined as related to study drug and either a) moderate or severe in 
intensity or b) meets the criteria for a serious adverse event); or 
o
The maximal allowable dose is reached. 

If a subject experiences a clinically significant adverse event attributable to 
SD-809, the Investigator will determine if a dose reduction or suspension is 
necessary. 
Part A
Long-Term Treatment:
For all subjects participating in the Long-Term Treatment Period, the dose of SD-809 
may be adjusted (upward or downward) in increments of 6 mg per day, if necessary, 
to optimize dyskinesia control while minimizing adverse events. However, such 
changes in dose may not occur more frequently than once per week. In the case of the 


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DOSE 
REGIMEN 
(continued)
addition of a strong CYP2D6 inhibitor (i.e., paroxetine, fluoxetine, bupropion), a 
greater dose reduction may be required. Dose reductions in this context should be 
reviewed with the Medical Monitor.
Part B
Double-Blind, Randomized Withdrawal Period:
Subjects in the Randomized Withdrawal Period will continue to receive their current 
dose of SD-809 or will receive matching placebo. At the end of the Randomized 
Withdrawal Period, subjects will continue with, or return to, the same dose of SD-809 
taken before the Randomized Withdrawal Period (last dose in Part A), beginning the 
day after the Post-withdrawal Visit and continuing for 12 weeks. Subjects who do not 
return for the Post-withdrawal Visit within the 10 days (1 week [+3 days maximum]) 
may be required to undergo titration, as decided by the Investigator in consultation 
with the Medical Monitor (if necessary).
Part C
52-Week Treatment Period:
Subjects in Part C will continue treatment with SD-809 at the dose administered 
during the 12-week open-label treatment period of Part B (last dose in Part B), unless 
they will experience a delay in the completion of all the activities related to Part B 
EOT Visit, especially of study drug dispensation, in which case they may be required 
to undergo titration, as decided by the Investigator in consultation with the Medical 
Monitor.
SAMPLE SIZE
Approximately 330 subjects (eligible subjects who completed a previous controlled 
study of SD-809 for treatment of moderate to severe TD) may enroll in Part A. 
During the Randomized Withdrawal Period in Part B, there will be up to 194 subjects 
randomized (SD-809 or placebo). Approximately 102 subjects may enroll in Part C
conducted in the EU countries.
INCLUSION 
CRITERIA
1.
Subject is at least 18 years of age at Screening.
2.
Subject has successfully completeda Study SD-809-C-18, Study SD-809-C-23, or 
any other controlled study of SD-809 for treatment of moderate to severe TD.
3.
Subject has a history of using a DRA for at least 3 months (or 1 month in subjects 
60 years of age and older).
4.
Subject has a clinical diagnosis of TD and has had symptoms for at least 3 months 
prior to Screening.
5.
For subjects with underlying psychiatric illness:

Subject is psychiatrically stable and has had no change in psychoactive 
medications (including, but not limited to, neuroleptics, benzodiazepines, 
anticonvulsants, and mood stabilizers) for ≥30 days before Screening 
(45 days for antidepressants).

Subjects on long-acting (depot) medications have been on stable therapy 
(dose, frequency) for ≥3 months before Screening. 

Subject has a health care provider who is aware of the subject’s 
participation in the trial and does not anticipate any changes to the 
                                                
a Successful completion is defined as (1) study participation through Week 13 (2) the subject has generally been 
compliant with study drug and procedures, in the opinion of the investigator, and (3) the subject has no ongoing AEs 
that are serious or severe in intensity or are expected to interfere with safety evaluations in this study.


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subject’s treatment regimen (drug, dose, frequency) in the next 3 months. 
6.
Subject has a history of being compliant with prescribed medications.
7.
Subject is able to swallow study drug whole.
8.
Subject has provided written, informed consent or, if subject lacks the capacity to 
provide informed consent, a legally authorized representative (LAR) has provided 
written informed consent and the subject has provided assent.
9.
In the opinion of the Investigator, the subject lives in a stable environment, and 
has adequate supervision when necessary to comply with all study procedures, 
attend all study visits, and safely participate in the trial. 
10. Subject has sufficient reading skills to comprehend the subject-completed rating 
scales.
11. Female subjects of childbearing potentialb agree to use one of the following 
acceptable methods of contraception from Screening through study completion if 
sexually active:

IUD or intrauterine system in place for at least 3 months prior to 
screening;

Subject or partner using barrier method (e.g., condom, diaphragm, or 
cervical cap) with spermicide from Screening through study completion;

Partner has a documented vasectomy >6 months prior to enrollment;

Stable hormonal contraception (with approved oral, transdermal, or depot 
regimen) for at least 3 months prior to Screening.
EXCLUSION 
CRITERIA
1.
Subject has received tetrabenazine within 7 days of Baseline.
2.
Subject has received any of the following medications within 30 days of Baseline: 
Reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of 
Baseline), and medications with strong anticholinergic activity (e.g., 
trihexyphenidyl, benztropine, orphenadrine, procyclidine, and biperiden)
Metoclopramide, promethazine, and prochlorperazine
Stimulants (e.g., methylphenidate, amphetamine/dextroamphetamine, 
lisdexamphetamine.), or monoamine oxidase inhibitors (MAOIs)
Levodopa or dopamine agonists
3.
Subject has a neurological condition other than TD that may interfere with 
assessing the severity of dyskinesias.
4.
Subject has a serious untreated or undertreated psychiatric illness at Baseline. 
5.
Subject has active suicidal ideation at Baseline.
6.
Subject has a history of any of the following within 6 months of Baseline:

Previous intent to act on suicidal ideation with a specific plan, irrespective of 
level of ambivalence at the time of suicidal thought

Previous preparatory acts to commit suicide or suicidal behavior

A previous actual, interrupted, or aborted suicide attempt
7.
Subject has a score ≥11 on the depression subscale of the Hospital Anxiety and 
                                                
b Non-childbearing potential for females is defined as postmenopausal (amenorrheic for at least 1 year and serum 
follicle stimulating hormone (FSH) level consistent with postmenopausal status), or a documented hysterectomy; 
bilateral oophorectomy; or bilateral tubal ligation >6 months prior to study initiation. 


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EXCLUSION 
CRITERIA 
(continued)
Depression Scale (HADS) at Baseline.
8.
Subject is developmentally disabled or has evidence of dementia.
9.
Subject has an unstable or serious medical illness at Baseline.
10. Subject has history (within 3 months) or presence of violent behavior.
11. Subject has a Fridericia-corrected QT interval (QTcF) value >450 ms (males) or 
>460 ms (females), or >480 ms (with right bundle branch block [RBBB]) on 12-
lead electrocardiogram (ECG) at Baseline.
12. Subject has evidence of hepatic impairment at Screening of the parent study, as 
indicated by: 
Aspartate transaminase (AST) or alanine aminotransferase (ALT) >2.5 times 
the upper limit of normal (ULN)
Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the ULN
o
Note: Subjects with Gilbert’s Syndrome are eligible to participate if 
approved by the Medical Monitor. 
o
Note: Subjects with abnormalities in two or more of these analytes (AST, 
ALT, ALP, TBil) must be approved by the Medical Monitor to be 
enrolled. 

Prothrombin time >17 seconds (i.e., prothrombin time prolonged >4 seconds 
over the ULN)

Positive Hepatitis B surface antigen (HBsAg)
13. Subject has evidence of significant renal impairment at Screening of the parent 
study, indicated by a creatinine clearance <50 mL/min, as estimated by the 
Cockroft-Gault formula.
14. Subject has known allergy to tetrabenazine or to any of the components of 
SD-809.
15. Subject has participated in an investigational drug or device trial (other than 
Study SD-809-C-18, Study SD-809-C-23, or any other eligible SD-809 parent 
study) and received study drug within 30 days (or 5 drug half-lives) of Baseline, 
whichever is longer.
16. Subject is pregnant or breastfeeding at Baseline.
17. Subject acknowledges present use of illicit drugs at Baseline.
18. Subject has a history of alcohol or substance abuse in the previous 12 months, as 
defined in the DSM-V, or subject is unable to refrain from substance abuse 
throughout the study.
SAFETY 
PARAMETERS
Safety and tolerability will be assessed throughout the study by monitoring the 
following parameters:
Adverse events
Clinical laboratory tests 
Physical examination
Vital signs
12-lead ECGs 
Unified Parkinson’s Disease Rating Scale 
(UPDRS) Part III (motor examination)
Barnes Akathisia Rating Scale (BARS) 
HADS 
Columbia Suicide Severity Rating Scale (C-SSRS)
Epworth Sleepiness Scale (ESS)
Montreal Cognitive Assessment (MoCA©)


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SAFETY 
ENDPOINTS
The following safety endpoints will be assessed in Part A

Incidence of adverse events, serious adverse events, severe adverse events, 
drug-related adverse events, adverse events leading to withdrawal during the 
following periods:
-
Overall
-
During titration 
-
During long term treatment 

Observed values and changes from Baseline in clinical laboratory parameters 
(hematology, chemistry, and urinalysis)

Observed values and changes from Baseline in vital signs

Observed values in ECG parameters and abnormal findings

Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms, 
or a change from Baseline in QTcF of >30 ms or >60 ms

Observed values and changes in UPDRS Part III (motor examination), BARS, 
HADS, C-SSRS, ESS, and MoCA©

Duration of time to achieve stable dosing of SD-809
The following secondary safety endpoints will be assessed in Part B

Secondary safety endpoints:
-
Incidence of adverse events, serious adverse events, severe adverse events, 
drug-related adverse events, and adverse events leading to withdrawal
-
Observed values and changes from start of randomized withdrawal in clinical 
laboratory parameters (hematology, chemistry, and urinalysis)
-
Observed values and changes from start of randomized withdrawal in vital 
signs
-
Observed values in ECG parameters and abnormal findings
-
Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 
ms, or a change from baseline in QTcF of >30 ms or >60 ms
-
Observed values and changes in UPDRS Part III (motor examination), BARS, 
HADS, C-SSRS, ESS, and MoCA©
The following secondary safety endpoints will be assessed in Part C

Secondary safety endpoints:
-
Incidence of adverse events, serious adverse events, severe adverse events, 
drug-related adverse events, and adverse events leading to withdrawal from 
start of Part C
-
Observed values and changes in vital signs from start of Part C
-
Observed values and changes in C-SSRS from start of Part C
-
Observed values in ECG parameters and abnormal findings from start of 
Part C
-
Number of subjects with on-treatment QTcF values >450 ms, >480 ms, 
>500 ms, or a change from baseline in QTcF of >30 ms or >60 ms from start 
of Part C


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EFFICACY 
MEASURES
Efficacy Measures during Part A:

The change in AIMS score (items 1 through 7) from Baseline of this study at each 
visit that this is measured, as assessed by the site rating.

The proportion of subjects who are a treatment success based on the Clinical 
Global Impression of Change (CGIC) at each visit that this is measured. A 
treatment success is defined as Much or Very Much Improved on the CGIC from 
Baseline of this study. 

The proportion of subjects who have a 50% or greater reduction in AIMS score 
from Baseline of this study at each visit that this is measured.

The change in the modified Craniocervical Dystonia (CDQ-24) score from 
Baseline of this study at each visit that this is measured.

The proportion of subjects who are a treatment success based on the Patient 
Global Impression of Change (PGIC) at each visit that this is measured. A 
treatment success is defined as Much or Very Much Improved on the PGIC from 
Baseline of this study.

The percent change in AIMS score from Baseline of this study at each visit that 
this is measured.
The following efficacy measure will be assessed during Part B (Double-Blind,
Randomized Withdrawal Period):

Primary efficacy endpoint: change from Pre-withdrawal Visit AIMS scores 
(items 1 through 7) as assessed by blinded central video rating to the Post-
withdrawal Visit between subjects treated with SD-809 and subjects treated with 
placebo.
STATISTICS
Safety:
Safety data will be summarized descriptively for the overall population and based on 
prior treatment (SD-809 or placebo) in the parent study. Descriptive statistics will be 
calculated for quantitative data and frequency counts and percentages will be 
provided for categorical data. The nature, frequency, and severity of adverse events 
will be tabulated for all subjects combined and by prior treatment. Baseline, within 
study, end of study, and change-from-baseline values for clinical laboratory 
evaluations and vital signs will be summarized as appropriate.
Treatment-emergent adverse events and laboratory, vital sign, and ECG parameters 
will be summarized. In addition, change from baseline will be summarized for 
laboratory and vital sign parameters. Shift tables will be provided for clinical 
laboratory results. ECG results will be classified as normal and abnormal and 
summarized.
Descriptive statistics of change-from-baseline will use the Baseline from the present 
study and will be specified in the Statistical Analysis Plan.
Efficacy:
Descriptive statistics will be used to summarize efficacy measures for the overall 
population and based on prior treatment (SD-809 or placebo) in the parent study.
Descriptive statistics will be calculated for quantitative data and frequency counts and 
percentages will be provided for categorical data. 
Descriptive statistics of change-from-baseline will utilize Baseline from the present 
study (SD-809-C-20 Baseline). 
Double-Blind, Randomized Withdrawal Period Power and Sample Size:
It is estimated that approximately 91 subjects per arm will enable a power of at least 
90% to detect a beneficial effect of 1.4 points or more in the change from 
pre-withdrawal to post-withdrawal in centrally read AIMS when the SD-809 arm is 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
12
compared to placebo, assuming a standard deviation of 2.9 and a 2-sided type I error 
rate of 5%.
Analysis of the change in centrally read AIMS score during the Randomized 
Withdrawal Period (from the Pre-withdrawal Visit to the Post-withdrawal Visit) will 
use an analysis of covariance (ANCOVA) model with the change in AIMS score as 
the dependent variable. The model will include randomized withdrawal treatment 
group, AIMS score at the Pre-withdrawal Visit, and DRA status at the Pre-withdrawal 
Visit as fixed effects. The least squares means of the change in AIMS score will be 
compared between the SD-809 treatment and placebo groups using a 2-sided test at 
the alpha=0.05 level of significance. In addition, actual values and changes in AIMS 
score will be summarized using descriptive statistics.
The primary efficacy analysis will be tested at the α=0.05 level. If less than 135 
subjects are enrolled into the randomized withdrawal portion of the study, inferential 
statistics will not be provided as the study will be insufficiently powered to detect a 
treatment effect given the sample size assumptions.


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Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
14
Screening
Year 1
Year 2
Year 3
Follow-up 
clinic visit 
Follow-up
Call
Unscheduled
Long-Term Treatment Period
Titration Period
Study Weekǁ →
Prior 
Data 
from 
Parent 
Study†
Base-
line‡
1
2
3
4
5
6
15 28
41
54
67
80
93 106
119
132
145 15810/ET11
159 or 1 
week after 
ET
162 or 4 
weeks 
after ET
Visit Window (days) 
+3
± 1 
± 3
Activity Visit Type 
→
V
TC V TC
V TC V
V
V
V
V
V
V
V
V
V
V
V
V
V
TC
V
TC
UPDRS Part III -
Motor
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
BARS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
HADS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS5
**
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
CGIC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGIC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MoCA©
X
X
X
X
X
X
X
X
X
X
X
X
Modified CDQ-24
X
X
X
X
X
X
X
X
Dispense/Order Study 
Drug6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3 
X3
Assess Study Drug 
Accountability/
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess AEs
*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Concomitant 
Meds
*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluate Dyskinesia 
Control (subject/
caregiver)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
15
SCHEDULE OF EVENTS (Part A) KEY
[V]
Clinic Visit
[TC]
Telephone Contact
[ET] 
Early Termination Visit
[U]
Urine pregnancy test for women of childbearing potential only
Abbreviations: AEs, adverse events; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; CDQ-24, Craniocervical Dystonia 
Questionnaire; CGIC, Clinical Global Impression of Change; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; ESS Epworth 
Sleepiness Scale; HADS, Hospital Anxiety and Depression Scale; MoCA©, Montreal Cognitive Assessment; PGIC, Patient Global Impression of Change; 
PK, pharmacokinetics; SAE, serious adverse event; UA, urinalysis; UPDRS, Unified Parkinson’s Disease Rating Scale. 
ǁ
All stable subjects will be invited to participate in Part B after Amendment 06 implementation regardless of current study week. Subjects will need to be 
on a stable dose of SD-809 and any concomitant dopamine receptor antagonist for a minimum of 4 weeks before starting the Double-Blind, Randomized 
Withdrawal Period.
†
After Informed Consent is obtained, prior data from the parent study will be used in this study as part of screening information as detailed in the 
informed consent/assent.
‡
Data from the Week 13 evaluation of the parent study will provide some of the Baseline data for the present study, although such data will not become 
available for this study until informed consent/assent has been provided.
§
May be performed up to 30 days in advance of Baseline
*
Data (Week 12 or earlier) from the parent study will be used in this study as part of screening information. 
**
Data (Week 13) from the parent study will be used as part of Baseline assessment. Additional specific activities required at this visit are denoted by an 
“X”
1   
Assessment transferred from Screening or Baseline evaluation in the parent study.
2   
Perform orthostatic blood pressure and pulse after subject is in standing position for at least 3 minutes.
3   
Assessments to be completed at Investigator’s discretion.
4   
Brief physical examination, which includes evaluation of the cardiovascular, respiratory, and abdominal systems.
5   
The C-SSRS Since Last Visit version is administered at all visits.
6   
Study medication supply will be ordered (see Operations Manual for further details).
7   
Subjects who experience an SAE should have a blood sample collected for pharmacokinetic assessment as soon as possible after the SAE and within 
48 hours of last dose of study drug, if possible.
8   
Subjects who have not achieved adequate control of dyskinesia during the study may have up to two blood samples collected within 48 hours of the last 
dose of study drug for future pharmacokinetic assessment of α- and β-HTBZ. The pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor.
9   
Subjects undergoing an increase in dose of their current antipsychotic treatment, switching to a new antipsychotic agent, or having an additional 
antipsychotic treatment added to their regimen will require additional ECG monitoring (see Section 6.7.1).
10   
Subjects who have been on a stable dose of SD-809 and any concomitant dopamine receptor antagonist for 4 weeks will be invited to participate in the 
Randomized Withdrawal Period (Part B). If the subject chooses to participate in Part B, then participation in Part A will end.
11   
Subjects will complete a follow-up visit 1 week after ET and a Follow-up Call 4 weeks after ET.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
16
SCHEDULE OF EVENTS
Part B 
Randomized Withdrawal Period
Open-label 
Treatment
Follow-up
Part B
Pre-withdrawal Visit
Part B
Post-withdrawal Visit11
EOT2/ET
Follow-up 
clinic visit
(ET only)
Follow-up 
Call
Unscheduled
Study Week →
After Amendment 06 
Implementation1,12
+1 Week
12 Weeks after 
Post-withdrawal 
Visit
1 Week after 
ET
4 Weeks 
after 
EOT/ET
Visit Window (days) 
+3
±3
Activity Visit Type →
V
V
V
V
TC
V
TC
Evaluate/Adjust Dose3
X4
X4
Informed Consent/Assent
X5
Randomization via IRT
X
Screening/
Demographics
Inclusion/
Exclusion Criteria
Update Medical History
Vital Signs/
Weight
X6
X
X6
X
X
Physical Examination
X
Complete Neurological Exam
X
12-lead ECG
X
X
X
X4,11
Blood Sampling for PK
X
X9,10
Chemistry/
Hematology/
UA
X
X 
X
X4
Pregnancy Test
U
U
AIMS
X
X
X
X
Video Recording of AIMS
X
X
X
UPDRS Part III - Motor
X
X
X
X
X4
BARS
X
X
X
X
X4
HADS
X
X
X
X
X
C-SSRS7
X
X
X
X
X
ESS
X
X
X
X
X4
CGIC
PGIC


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
17
Randomized Withdrawal Period
Open-label 
Treatment
Follow-up
Part B
Pre-withdrawal Visit
Part B
Post-withdrawal Visit11
EOT2/ET
Follow-up 
clinic visit
(ET only)
Follow-up 
Call
Unscheduled
Study Week →
After Amendment 06 
Implementation1,12
+1 Week
12 Weeks after 
Post-withdrawal 
Visit
1 Week after 
ET
4 Weeks 
after 
EOT/ET
Visit Window (days) 
+3
±3
Activity Visit Type →
V
V
V
V
TC
V
TC
MoCA©
X
X
X
Modified CDQ-24
Dispense/Order Study Drug8
X
X
X4 
X3
Assess Study Drug Accountability/
Compliance13,14
X
X
X
Assess AEs
X
X
X
X
X
X
X
Assess Concomitant Meds
X
X
X
X
X
X
X
Evaluate Dyskinesia Control 
(subject/caregiver)
X
X
X
X
X
X
SCHEDULE OF EVENTS (Part B) KEY
[V]
Clinic Visit
[TC] Telephone Contact
[EOT]
End of Treatment
[ET]
Early Termination Visit
[U]
Urine pregnancy test for women of childbearing potential only
Abbreviations: AEs, adverse events; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; CDQ-24, Craniocervical Dystonia 
Questionnaire; CGIC, Clinical Global Impression of Change; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; ESS Epworth 
Sleepiness Scale; HADS, Hospital Anxiety and Depression Scale; IRT, MoCA©, Montreal Cognitive Assessment; PGIC, Patient Global Impression of Change; 
PK, pharmacokinetics; SAE, serious adverse event; UA, urinalysis; UPDRS, Unified Parkinson’s Disease Rating Scale. 
1   
Assessments required for the Pre-withdrawal Visit will be those required for the next scheduled visit, or visit as determined by the Investigator, after 
Amendment 06 implementation and subject consent for Part B.
2   The EOT visit will occur 12 weeks after the Post-withdrawal Visit.
3   
Titration is not permitted during the Randomized Withdrawal Period and will be allowed after return to open-label dosing.
4   Assessments to be completed at Investigator’s discretion.
5   
Subjects who do not sign the informed consent for Part B will continue participation in Part A. Subjects who decline participation in Part B will be 
given an ongoing option to participate at subsequent study visits.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
18
6   
Perform orthostatic blood pressure and pulse.
7   
The C-SSRS Since Last Visit version is administered at all visits.
8   
Study medication supply will be ordered (see Operations Manual for further details).
9   
At the discretion of the Principal Investigator and/or Medical Monitor, subjects who experience an SAE may have a blood sample collected for 
pharmacokinetic assessment after experiencing the SAE. All such blood samples will be collected within 48 hours of last dose of study drug.
10   
Subjects who have not achieved adequate control of dyskinesia during the study may have up to two blood samples collected within 48 hours of the last 
dose of study drug for future pharmacokinetic assessment of α- and β-HTBZ. The pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor.
11   
Subjects undergoing an increase in dose of their current antipsychotic treatment, switching to a new antipsychotic agent, or having an additional 
antipsychotic treatment added to their regimen will require additional ECG monitoring (see Section 6.7.1).
12   
If the subject chooses to participate in Part B, the first visit will be the subject’s next scheduled visit, or as soon as possible, as determined by the 
Investigator, after Amendment 06 implementation. The Post-withdrawal Visit will occur 1 week (+3 days maximum). If the Post-withdrawal Visit is >3 
days beyond the 1-week time period, the subject may be required to undergo titration, as decided by the Investigator in consultation with the Medical 
Monitor (if necessary) per the guidelines in Table 3. After the Randomized Withdrawal Period, the subject will continue on or return to previous (before 
placebo) SD-809 dose.
13   
Prior to the Pre-withdrawal Visit, the Investigator or designated site staff must place a call to remind the subject to bring all remaining study drugs to the 
visit. The Investigator or designated site staff must collect the study drug(s) from the subject and conduct drug accountability.
14   
Prior to the Post-withdrawal Visit, the Investigator or designated site staff must place a call to remind the subject to bring all remaining study drugs to 
the visit. The Investigator or designated site staff must collect the study drug(s) from the subject and conduct drug accountability.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
19
SCHEDULE OF EVENTS
Part C EU Countries (Slovakia and Poland)
Part C1
EOT/ET
Follow-up 
Clinic Visit (ET 
Only)
Follow-up 
Call
Unscheduled
Study Week →After Amendment 07 Implementation2
52 Weeks after Part 
C V1
1 Week after 
ET
4 Weeks after 
Part C 
EOT/ET
Visit Window (days) 
+7
Part C V2, V3, V4 
(q13 weeks) ±7 
days
±7 days
±3 days
±3 days
Activity Visit Type →Part B EOT/Part 
C V13
V
V
V
TC
V
TC
Informed Consent/Assent
X4
Screening/
Demographics
Inclusion/
Exclusion Criteria
Update Medical History
Vital Signs/
Weight5
X
X
X
X
X
Physical Examination
X
X
X
Complete Neurological Exam
X
X
12-lead ECG
X
X
X
X11,12
Blood Sampling for PK
Chemistry/Hematology/UA
X
Pregnancy Test6
U
U
U
AIMS
X
Video Recording of AIMS
X
UPDRS Part III - Motor
X
BARS
X
HADS
X
C-SSRS7
X
X
X
X
X
ESS
X
MoCA©
X
Dispense Study Drug8
X9
X
X12


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
20
Part C1
EOT/ET
Follow-up 
Clinic Visit (ET 
Only)
Follow-up 
Call
Unscheduled
Study Week →After Amendment 07 Implementation2
52 Weeks after Part 
C V1
1 Week after 
ET
4 Weeks after 
Part C 
EOT/ET
Visit Window (days) 
+7
Part C V2, V3, V4 
(q13 weeks) ±7 
days
±7 days
±3 days
±3 days
Activity Visit Type →Part B EOT/Part 
C V13
V
V
V
TC
V
TC
Assess Study Drug Accountability/
Compliance10
X
X
Assess AEs
X
X
X
X
X
X
X
Assess Concomitant Meds
X
X
X
X
X
X
X
Evaluate Dyskinesia Control 
(subject/caregiver)
X
SCHEDULE OF EVENTS (Part C) KEY
[V]
Clinic visit
[TC]
Telephone contact
[EOT]
End of Treatment
[ET]
Early Termination Visit
[U]
Urine pregnancy test for women of childbearing potential only
Abbreviations: AEs, adverse events; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; C-SSRS, Columbia Suicide Severity Rating Scale; 
ECG, electrocardiogram; ESS, Epworth Sleepiness Scale; EU, European Union; HADS, Hospital Anxiety and Depression Scale; MoCA©, Montreal Cognitive Assessment; PK, 
pharmacokinetics; q13 weeks, every 13 weeks; UA, urinalysis; UPDRS, Unified Parkinson’s Disease Rating Scale; V1, Visit 1. 
1   
In the EU, if subjects reach the end of Part A, they may be enrolled in Part B and complete the randomized withdrawal and follow-up treatment of Part B and then enroll 
in Part C. 
2   
If the subject chooses to participate in Part C, the first visit will be combined with the EOT visit in Part B, after Amendment 07 implementation. The subject will 
continue with the current SD-809 dose.
3   
One set of assessments will be performed for Part B EOT/Part C V1 (do not duplicate assessments).
4   
Subjects who do not sign the informed consent/assent for Part C will complete the study at Part B Follow-up Call.
5   
Perform orthostatic blood pressure and pulse at Part B EOT/Part C V1 and resting blood pressure and pulse at all other visits. 
6   
The pregnancy test will be done locally at the study site.
7   
The C-SSRS Since Last Visit version is administered at all visits.
8   
Study medication supply will be dispensed (see Operations Manual for further details).


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
21
9   
Drug will dispensed for Part C V1.
10   
Prior to each visit, the Investigator or designated site staff should call to remind the subject to bring all remaining study drugs to the visit.
11   
Subjects undergoing an increase in dose of their current antipsychotic treatment, switching to a new antipsychotic agent, or having an additional 
antipsychotic treatment added to their regimen will require additional ECG monitoring (see Section 6.7.1).
12   
Assessments to be completed at Investigator’s discretion.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
22
STUDY SCHEMATIC DIAGRAM (PARTS A, B, AND C)


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
23
PROTOCOL APPROVAL PAGE


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
24
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STUDY CONTACTS......................................................................................................................2
PROTOCOL SYNOPSIS ................................................................................................................3
SCHEDULE OF EVENTS ............................................................................................................13
STUDY SCHEMATIC DIAGRAM (PARTS A, B, AND C).......................................................22
PROTOCOL APPROVAL PAGE.................................................................................................23
TABLE OF CONTENTS...............................................................................................................24
LIST OF APPENDICES................................................................................................................29
LIST OF TABLES.........................................................................................................................30
LIST OF ABBREVIATIONS........................................................................................................31
1.
INTRODUCTION......................................................................................................35
1.1.
Disease Background ...................................................................................................35
1.2.
Tetrabenazine..............................................................................................................36
1.2.1.
Limitations of the Current Commercial Product ........................................................37
1.3.
Deuterium ...................................................................................................................37
1.3.1.
Clinical Experience with Deuterium ..........................................................................38
1.4.
SD-809 (Deutetrabenazine) ........................................................................................38
2.
STUDY OBJECTIVES ..............................................................................................40
3.
INVESTIGATIONAL PLAN.....................................................................................41
3.1.
Study Design...............................................................................................................41
3.2.
Rationale for Study Design.........................................................................................44
3.3.
Rationale for Dose Selection ......................................................................................44
4.
STUDY POPULATION.............................................................................................48
4.1.
Population Characteristics ..........................................................................................48
4.2.
Inclusion Criteria ........................................................................................................48
4.3.
Exclusion Criteria.......................................................................................................49
5.
STUDY TREATMENT..............................................................................................51
5.1.
Study Drug..................................................................................................................51
5.1.1.
SD-809........................................................................................................................51
5.1.2.
Placebo (Part B: Double-Blind, Randomized Withdrawal Period Only) ...................51


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5.2.
Treatment Regimen ....................................................................................................51
5.2.1.
General Guidelines .....................................................................................................51
5.2.2.
Dosing in Long-Term Treatment (Week 3 Until the Last Dose in Part A) ................52
5.2.3.
Dosing in the Double-Blind, Randomized Withdrawal Period ..................................53
5.2.4.
Dosing in Part C..........................................................................................................53
5.2.5.
Dose Reduction, Suspension, or Discontinuation.......................................................54
5.3.
Treatment Administration...........................................................................................55
5.4.
Accountability of Study Drug.....................................................................................55
5.5.
Study Drug Compliance .............................................................................................56
6.
STUDY METHODS AND PROCEDURES..............................................................57
6.1.
Screening Period.........................................................................................................57
6.1.1.
Prior Data from Subject’s Parent Study......................................................................57
6.1.2.
Baseline Visit (Day 0) ................................................................................................57
6.2.
Dose Adjustment/Titration Period..............................................................................58
6.2.1.
Weeks 1 and 2.............................................................................................................58
6.3.
Long-Term Treatment Period (Week 3 Until the Last Dose in Part A) .....................59
6.3.1.
Telephone Contacts (Week 3 ± 3 Days and Week 5 ± 3 Days)..................................60
6.3.2.
Clinic Visits (Weeks 4, 6, 15, 41, 67, 80, 93, 106, 119, 132, and 145 [All ± 3 
Days]) .........................................................................................................................60
6.3.3.
Clinic Visits (Part A) (Weeks 28, 54, 106 and 158 [All ± 3 Days] or Early 
Termination) ...............................................................................................................60
6.4.
Double-Blind, Randomized Withdrawal Period (Part B)...........................................61
6.5.
Reduced Burden Safety Assessments (Part C)...........................................................62
6.6.
Post-Treatment Safety Follow-up...............................................................................63
6.6.1.
Clinic Visit (Week 159 ±3 Days or 1 Week after Early Termination ±3 
Days)...........................................................................................................................63
6.6.2.
Telephone Contact (4 Weeks After EOT/ET ± 3 Days).............................................64
6.7.
Unscheduled Visit(s) ..................................................................................................64
6.7.1.
Unscheduled Visit(s) for Change in Antipsychotic Regimen.....................................65
6.7.2.
Unscheduled Telephone Visit(s).................................................................................65
6.8.
Efficacy and Quality of Life Measures.......................................................................66
6.8.1.
Abnormal Involuntary Movement Scale ....................................................................66
6.8.2.
Independent Rating of Dyskinesia..............................................................................66


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6.8.3.
Clinical Global Impression of Change .......................................................................67
6.8.4.
Patient Global Impression of Change.........................................................................67
6.8.5.
Modified Craniocervical Dystonia Questionnaire......................................................67
6.9.
Safety Evaluations ......................................................................................................67
6.9.1.
Demographics and Medical History...........................................................................67
6.9.2.
Physical Examination .................................................................................................67
6.9.3.
Complete Neurological Examination .........................................................................68
6.9.4.
Vital Signs ..................................................................................................................68
6.9.5.
Orthostatic Blood Pressure and Pulse.........................................................................68
6.9.6.
Laboratory Tests .........................................................................................................68
6.9.7.
12-lead Electrocardiogram..........................................................................................69
6.9.8.
Detecting Adverse Events...........................................................................................69
6.9.9.
Rating Scales ..............................................................................................................70
6.10.
Pharmacokinetic Evaluations......................................................................................71
6.11.
Subject Restrictions ....................................................................................................71
6.11.1.
Concomitant Medications...........................................................................................71
6.11.2.
Use of Alcohol or Sedating Drugs..............................................................................72
6.11.3.
Other Restrictions.......................................................................................................72
6.12.
Caregiver Responsibilities..........................................................................................73
6.13.
Withdrawal Criteria ....................................................................................................73
6.14.
Discontinued Subjects ................................................................................................73
6.15.
Study Termination ......................................................................................................73
7.
ADVERSE EVENTS..................................................................................................74
7.1.
Definitions ..................................................................................................................74
7.1.1.
Adverse Event.............................................................................................................74
7.1.2.
Suspected Adverse Reaction.......................................................................................75
7.1.3.
Adverse Reaction........................................................................................................75
7.1.4.
Unexpected Adverse Event.........................................................................................75
7.1.5.
Serious Adverse Event................................................................................................75
7.2.
Recording of Adverse Events.....................................................................................76
7.2.1.
Recording of Non-Serious Adverse Events................................................................76
7.2.2.
Recording of Serious Adverse Events ........................................................................76
7.3.
Evaluation of Adverse Events (Serious and Non-Serious).........................................77


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7.3.1.
Severity.......................................................................................................................77
7.3.2.
Relationship to Study Drug ........................................................................................78
7.3.3.
Action Taken with Study Treatment...........................................................................78
7.3.4.
Treatment Required ....................................................................................................78
7.3.5.
Outcome......................................................................................................................78
7.4.
Procedures for Reporting Serious Adverse Events.....................................................79
7.4.1.
Completion and Transmission of the Serious Adverse Event Report ........................79
7.4.2.
Regulatory Reporting Requirements for Serious Adverse Events .............................79
7.5.
Procedures for Reporting Pregnancy Exposure and Birth Events..............................79
8.
STATISTICAL PROCEDURES AND DATA ANALYSIS .....................................80
8.1.
Analysis Populations ..................................................................................................80
8.2.
Demographics and Baseline Data...............................................................................80
8.3.
Safety Analyses ..........................................................................................................80
8.4.
Safety Endpoints.........................................................................................................81
8.5.
Efficacy Measures ......................................................................................................82
8.6.
Efficacy Analysis (Randomized Withdrawal Period; Part B) ....................................82
8.7.
Sample Size ................................................................................................................82
8.8.
Protocol Deviations and Violations............................................................................83
8.9.
Data Recording...........................................................................................................83
8.10.
Data Quality Assurance ..............................................................................................83
8.11.
Data Management.......................................................................................................83
9.
ADMINISTRATIVE ISSUES....................................................................................84
9.1.
Investigator Obligations..............................................................................................84
9.1.1.
Independent Ethics Committee/Institutional Review Board Approval ......................84
9.1.2.
Written Informed Consent..........................................................................................84
9.1.3.
Emergency Contact with Investigator ........................................................................85
9.1.4.
Ethical Considerations................................................................................................85
9.1.5.
Privacy Rule................................................................................................................85
9.2.
Protocol Amendments ................................................................................................85
9.3.
Records Retention.......................................................................................................86
9.4.
Study Monitoring........................................................................................................86
9.5.
Clinical Product Complaints.......................................................................................86
9.5.1.
Product Complaint Reporting and Documentation.....................................................86


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9.5.2.
Handling the Suspect Study Drug at the Investigational Site.....................................87
9.5.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................87
9.5.4.
Quality Assurance.......................................................................................................87
10.
INFORMATION DISCLOSURE AND INVENTIONS............................................88
10.1.
Ownership...................................................................................................................88
10.2.
Confidentiality............................................................................................................88
10.3.
Publication..................................................................................................................88
11.
REFERENCES ...........................................................................................................89
12.
APPENDICES ............................................................................................................92


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LIST OF APPENDICES
Appendix 1: Site Investigator Signature Page ...............................................................................92
Appendix 2: Abnormal Involuntary Movements Scale (AIMS)....................................................93
Appendix 3: Clinical Global Impression of Change (CGIC).........................................................96
Appendix 4: Patient Global Impression of Change (PGIC)...........................................................97
Appendix 5: Modified Craniocervical Dystonia Questionnaire (CDQ-24)...................................98
Appendix 6: Unified Parkinson’s Disease Rating Scale (UPDRS) PART III: Motor 
Examination................................................................................................................99
Appendix 7: Barnes Akathisia Rating Scale (BARS)..................................................................105
Appendix 8: Hospital Anxiety and Depression Scale (HADS) ...................................................107
Appendix 9: Columbia Suicide Severity Rating Scale (C-SSRS) – Baseline .............................108
Appendix 10: Columbia Suicide Severity Rating Scale (C-SSRS) – Since Last Visit................111
Appendix 11: Montreal Cognitive Assessment (MoCA©) ..........................................................114
Appendix 12: Epworth Sleepiness Scale (ESS)...........................................................................117
Appendix 13: Strong CYP2D6 Inhibitors....................................................................................118
Appendix 14: Prohibited or Restricted QT Prolonging Drugs.....................................................119
Appendix 15: Dopamine Receptor Antagonists ..........................................................................120
Appendix 16: Citalopram and Escitalopram Dosing Information...............................................121
Appendix 17: Protocol Summary of Changes, Original Protocol (Dated 24 March 2014) 
to Amendment 01 (Dated 28 May 2014)..................................................................122
Appendix 18: Protocol Summary of Changes, Amendment 01 (dated 28 May 2014) to 
Amendment 02 (dated 08 July 2014)........................................................................125
Appendix 19: Protocol Summary of Changes, Amendment 02 (dated 08 July 2014) to 
Amendment 03 (dated 14-Oct-2015)........................................................................136
Appendix 20: Protocol Summary of Changes, Amendment 03 (dated 14 Oct 2015) to 
Amendment 04 (dated 27 Sept 2016).......................................................................146
Appendix 21: Protocol Summary of Changes, Amendment 04 (dated 27 Sept 2016) to 
Amendment 05 (dated 08 Feb 2017) ........................................................................157
Appendix 22: Protocol Summary of Changes, Amendment 05 (dated 08 Feb 2017) to 
Amendment 06 (dated 23 Jan 2018).........................................................................164
Appendix 23: Protocol Summary of Changes, Amendment 06 (dated 23 Jan 2018) to 
Amendment 07 (dated 02 May 2018).......................................................................181


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LIST OF TABLES
Table 1:
Published Reports Describing the Use of Tetrabenazine in Patients with TD ...........46
Table 2:
Maximum Daily Dose Level During the Maintenance Period ...................................52
Table 3:
Titration Schedule After 1-Week Randomized Withdrawal Period (if 
Necessary)...................................................................................................................53
Table 4:
Titration Schedule Part C End of Treatment Period (if Necessary) ...........................53
Table 5:
Laboratory Tests .........................................................................................................69


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LIST OF ABBREVIATIONS
Abbreviation
Definition
≤
less than or equal to
≥
greater than or equal to
°C
degrees Celsius
°F
degrees Fahrenheit
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AMPT
α-methyl-p-tyrosine
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under curve
BARS
Barnes Akathisia Rating Scale
BID
twice daily
BPS
blepharospasm
BUN
blood urea nitrogen
C
carbon
CATIE
Clinical Antipsychotic Trials for Intervention Effectiveness
CD
cervical dystonia
CDQ-24
Craniocervical Dystonia Questionnaire
CFR
Code of Federal Regulations
CGIC
Clinical Global Impression of Change
Cmax
maximum concentration
CNS
central nervous system
eCRF
electronic case report form
EDC
electronic data capture
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CUTLASS1
Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study


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Abbreviation
Definition
CYP2D6
cytochrome P450 2D6
CYP450
cytochrome P450
D, d
deuterium
DRA
dopamine receptor antagonist
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
electrocardiogram
ESS
Epworth Sleepiness Scale
EOT
End of treatment
ET
Early termination
EU
European Union
FDA
Food and Drug Administration
g
grams
GCP
Good Clinical Practice
H
hydrogen
HADS
Hospital Anxiety and Depression Scale
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HD
Huntington’s disease
HIV
human immunodeficiency virus
HTBZ
dihydrotetrabenazine
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization 
IEC
Independent Ethics Committee 
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
kg
kilogram
LAI
long-acting injectable
LAR
legally authorized representative


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Abbreviation
Definition
LDH
lactate dehydrogenase
LTS
long-term safety
MAOI
monoamine oxidase inhibitor
MCV
mean cell volume
mg
milligram
mITT
modified intent-to-treat
mL
milliliter
MoCA©
Montreal Cognitive Assessment
ms
millisecond
NIMH
National Institute of Mental Health
NINDS
National Institute of Neurological Disorders & Stroke
O
oxygen
PGIC
Patient Global Impression of Change
PK
pharmacokinetic
PPK
population pharmacokinetics
PR
PR interval - measured from the beginning of the P wave to the beginning of 
the QRS complex
PR
prothrombin time
QRS
QRS duration (complex) - a structure on the ECG that corresponds to the 
depolarization of the ventricles
QT
QT interval - 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
QTcF
Fridericia-corrected QT interval 
RBBB
right bundle branch block
RBC
red blood cell
SAE
serious adverse event 
SOP
Standard Operating Procedure
SSRI
selective serotonin reuptake inhibitor
TBil
total bilirubin
TBZ
tetrabenazine
TD
Tardive dyskinesia
tmax
time of maximum drug concentration


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Abbreviation
Definition
ULN
upper limit of normal
UPDRS
Unified Parkinson’s Disease Rating Scale
US
United States
VMAT
vesicular monoamine transporter 


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1.
INTRODUCTION
1.1.
Disease Background
Tardive dyskinesia (TD) is a serious delayed-onset hyperkinetic movement disorder that appears 
as a complication of prolonged use of dopamine receptor antagonists (DRAs) including 
antipsychotic agents (neuroleptics) and the prokinetic agent, metoclopramide. The clinical 
manifestations of TD include chorea, athetosis, dystonia, akathisia, stereotyped behaviors and 
occasionally, tremor. Although early identification of TD in younger outpatients can be 
associated with higher rates of recovery (50% to 90%; [Tarsy, 1983; Tarsy & Baldessarini, 
1984]), TD is often irreversible, and can be significantly disabling and distressing to both 
patients and their family members and caregivers. 
Although the pathophysiology of TD is not fully understood, the prevailing theory centers 
around the concept of dopamine-receptor hypersensitivity (Teo, Edwards, & Bhatia, 2012). 
Based on this theory, the chronic use of dopamine antagonists results in a gradual 
hypersensitization of dopamine receptors, leading to the clinical features of TD. Supporting this 
concept is the observation that increasing the dose of an antipsychotic drug temporarily 
suppresses the symptoms of TD, while withdrawing the antipsychotic or administering a 
dopamine agonist exacerbates the dyskinesia in the short term. In addition, the imbalance 
between D1 and D2 receptor-mediated effects in the basal ganglia has also been considered to be 
a contributing factor (Gerlach & Hansen, 1992; Trugman, 1998). The first-generation (typical) 
antipsychotics (i.e., haloperidol, chlorpromazine, fluphenazine, etc.), which are causally 
associated with TD, are potent inhibitors of the D2 receptors, resulting in excessive D1-mediated 
effects and high frequencies of extrapyramidal syndromes. Additionally, the development of TD 
has also been attributed to the possible destruction of striatal interneurons from excitotoxicity 
and oxidative stress, or more specifically, to the loss of the subpopulation of striatal GABAergic
interneurons (Teo, et al., 2012).
The prevalence of TD can be difficult to establish, as the antipsychotic medications are known to 
cause, as well as mask, the symptoms of TD due to their hypokinetic effects (Tardive Dyskinesia 
Task Force, 1980; Tarsy & Baldessarini, 2006). Thus, prevalence rates in TD are frequently 
underestimated (Tarsy & Baldessarini, 2006). Nevertheless, the risk is substantial among patients 
exposed to DRBAs with rates ranging from 16% to 43% according to several studies reported 
between 1996 and 2002 (Tarsy & Baldessarini, 2006). The severity of TD often varies with 
behavioral and emotional arousal, and differences in population age, gender, treatment duration, 
and type and dose of antipsychotic medication can further confound the diagnosis (Kane, 2004; 
Lohr, 2008). Among outpatient schizophrenia patients treated with DRBAs, the prevalence of 
tardive syndromes is also high, and has been estimated to be 30% (American Psychiatric 
Association., 2000; Chouinard, Annable, Ross-Chouinard, & Mercier, 1988; Correll, Rummel-
Kluge, Corves, Kane, & Leucht, 2009). 
With the advent of the second-generation (atypical) antipsychotics (i.e., aripiprazole, clozapine, 
olanzapine, respiradone, quetiapine, and ziprasidone), which carry a lower risk for 
extrapyramidal syndromes, it has been suggested that the prevalence of TD should decline over 
time. However, a meta-analysis by Leucht and colleagues of 31 controlled studies comparing 


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older neuroleptics to newer, atypical agents found that only clozapine was associated with a 
significantly lower risk of acute extrapyramidal syndromes (Leucht, Wahlbeck, Hamann, & 
Kissling, 2003). Additionally, recent trials, including the Clinical Antipsychotic Trials of 
Intervention Effectiveness (CATIE) and the Cost Utility of the Latest Antipsychotic Drugs in 
Schizophrenia Study (CUTLASS1), have not found significant differences in Abnormal 
Involuntary Movement Scale (AIMS) scores between patients taking first- or second-generation 
antipsychotics (Lieberman, 2005; Jones, 2006).
There are currently no approved medical therapies for the treatment of TD. Prevention and early 
detection are critical in the management of this disorder. Avoidance of treatment with 
antipsychotic medications and metoclopramide is the only definitive method of prevention. 
However, avoidance of antipsychotic therapies in patients with schizophrenia and other chronic 
psychoses is often not feasible. Evidence to support the withdrawal of, or switch from a typical 
to atypical DRBA in a patient who develops TD is limited at this time and must be weighed 
carefully against the risk of disease relapse and/or worsening of psychotic symptoms 
(Bhidayasiri et al., 2013). 
Numerous pharmacologic therapies for TD have been evaluated, but few have shown more than 
modest clinical benefits in practice. According to recent evidence-based recommendations from 
the American Academy of Neurology (Bhidayasiri, et al., 2013), data do not support the use of 
diltiazem, galantamine, or eicosapentaenoic acid as treatments for TD. In addition, data are 
insufficient to either support or refute the use of several other agents previously studied in TD, 
including acetazolamide, bromocriptine, baclofen, vitamins/antioxidants (vitamins E, B6, 
thiamine, melatonin, or selegiline), most first or second-generation antipsychotic medications, 
levetiracetam, buspirone, and nifedipine. At the present time, only clonazepam, ginkgo biloba, 
amantadine, and tetrabenazine may be considered as treatment options for TD based on available 
data. As such, the medical need for developing safe and effective novel therapies in TD remains 
high. 
1.2.
Tetrabenazine
Tetrabenazine is approved in the United States (US), Canada and several European Union (EU) 
countries as a therapy for the treatment of chorea associated with Huntington’s disease (HD). 
Tetrabenazine has also been used for several decades for the treatment of a variety of other 
hyperkinetic movement disorders including TD (Jankovic & Clarence-Smith, 2011; Kenney, 
Hunter, & Jankovic, 2007). In a single-blind study evaluating the efficacy and safety of 
tetrabenazine using a randomized videotape protocol pre- and post-treatment, significant 
reductions were observed post-treatment (mean dose 57.9 mg/d) in both the patient AIMS self 
rating and the AIMS motor subset evaluated by blinded videotape reviewers (Ondo, Hanna, & 
Jankovic, 1999). The patient AIMS self-rating scores improved 60.4% from a mean of 9.1 to 
3.6 (p<0.001), while the AIMS motor subset scores improved 54.2% from 17.9 to 8.2 (p<0.001). 
In this study, tetrabenazine was well tolerated and all patients continued to the drug post-study. 
Overall, data on the treatment of TD with tetrabenazine in more than 400 patients have been 
reported across published studies (Jankovic & Clarence-Smith, 2011). On the basis of this 
clinical experience, several treatment algorithms have reported that tetrabenazine is effective for 
the treatment of TD, including the American Academy of Neurology evidence-based guidelines 


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in 2013 indicating that tetrabenazine may be considered in the treatment of tardive dyskinesia 
syndromes (Bhidayasiri, et al., 2013).
Tetrabenazine is rapidly and extensively converted in the liver by carbonyl reductase to alpha-
dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ). These metabolites are 
potent and selective inhibitors of vesicular monoamine transporter (VMAT)-2, resulting in 
reduced storage and release of presynaptic dopamine, and are responsible for mediating the in 
vivo efficacy of orally administered tetrabenazine.
Details on the previous experience with tetrabenazine can be found in the SD-809 Investigator’s 
Brochure (IB), which includes the tetrabenazine prescribing information for the treatment of 
chorea associated with HD.
1.2.1.
Limitations of the Current Commercial Product
Tetrabenazine (Xenazine®, Nitoman®) is an immediate-release formulation. While generally 
effective in treating chorea of HD and other hyperkinetic movement disorders, tetrabenazine has 
limitations including:

High peak concentrations of the active metabolites. Clinical experience in patients, and Phase 
1 data in healthy volunteers, indicate that important adverse events of tetrabenazine, such as 
somnolence, akathisia, and anxiety are often associated with peak concentration after dosing. 

Short half-lives of the active metabolites and the attendant requirement to dose the immediate 
release formulation frequently. The rapid decline in plasma concentrations may lead to loss 
of efficacy at the end of the dosing interval. The fluctuation in plasma concentration, as 
indicated by high peak concentrations and low trough concentrations, necessitates more 
frequent dosing. Therefore, many patients must take tetrabenazine three times a day due to 
the short half-lives of the active metabolites, α-HTBZ and β-HTBZ. A less frequent dosing 
schedule is preferred as it may improve medication compliance. 

The active metabolites α- and β-HTBZ are either primarily (α) or exclusively (β) metabolized 
by cytochrome P450 2D6 (CYP2D6). Polymorphisms in the CYP2D6 gene necessitate 
genotyping to prevent poor metabolizers from significantly greater exposure to the active 
drug moiety than extensive metabolizers. 
To address the limitations of tetrabenazine, Auspex has developed a deuterated form of 
tetrabenazine (referred to as deutetrabenazine or SD-809) which is eliminated more slowly than 
tetrabenazine. As outlined in Section 1.4 and the IB, SD-809 has been shown to reduce plasma 
fluctuation and dosing frequency and thus, has the potential to improve overall tolerability 
compared with tetrabenazine.
1.3.
Deuterium
Deuterium (D) is a naturally-occurring, non-radioactive stable isotope of hydrogen (H) which, 
due to the presence of a neutron, has twice the mass as H. Deuterium has a natural abundance of 
approximately 0.0156% of all H atoms (Baillie, 1981). The adult male body contains 
approximately 57% water (Guyton, 1991), the major source of H in the body (Chang, 2007). A 
70 kg male contains approximately 39,900 g of water of which 0.0156% or 6.22 g is D2O, 
yielding a naturally-occurring body content of 1.24 g of deuterium. 
Small molecule drugs have been developed in which carbon (C)-H bonds have been replaced 
with C-D bonds (Kushner, Baker, & Dunstall, 1999). The increased mass of deuterium in the 


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C-D bond in small molecule drugs requires more energy for cleavage by cytochrome P450
(CYP450) enzymes as compared to the corresponding C-H bond, a phenomenon known as the 
Deuterium Kinetic Isotope Effect (Baillie, 1981). Replacing H with D at a C-H bond in a 
molecule has the potential to attenuate its metabolism if that C-H bond is the site of rate-limiting 
cleavage by a CYP isozyme. By attenuating metabolism in this manner, area under the curve 
(AUC), maximum concentration (Cmax), and half-life may all be increased relative to the 
non-deuterated molecule (Kushner, et al., 1999).
The presence of D in the C-D bonds of small molecule drugs does not pose a unique safety risk. 
The C-D bond is more stable than the C-H bond and as such, D is not readily subject to exchange 
with H in H2O or in other organic materials (Kushner, et al., 1999). The shape and surface charge 
of small molecule drugs is defined by the electron cloud of the component atoms. The surface 
charge and spatial characteristics of deuterated drugs are thought to be biologically 
indistinguishable from their non-deuterated forms (Di Costanzo, Moulin, Haertlein, Meilleur, & 
Christianson, 2007; Fisher & Helliwell, 2008). As a consequence, deuterium-substituted small 
molecule drugs and their non-deuterated forms are not likely to be physiologically different in 
their binding to macromolecular structures such as receptors, transporters, enzymes, or ion 
channels. 
1.3.1.
Clinical Experience with Deuterium
A number of studies in healthy volunteers and patients have evaluated the effects of acute and 
long-term use of deuterated water (D2O). Acute exposures of to up to 23% D replacement in 
plasma were tolerated without reported adverse events (Blagojevic, Storr, & Allen, 1994). In 
several metabolic labeling studies, healthy subjects consumed daily doses of up to 9.8g D in the 
form of D2O for up to 4 to 9 weeks, treatments sufficient to maintain 1.0% to 2.0% D enrichment 
in body water. No adverse events were reported in these studies (Collins, Eng, Hoh, & 
Hellerstein, 2003; Kassis & Jones, 2008; Leitch & Jones, 1993; Neese et al., 2002; Strawford, 
Antelo, Christiansen, & Hellerstein, 2004). Deuterium has also been delivered to humans in the 
form of D-substituted glucose. Twenty-five subjects with human immunodeficiency virus (HIV) 
and 10 control subjects were infused intravenously over 48 hours with up to 200 g of [6,6-d2]-
glucose, an amount which corresponds to 4.4 g of deuterium. These infusions were not 
associated with adverse events (Hellerstein et al., 2003). 
1.4.
SD-809 (Deutetrabenazine)
SD-809 is a deuterated form of tetrabenazine in which the two O-linked methyl groups (CH3) of 
the tetrabenazine molecule have been replaced by two trideuteromethyl groups (CD3). The 
conversion of SD-809 and tetrabenazine to their respective active metabolites, α-HTBZ and 
β-HTBZ, proceeds similarly in human liver S9 fraction and in human liver microsomes. The CD3 
groups in SD-809, which are conserved in α-HTBZ and β-HTBZ, attenuate the metabolism of 
these active metabolites by CYP2D6 relative to the non-deuterated metabolites from 
tetrabenazine, leading to longer in vitro half-lives in human liver microsomes, human liver S9 
fraction, and in cells transfected with CYP2D6. These pharmacokinetic benefits have been 
confirmed in a clinical setting and enable less frequent dosing and reduced the plasma fluctuation 
of the active metabolites. Furthermore, the attenuated metabolism achieved through deuteration 
reduces the impact of CYP2D6 genotype on exposure as compared to tetrabenazine with the 
potential to simplify dosing.


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The safety and pharmacokinetics of oral SD-809 have been evaluated in five Phase 1 studies in 
healthy adult volunteers. Additionally, two Phase 3 studies in adult patients with chorea 
associated with HD and one Phase 1b study in adolescent patients with tics associated with 
Tourette syndrome have been completed.
Single doses of SD-809 have been administered to 132 subjects at doses ranging from 7.5 to 
25 mg, either alone or in conjunction with CYP2D6 inhibition. Multiple dose regimens of the 
tablet formulation have also been administered to 24 of those subjects for up to 5 days (at doses 
up to 22.5 mg twice daily [BID] for 3 days). 
For all studies, plasma concentrations of parent drug were low and sporadic because of the rapid 
and extensive hepatic metabolism of SD-809 to the active metabolites d6-αHTBZ and 
d6-β-HTBZ. Peak plasma concentrations of the active moieties d6-α-HTBZ and d6-β-HTBZ were 
reached within 3 to 4 hours for the tablet formulation without a comparable loss of exposure. In 
all studies where tetrabenazine was included as a control arm, deuteration was shown to 
significantly prolong the half-lives of both α - and β-HTBZ, resulting in an increase in exposure 
(~130% increase) for both active metabolites at comparable doses. Based on the 
pharmacokinetics over a dose range of 7.5 to 22.5 mg SD-809, it is estimated that a 6-mg dose of 
SD-809 will provide an exposure (AUC(inf)) comparable to 12.5 mg of tetrabenazine. Inhibition 
of CYP2D6 metabolism by paroxetine administration led to a 3-fold increase in bioavailability of 
d6-(α+β)-HTBZ.
In the Phase 1 studies summarized above, no serious adverse events were reported and all 
adverse events were mild to moderate in intensity. Commonly reported adverse events included 
headache, somnolence, nausea, dizziness and vessel puncture reaction. 
Additional information on the study results may be found in the SD-809 Investigator’s Brochure. 


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2.
STUDY OBJECTIVES
The objectives of this study are: 

Evaluate the safety and tolerability of long-term maintenance therapy with SD-809

Evaluate the efficacy of long-term maintenance therapy of SD-809 to reduce the severity 
of abnormal involuntary movements of TD

Evaluate the persistence of the therapeutic effect of SD-809


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3.
INVESTIGATIONAL PLAN
This is an open-label, single-arm study designed to evaluate the long-term safety and tolerability 
of SD-809 for the treatment of subjects with moderate to severe drug-induced TD. 
Approximately 330 subjects who have successfully completed a parent study (Study SD-809-C-
18, Study SD-809-C-23, or any other SD-809 study for treatment of moderate to severe TD) will 
be enrolled. The study will be conducted at approximately 80 centers in the U.S., Europe, and 
possibly other regions. The study is divided into different parts: Part A and Part B for all 
countries and an additional Part C for the EU countries. These parts include a Screening Period 
(Part A), a Titration Period (Part A), a Long-Term Treatment Period (Part A), a Double-Blind,
Randomized Withdrawal Period (Part B), treatment after completion of the Randomized 
Withdrawal Period (Part B), a continued treatment period (Part C), and a Post-Treatment Safety 
Follow-up Period (Part A, Part B, and Part C).
3.1.
Study Design
This is an open-label; single-arm study in which subjects with moderate to severe drug-induced 
TD who have successfully completed a parent study will be invited to participate. Successful 
completion of a parent study is defined as (1) study participation through Week 13; (2) the 
subject has generally been compliant with study drug and procedures, in the opinion of the 
investigator; and (3) the subject has no ongoing adverse events that are serious (serious adverse 
events)c, severe in intensity, or expected to interfere with their participation in this study. 
Informed consent/assent (Part A) will be obtained before any study procedures are performed. 
Subjects may have informed consent/assent obtained up to 30 days in advance of subject’s parent 
study Week 13 Visit/TD-Long Term Safety (LTS) Baseline Visit. Subjects who meet the 
selection criteria will be eligible to participate. 
Informed consent/assent for Part B will be obtained after Amendment 06 implementation and 
before any study procedures related to Part B are performed. 
Informed consent/assent for Part C will be obtained after Amendment 07 implementation and 
before any study procedures related to Part C are performed. Subjects who do not sign the 
informed consent/assent for Part C will complete the study at Part B Follow-up Call. 
Subjects who have successfully completed a parent study may be eligible to rollover directly into
this study after they complete a 1-week washout period and the Week 13 evaluation of the parent 
study. To reduce subject burden, after obtaining informed consent/assent, some data collected in 
the parent study will be used in the SD-809-C-20 study and will provide some of the baseline 
data for SD-809-C-20 (see Schedule of Events). In addition to assessments completed for the 
parent study Week 13 visit, evaluations required as part of the SD-809-C-20 study will be 
completed on the same day as the Week 13 visit.
                                                
c See Section 7 for evaluation of AEs with regard to severity, relationship to study drug, and definition of SAE.


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Part A:
Titration Period (up to 6 weeks): As all subjects will have discontinued study drug (SD-809 or 
placebo) for 1 week at completion of the parent study, they will undergo titration on SD-809 in 
this study. During titration, the Investigator, in consultation with the subject (and caregiver, if 
appropriate), will determine when an adequate level of dyskinesia control has been achieved. 
The dose of SD-809 should be adjusted (upward or downward) once per week, in increments of 
6 mg per day, until there is adequate control of dyskinesia, the subject experiences a 
protocol-defined clinically significant adverse event (defined as related to study drug and either: 
a) moderate or severe in intensity or b) meeting the criteria for an serious adverse event), or the 
maximal allowable dose is reached. If a subject experiences a clinically significant adverse event 
attributable to SD-809, the Investigator will determine if a dose reduction, dose suspension, or 
withdrawal from the study is necessary. Subjects will have a telephone contact at Week 1 and a 
clinic visit at Week 2 to evaluate safety and establish a dose of study drug that adequately 
controls dyskinesia and is well tolerated. Although subjects will enter the Long-Term 
Treatment Period after Week 2, titration to optimize dose should occur through Week 6. 
Long-Term Treatment Period (Week 3 until the last dose in Part A): During the Long-Term 
Treatment Period, subjects will continue titration through Week 6. During titration, all subjects 
will be contacted by telephone at Week 3 (the first week of the Long-Term Treatment Period) 
and Week 5 and will return to the clinic at Week 4 and Week 6 for evaluation of safety and 
dyskinesia control. Subjects who have not achieved a stable dose by the Week 6 visit may have 
unscheduled visits or telephone contacts to further adjust their dose upward or downward. Site 
interactions for dose adjustment should alternate between telephone contacts and clinic visits. 
During the remainder of the Long-Term Treatment Period, subjects will return to the clinic for 
evaluation of safety and dyskinesia once every 13 weeks, starting at Week 15 and ending at the 
last dose in Part A (completion of Part A=Week 158 or beginning of Part B after Amendment 06 
implementation). During long-term treatment, further dose adjustments of SD-809 may be made, 
if necessary, but not more often than weekly and in increments of 6 mg per day. In the case of 
the addition of a strong CYP2D6 inhibitor (i.e., paroxetine, fluoxetine, and bupropion), a greater 
dose reduction may be required. Dose reductions in this context should be reviewed with the 
Medical Monitor. Dose adjustments should be based on all available information, including the 
subject’s and caregiver’s reports of adverse events and dyskinesia control, information from 
rating scales, and all safety evaluations. If warranted, study sites are encouraged to conduct 
periodic phone calls with the subjects to ensure adherence to the treatment regimen and retention 
of unused drug containers.
Subjects who have been on a stable dose of SD-809 and any concomitant DRA for a minimum of 
4 weeks will be invited to participate in the Randomized Withdrawal Period (Part B) at the next 
routine visit at the site after approvals from IRB/Ethics Committee and as required by country 
regulations. If the subject chooses to participate in Part B, then participation in Part A will end.
Subjects who decline to participate in Part B will continue in Part A until Week 158. Subjects 
who decline participation in Part B will be given an ongoing option to participate at subsequent 
study visits.
Part B:
Part B will consist of a double-blind; randomized withdrawal period; treatment with SD-809; and 
post-treatment safety follow-up. The Randomized Withdrawal Period will be 1 week (+3 days 


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maximum) in duration and will consist of 2 visits, the Pre-withdrawal Visit and the 
Post-withdrawal Visit. After the Randomized Withdrawal Period, the subjects will resume 
treatment with SD-809 on the prior established dose for an additional 12 weeks until end of 
treatment (EOT). A follow-up telephone call will occur 4 weeks after EOT.
At the beginning of the Randomized Withdrawal Period, subjects will be randomized in a 
blinded fashion to either SD-809 (current dose) or placebo in a 1:1 ratio stratified by concomitant 
DRA usage. Up to 194 subjects (active subjects as of the approval date of Amendment 06) will 
be randomized (SD-809 or placebo). Subjects will be required to sign a written informed 
consent. 
Subjects will need to be on a stable dose of SD-809 and any concomitant DRA for a minimum of 
4 weeks before starting the Randomized Withdrawal Period. 
Subjects will be scheduled to return 1 week (+3 days maximum) after the Pre-withdrawal Visit 
of the Randomized Withdrawal Period for efficacy and safety assessments.
At the end of this period, subjects will continue treatment with SD-809 at the previous dose 
administered before the Randomized Withdrawal Period (last dose in Part A). Treatment with 
SD-809 will continue for 12 weeks until the EOT visit. 
Video ratings of the AIMS will occur at the Pre-withdrawal Visit, the Post-withdrawal Visit, and 
the EOT/early termination (ET) visit.
Part C:
For the EU countries, the study will include a reduced burden safety assessments period (Part C) 
of 52 weeks for subjects willing to continue in the study and who have completed Part B.
Subjects will continue treatment with SD-809 at the current dose administered during the 12-
week open-label period of Part B. Subjects will be scheduled to return every 13 weeks (±1 week)
until EOT. A follow-up clinic visit will occur 1 week after ET and a follow-up telephone call 
will occur 4 weeks after EOT/ET.
Post-Treatment Safety Follow-up:
Part A:
Subjects who do not participate in Part B will continue in Part A, discontinue study drug at the 
Week 158 visit, and return for their final clinic visit at Week 159 for evaluation of safety, 
dyskinesia control, and motor function. During this 1-week follow-up period, subjects should 
continue to not take prohibited concomitant medications. Subjects will also have a follow-up 
telephone contact at Week 162, 4 weeks after their last dose of study drug, to evaluate adverse 
events and concomitant medication usage.
Subjects who discontinue study drug in Part A will complete an ET visit; a follow-up clinic visit 
1 week later to evaluate safety, dyskinesia, and motor function; and a follow-up telephone 
contact 4 weeks after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since ET.
Part B:
Subjects who complete the Randomized Withdrawal Period and subsequent 12 weeks of 
treatment will complete an EOT visit and a follow-up telephone contact 4 weeks after the last 
dose of study drug to evaluate the adverse events and concomitant medication use since EOT.
Subjects who discontinue study drug in Part B will complete an ET visit; a follow-up clinic visit 
1 week later to evaluate safety, dyskinesia, and motor function; and a follow-up telephone 
contact 4 weeks after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since ET.


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Part C:
Subjects who complete the 52 weeks of reduced burden safety assessments period will complete 
a Part C EOT visit and a follow-up telephone contact 4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant medication use since Part C EOT. Subjects who 
discontinue study drug in Part C will complete an ET visit, a follow-up clinic visit 1 week later 
for safety evaluation, and a follow-up telephone contact 4 weeks after the last dose of study drug 
to evaluate the adverse events and concomitant medication use since ET.
3.2.
Rationale for Study Design
The study is designed to evaluate the long-term safety and tolerability of SD-809 in subjects with 
moderate to severe dyskinesia associated with TD (Part A) and the persistence or maintenance of 
the therapeutic effect of SD-809 in subjects with TD (Part B). Subjects who successfully 
complete a placebo-controlled efficacy study (Study SD-809-C-18, Study SD-809-C-23, or any 
other controlled study of SD-809 as treatment for moderate to severe TD) will be eligible to 
enroll. An extension of the study (Part C) with reduced burden safety assessments is added to 
provide continued therapy for subjects in the EU countries. Part C will be offered only to 
subjects who completed Part B.
All subjects will have discontinued study drug (SD-809 or placebo) for at least 1 week and 
consequently will begin dosing at 6 mg BID and titrate to their optimal dose for up to 6 weeks. 
Although the time to reach an optimal dose will differ among subjects, it is expected that 
subjects will have reached a pharmacologically active dose by 2 weeks. Accordingly, the 
long-term period of the study will be deemed to have started after 2 weeks of treatment even 
though dose adjustment may continue after this point.
The SD-809 dose should be adjusted to identify a dose that reduces dyskinesia and is well 
tolerated. In addition to the assessments of dyskinesia control and tolerability by the subject, 
caregiver, and study staff, safety evaluations that target adverse events observed in the drug class 
(e.g., akathisia) will be employed and considered in the dose-adjustment decision. In this 
manner, the daily dose of study drug for treating dyskinesia is determined individually for each 
subject. Once adequate control of dyskinesia has been achieved, the dose of study drug 
should not be increased further. In general, subjects will continue the dose established during 
titration into the long-term treatment period, but dose adjustments (upward or downward) are 
permitted so long as they do not occur more often than once per week.
The present investigation is an open-label safety study with a nested, randomized, double-blind, 
1-week withdrawal period of SD-809. The study will enroll subjects with TD who were 
previously exposed to either SD-809 or placebo in a parent study.
The US prescribing information for tetrabenazine indicates that CYP2D6 genotyping should be 
performed at doses higher than 50 mg, although genotyping is often not performed in clinical 
practice as the drug is titrated. In the present study, CYP2D6 genotyping will have been 
performed in a blinded manner in the parent study to allow evaluation of the effect of phenotype 
on safety parameters at the conclusion of the study.
3.3.
Rationale for Dose Selection
As with tetrabenazine, SD-809 treatment will be individualized; therefore, fixed doses will not 
be evaluated in the study. The starting dose of 6 mg BID of SD-809 provides an AUC of total 
(α+β)-HTBZ that is comparable to a starting dose of 12.5 mg BID of tetrabenazine, but with a 
lower peak concentration and reduced plasma fluctuation. Although not approved for the 


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treatment of TD, there is a substantial body of clinical experience with tetrabenazine in this 
population. Table 1 provides a summary of 10 published reports describing the use of 
tetrabenazine in TD. 


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Table 1:
Published Reports Describing the Use of Tetrabenazine in Patients with TD
Publication 
Study 
design
Patients 
(N)
Dose range 
(mg/d)
Treatment 
duration
Responders
Comments
Brandrup, 
1961
CR
4
3 pts: 75;
1 pt: ≥150
1.5-3.5 mo
4/4
Marked response in 3/4 patients; 1/4 
had somnolence 
MacCullum, 
1970
CR
2
50
10 mo
2/2
Complete resolution of symptoms; no 
AEs reported
Godwin-
Austen & 
Clark, 1971
OL;
X
6
100
1 wk
5/6
3/6 had complete resolution of 
symptoms; 2/6 had mild 
improvement; somnolence reported 
in ‘most’ patients
Kazamatsuri, 
Chien, & 
Cole, 1972
OL
24
Range: 100-
150 
4 wk
17/24
13/24 had ≥50% reduction in 
symptoms; 2/24 withdrew for AEs at 
doses ≥100 mg/day 
Jankovic & 
Orman, 1988
OL
44
Mean: 97.4 
(Range: 
25-200)
21 mo 
(mean)
Mean Score: 
2.1*
*Improvement rated 1-5: (1=marked, 
2=moderate, 3=fair, 4=poor/none, 
5=worse); AEs (N=217): 
parkinsonism > sedation > depression 
Stacy, 
Cardoso, & 
Jankovic, 
1993
R
78
Not 
Reported
62 mo 
(mean)
Mean Score: 
3.5†
†Improvement rated 1-4 (1=mild; 
2=mod,; 3=mod with function 
benefit; 4=marked) 
Jankovic & 
Beach, 1997
R
94
Mean: 97 
(Range: 
25-400)
35 mo 
(mean)
87/94
Responders had marked or moderate 
improvement.
Most common AEs: somnolence > 
parkinsonism > depression > 
insomnia 
Ondo, et al., 
1999
OL
20
Mean: 57.9
(Range: 
25-150)
20 wk 
(mean)
Mean reduction 
of 9.7 points in 
AIMS motor 
score
1/20 patients withdrew for 
somnolence (somnolence in 5/20,
parkinsonism in 5/20) 
Jankovic, 
Hunter, Mejia, 
& Vuong, 
2004
R
139
Mean: 56.6 
(Range: 
6.25–200)
30 mo 
(mean)
116/139
Had marked or moderate 
improvement
Parkinsonism (27.5%), drowsiness or 
fatigue (24.2%), akathisia (10.1%) 
Paleacu et al., 
2004
R
15
Range: 
25-150
22 mo 
(mean)
10/15+
+7/15 with moderate/marked 
improvement 
Abbreviations: AE, adverse event; AIMS, Abnormal Involuntary Movement Scale; CR, case report; mo, month; 
OL, open-label study; pt, patient; R, retrospective review; X, crossover study; wk, week.
Treatment durations of over 5 years (Stacy, et al., 1993) and daily doses of up to 400 mg/day 
(Jankovic & Beach, 1997) have been reported with tetrabenazine. Starting doses varied across 
studies, but several authors reported initiating treatment at 12.5 mg BID and titrating based on 
symptom control and tolerability (Jankovic & Beach, 1997; Ondo, et al., 1999; Paleacu, et al., 
2004). In addition, a mean dose of approximately 100 mg per day was frequently reported in 
these studies and was associated with a high response rate and an acceptable adverse event 


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profile. The frequencies and types of adverse events observed in the TD population have 
generally been similar to those described in the HD population. 
Based on the available published literature for tetrabenazine, and the comparability of 6 mg of 
SD-809 with 12.5 mg of tetrabenazine with regard to plasma AUCs, initiating treatment with 
SD-809 at 6 mg BID and titrating to a total daily dose of 48 mg per day (comparable in AUC to 
100 mg of tetrabenazine) is considered to be appropriate for the present study. 
In the present study, the dose level of SD-809 treatment will be evaluated on a weekly basis 
during the dose adjustment or Titration Period, based on assessments of dyskinesia control and 
adverse events, in order to determine if dose adjustment is needed. This approach is consistent 
with the tetrabenazine prescribing information for the treatment of chorea associated with HD. 
Weekly dose adjustments for insufficient dyskinesia control should occur in increments of 6-mg 
changes in the total daily dose. Dose reductions greater than 6 mg should be reviewed with the 
Medical Monitor (see Section 5.2.4). 
In a population pharmacokinetics (PPK) analysis from Study SD-809-C-18, for patients ≥100 kg 
with functional CYP2D6 status, 60 mg/day given in 2 divided doses resulted in similar total 
(α+β)-HTBZ to that in healthy subjects administered 24 mg BID. For lower body weight patients 
(i.e., those <100 kg) with functional CYP2D6 status, a 48 mg/day dose was identified as 
resulting in similar total (α+β)-HTBZ exposure compared to healthy subjects administered 24 mg 
BID. Based on these simulations, dosing in the current study will be based on baseline body 
weight (<100 kg and ≥100 kg) and CYP2D6 impairment status at baseline (i.e., impaired 
[receiving a strong CYP2D6 inhibitor or is a CYP2D6 poor metabolizer] or not impaired) (see 
Appendix 13 for details).
For subjects with a body weight less than 100 kg, the maximum total daily dose of SD-809 is 
48 mg/day (24 mg BID), unless the subject is receiving a strong CYP2D6 inhibitor (e.g., 
paroxetine; see Appendix 13), in which case the maximum total daily dose is 36 mg/day. For 
subjects with a body weight of 100 kg or more, the maximum total daily dose of SD-809 is 
60 mg/day (30 mg BID), unless the subject is on a strong CYP2D6 inhibitor (paroxetine, 
fluoxetine, or bupropion), in which case the maximum daily dose is 42 mg/day.


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4.
STUDY POPULATION
4.1.
Population Characteristics
Male and female adult subjects with TD who have successfully completed the parent efficacy 
study (Study SD-809-C-18, Study SD-809-C-23, or any other controlled study of SD-809 for 
treatment of moderate to severe TD) and meet eligibility criteria will be enrolled.
4.2.
Inclusion Criteria
1. Subject is at least 18 years of age at Screening.
2. Subject has successfully completedd Study SD-809-C-18, Study SD-809-C-23, or any other 
controlled study of SD-809 for treatment of moderate to severe TD.
3. Subject has a history of using a DRA for at least 3 months (or 1 month in subjects 60 years of 
age and older). See Appendix 15.
4. Subject has a clinical diagnosis of TD and has had symptoms for at least 3 months prior to 
Screening.
5. For subjects with underlying psychiatric illness:

Subject is psychiatrically stable and has had no change in psychoactive medications 
(including, but not limited to, neuroleptics, benzodiazepines, anticonvulsants, and mood 
stabilizers) for ≥30 days before Screening (45 days for antidepressants).

Subjects on long acting (depot) medications have been on stable therapy (dose, 
frequency) ≥3 months before Screening. 

Subject has a health care provider who is aware of the subject’s participation in the trial, 
and does not anticipate any changes in the subject’s treatment regimen (drug, dose, 
frequency) in the next 3 months. 
6. Subject has a history of being compliant with prescribed medications.
7. Subject is able to swallow study drug whole.
8. Subject has provided written, informed consent or, if subject lacks the capacity to provide 
informed consent, a legally authorized representative (LAR) has provided written informed 
consent and the subject has provided assent.
9. In the opinion of the Investigator, the subject lives in a stable environment and has adequate 
supervision when necessary to comply with all study procedures, attend all study visits, and 
safely participate in the trial.
10. Subject has sufficient reading skills to comprehend the subject-completed rating scales.
11. Female subjects of childbearing potentiale agree to use one of the following acceptable 
methods of contraception from Screening through study completion if sexually active:

IUD or intrauterine system in place for at least 3 months prior to screening;
                                                
d Successful completion is defined as (1) study participation through Week 13, (2) the subject has generally been compliant with 
study drug and procedures, in the opinion of the investigator, and (3) the subject has no ongoing AEs that are serious or severe in 
intensity or are expected to interfere with safety evaluations in this study.
e Non-childbearing potential for females is defined as postmenopausal (amenorrheic for at least 1 year and serum 
follicle stimulating hormone (FSH) level consistent with postmenopausal status), or a documented hysterectomy; 
bilateral oophorectomy; or bilateral tubal ligation >6 months prior to study initiation. 


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
Subject or partner using barrier method (e.g., condom, diaphragm, or cervical cap) with 
spermicide from Screening through study completion;

Partner has a documented vasectomy >6 months prior to enrollment;

Stable hormonal contraception (with approved oral, transdermal, or depot regimen) for at 
least 3 months prior to Screening.
4.3.
Exclusion Criteria
Subjects meeting any of the following criteria will be excluded:
1. Subject has received tetrabenazine within 7 days of Baseline.
2. Subject has received any of the following medications within 30 days of Baseline: 

Reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of Baseline), 
and medications with strong anticholinergic activity (trihexyphenidyl, benztropine, 
orphenadrine, procyclidine, and biperiden)

Metoclopramide, promethazine, and prochlorperazine

Stimulants (i.e., methylphenidate, amphetamine/dextroamphetamine, lisdexamphetamine, 
etc.), or monoamine oxidase inhibitors (MAOIs)

Levodopa or dopamine agonists
3. Subject has a neurological condition other than TD that may interfere with assessing the 
severity of dyskinesias.
4. Subject has a serious untreated or undertreated psychiatric illness at Baseline. 
5. Subject has active suicidal ideation at Baseline.
6. Subject has a history of any of the following within 6 months of Baseline:

Previous intent to act on suicidal ideation with a specific plan, irrespective of level of 
ambivalence at the time of suicidal thought

Previous preparatory acts to commit suicide or suicidal behavior

A previous actual, interrupted, or aborted suicide attempt
7. Subject has a score ≥11 on the depression subscale of the Hospital Anxiety and Depression 
Scale (HADS) at Baseline.
8. Subject is developmentally disabled or has evidence of dementia.
9. Subject has an unstable or serious medical illness at Baseline.
10. Subject has history (within 3 months) or presence of violent behavior.
11. Subject has a Fridericia-corrected QT interval (QTcF) value >450 ms (males) or >460 ms 
(females), or >480 ms (with right bundle branch block [RBBB]) on 12-lead 
electrocardiogram (ECG) at Baseline.
12. Subject has evidence of hepatic impairment at Screening of the parent study, as indicated by: 

Aspartate transaminase (AST) or alanine aminotransferase (ALT) >2.5 times the upper 
limit of normal (ULN)

Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the ULN
o
Note: Subjects with Gilbert’s Syndrome are eligible to participate if approved by the 
Medical Monitor. 
o
Note: Subjects with abnormalities in two or more of these analytes (AST, ALT, ALP, 
TBil) must be approved by the Medical Monitor to be enrolled. 

Prothrombin time >17 seconds (i.e., prothrombin time prolonged >4 seconds over the 
ULN

Positive hepatitis B surface antigen (HBsAg)


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13. Subject has evidence of significant renal impairment at Screening of the parent study, 
indicated by a creatinine clearance <50 mL/min, as estimated by the Cockroft-Gault formula.
14. Subject has known allergy to tetrabenazine or to any of the components of study drug.
15. Subject has participated in an investigational drug or device trial (other than Study 
SD-809-C-18, Study SD-809-C-23, or any other eligible SD-809 parent study) and received 
study drug within 30 days (or 5 drug half-lives) of Baseline, whichever is longer.
16. Subject is pregnant or breastfeeding at Baseline.
17. Subject acknowledges present use of illicit drugs at Screening.
18. Subject has a history of alcohol or substance abuse in the previous 12 months, as defined in 
the DSM-V, or subject is unable to refrain from substance abuse throughout the study.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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5.
STUDY TREATMENT
The study drug to be used in this trial is a tablet formulation of SD-809. Five dosage strengths of 
SD-809 will be available for use: 6, 9, 12, 15, and 18 mg tablets. The actual dose of SD-809 
received by the subject will be determined by the clinical pack supplied. The initial drug supply 
will be provided to the subject in the clinic at the Baseline visit.
5.1.
Study Drug
5.1.1.
SD-809
The study drug is a matrix formulation in the form of a tablet to be administered with food.
Study drug is coated with a polymer coating to aid in swallowing. SD-809 tablets have been 
manufactured according to current Good Manufacturing Practices regulations.
During titration/dose adjustment in Part A, SD-809 tablets will be labeled according to 
applicable regulatory guidelines and supplied in weekly blister packs as 6, 9, 12, 15, and/or 
18 mg tablets. Each blister pack will contain a sufficient supply of study drug until the next 
specified visit, plus overage to account for potential delays in study visits or evaluations or 
receipt of their supplies. During long-term treatment, SD-809 will be supplied in 30-count 
bottles and labeled according to applicable regulatory guidelines. During the 1-week 
double-blinded Randomized Withdrawal Period, SD-809 will be supplied in 20-count bottles and 
labeled according to the applicable regulatory guidelines.
During Part C, SD-809 will be supplied in 30-count bottles. 
Complete details regarding SD-809 supply, dispensing, and ordering will be provided in the 
study Operations Manual.
SD-809 tablets must be stored in a secure area with access limited to authorized staff, protected 
from light at controlled room temperature, 15°C to 25°C (59°F to 77°F).
5.1.2.
Placebo (Part B: Double-Blind, Randomized Withdrawal Period Only)
Placebo tablets are identical in appearance to the SD-809 and contain the same inactive 
ingredients as SD-809.
5.2.
Treatment Regimen
5.2.1.
General Guidelines
The following general guidance applies to treatment regimens for all subjects in the study:

All treatment regimens will be administered BID with meals, approximately 10 hours apart 
during the day.

The starting dose will be SD-809 12 mg/day (6 mg BID) regardless of previous treatment in 
the parent study. Prior treatment assignment from the parent study will remain blinded.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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52

For subjects with body weight less than100 kg, the maximum total daily dose of SD-809 is 
48 mg/day (24 mg BID), unless the subject is on a strong CYP2D6 inhibitor (paroxetine, 
fluoxetine, or bupropion), in which case the maximum daily dose is 36 mg/day. For subjects 
with body weight 100 kg or more, the maximum total daily dose of SD-809 is 60 mg/day 
(30 mg BID), unless the subject is on a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or 
bupropion), in which case the maximum daily dose is 42 mg/day.
Table 2:
Maximum Daily Dose Level During the Maintenance Period
Body weight (kg)*
Target dose (schedule)
Not CYP2D6 impaired
On strong CYP2D6 inhibitor
<100 kg
48 mg/day (24 mg BID)
36 mg/day (18 mg BID)
≥100 kg
60 mg/day (30 mg BID)
42 mg/day (21 mg BID)
*Body weight at the time of dose increase >48 mg/day

Daily doses will be administered according to instructions provided in the Pharmacy Manual.

During the titration period, the dose of SD-809 should be increased on a weekly basis in 
increments of 6 mg of the total daily dose until:
o
There is adequate control of dyskinesia;
o
The subject experiences a protocol-defined clinically significant adverse event 
(defined as related to study drug and either a) moderate or severe in intensity or 
b) meets the criteria for a serious adverse event); or 
o
The maximal allowable dose is reached. 

Study drug will be titrated over the initial 6 weeks of therapy, if necessary, to identify a dose 
that provides adequate dyskinesia control and is well tolerated. Changes in dose should not 
be made more often than once per week unless the subject is experiencing an intolerable 
adverse event.

If a subject experiences a clinically significant adverse event attributable to SD-809, the 
Investigator will determine if a dose reduction or dose suspension, or withdrawal from the 
study is necessary.
Once adequate control of dyskinesia has been achieved, the dose of study drug should not 
be increased further.
5.2.2.
Dosing in Long-Term Treatment (Week 3 Until the Last Dose in Part A)
Initially during the Long-Term Treatment Period, a well-tolerated dose of SD-809 that provides 
adequate dyskinesia control may not yet be established. Dose adjustments should continue 
during long-term treatment as specified in Section 5.2.1. Once a stable dose is achieved, SD-809 
should be dosed at the same level throughout the remaining Long-Term Treatment Period. If 
necessary, however, the dose may be adjusted further (upward or downward) to optimize 
dyskinesia control or minimize adverse events. In general, dose changes are limited to 6 mg of 
the total daily dose (see Section 5.2.4). However, such changes in dose should not occur more 
frequently than once per week.
Once subjects are on a stable dose of SD-809, drug will be provided to study subjects in 30-count 
bottles until the next specified visit. Each order will contain a sufficient supply of study drug 
until the next specified visit, plus overage to account for potential delays in study visits or 
evaluations or receipt of their supplies.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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53
5.2.3.
Dosing in the Double-Blind, Randomized Withdrawal Period
Subjects in the Randomized Withdrawal Period will continue to receive their current dose of 
SD-809 or will receive matching placebo. At the end of the Randomized Withdrawal Period, 
subjects will continue with, or return to, the same dose of SD-809 taken before the Randomized 
Withdrawal Period (last dose in Part A), beginning the day after the Post-withdrawal Visit and 
continuing for 12 weeks. Subjects who do not return for the Post-withdrawal Visit within the 
10 days (1 week [+3 days maximum]) may be required to undergo titration, as decided by the 
Investigator in consultation with the Medical Monitor (if necessary) per the guidelines in 
Table 3. Titration is not permitted during the Randomized Withdrawal Period and will be 
allowed after return to open-label dosing.
Table 3:
Titration Schedule After 1-Week Randomized Withdrawal Period (if Necessary)
1 Week blinded daily dose
1 Week SD-809 
titration daily dose 
(Step 1)
1 Week SD-809 titration 
daily dose (Step 2)
SD-809 daily dose after 
completing titration
12 mg or placebo
N/A
N/A
12 mg
18 mg or placebo
12 mg
N/A
18 mg
24 mg or placebo
12 mg
N/A
24 mg
30 mg or placebo
18 mg
24 mg
30 mg
36 mg or placebo
18 mg
24 mg
36 mg
42 mg or placebo
24 mg
30 mg
42 mg
48 mg or placebo
24 mg
36 mg
48 mg
54 mg or placebo
30 mg
42 mg
54 mg
60 mg or placebo
30 mg
48 mg
60 mg
Abbreviation: N/A, not applicable.
5.2.4.
Dosing in Part C
The drug will be provided to study subjects in 30-count bottles. Each order will contain a 
sufficient supply of study drug until the next specified visit, plus overage to account for potential 
delays in study visits or evaluations.
Subjects who do not return for Part C Visit 1 within 10 days of completing the Part B EOT Visit 
may be required to undergo titration, as decided by the Investigator in consultation with the 
Medical Monitor (if necessary) per the guidelines in Table 4 . 
Table 4:
Titration Schedule Part C End of Treatment Period (if Necessary)
Part B open-label period 
daily dose
1 week SD-809 
titration daily dose 
(Step 1)
1 week SD-809 titration 
daily dose (Step 2)
SD-809 daily dose after 
completing titration
12 mg or placebo
N/A
N/A
12 mg
18 mg or placebo
12 mg
N/A
18 mg
24 mg or placebo
12 mg
N/A
24 mg
30 mg or placebo
18 mg
24 mg
30 mg


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Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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Discontinuation
Discontinue study drug and complete an ET visit if, based on Investigator evaluation of readings 
of 12-lead ECGs, the subject meets either of the following criteria:

a meanf QTcF value >500 msec or

a meangf change in QTcF of >60 msec from Baseline
The reason for a dose reduction, suspension, or discontinuation must be clearly 
documented.
5.3.
Treatment Administration
Each tablet should be swallowed whole with water and not broken, crushed, or chewed. Tablets 
should be taken with food and not be taken on an empty stomach.
Subjects should be instructed to take the study drug with meals: tablets will be administered BID 
with meals in the morning and evening, as indicated on drug packaging. It is recommended that 
BID doses be taken approximately 10 hours apart during the day. A minimum of 6 hours should 
elapse between doses. If a subject misses a dose and it is within 6 hours of their next dose, the 
missed dose should be skipped. 
5.4.
Accountability of Study Drug
The study drug must be used in accordance with the protocol and only under the direction of the 
Investigator. All materials supplied are for use only in this clinical study and should not be used 
for any other purpose.
The Investigator is responsible for study drug accountability, reconciliation, and record 
maintenance at the investigational site. In accordance with all applicable regulatory 
requirements, the Investigator or designated site staff must maintain study drug accountability 
records throughout the course of the study. This person will document the amount of study drug 
received, dispensed, and disposition of unused study drug.
A drug dispensing log must be kept current and will contain 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.
Prior to the Pre-withdrawal Visit and Post-withdrawal Visit, the Investigator or designated site 
staff must place a call to remind the subject to bring all remaining study drugs to the visit. The 
Investigator or designated site staff must collect the study drug(s) from the subject and conduct 
drug accountability. 
The inventory must be available for inspection by the Sponsor and/or study monitor during the 
study. Drug supplies, including partially used or empty containers, will be fully accounted for at 
the end of the study by the study monitor. Records of final disposition of the study drug shall be 
maintained by the Investigator. These records must show the identification and quantity of each 
unit disposed of, the method of destruction (taking into account the requirements of local law), 
and the person who disposed of the study drug. Such records must be submitted to the Sponsor. 
                                                
f Mean value is calculated based on three 12-lead ECGs interpreted in the central ECG laboratory (Section 6.7.1). 
Patients with a ventricular pacemaker will be reviewed by the Medical Monitor.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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56
5.5.
Study Drug Compliance
The Investigator or designated study staff is responsible for monitoring the subject’s compliance 
with study drug during the trial. Compliance will be assessed by tablet count, i.e., evaluation of 
returned study drug blister cards/bottles (e.g., amount used/amount expected to be used in 
interval between visits) and must be reviewed at every visit while the subject is still in clinic to 
determine if the subject is taking study drug as directed. 
Compliance will be evaluated by calculating the number of tablets used (tablets dispensed minus 
tablets returned) divided by the expected number of tablets to be used. A subject will be deemed 
compliant over the overall treatment period if the subject has taken 80% to 105% of the expected 
tablets of study drug.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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6.
STUDY METHODS AND PROCEDURES
6.1.
Screening Period
6.1.1.
Prior Data from Subject’s Parent Study
See Schedule of Events for data to be imported from the parent study after informed 
consent/assent.
Subjects who have successfully completed a parent study may be eligible to rollover directly into 
this study after they complete a 1-week washout period and the Week 13 (visit window up to 
10 days) evaluation of the parent study. To reduce subject burden, after obtaining informed 
consent/assent, some data collected in the parent study will be used in the SD-809-C-20 study 
and provide some of the baseline data for SD-809-C-20 (see Schedule of Events). In addition to 
assessments completed for the parent study Week 13 visit, evaluations required as part of the 
SD-809-C-20 study will be completed on the same day as the Week 13 visit. All subjects 
participating in SD-809-C-20 are expected to rollover to SD-809-C-20 at the Week 13 visit of 
the parent study.
Baseline visit study drug will be shipped after site’s approval to receive study drug. See 
Operations Manual for further details.
6.1.2.
Baseline Visit (Day 0)
See the Schedule of Events for a detailed summary of activities.
Subjects will return to the clinic on Day 0 to undergo baseline evaluation. Subjects who continue 
to meet selection criteria will be enrolled in the study. 
Prior to conduct of any study-specific screening procedures, the Investigator or designee will 
explain to the subject (and caregiver, if applicable) the study procedures, including the risks 
involved and the fact that their participation is voluntary. If subject lacks the capacity to provide 
informed consent, a legally authorized representative must provide written informed consent and 
the subject must provide assent. Each subject (and caregiver, if applicable) will acknowledge 
receipt of this information by signing and dating a current, Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)-approved written informed consent, or subject assent 
if an LAR is utilized, for their involvement in the study in the presence of the Investigator, or 
designee, who will also sign and date the informed consent or assent.
The Baseline clinic visit will consist of the following:

Obtain or verify informed consent or assent (for subjects who do not have a legally 
authorized representative)

Update medical history 

Urine pregnancy test (women of child-bearing potential only)

AIMS

Video recording of AIMS (see Section 6.8.1)

12-lead ECG

Montreal Cognitive Assessment (MoCA©)

Modified Craniocervical Dystonia Questionnaire (CDQ-24)

Baseline results will be assessed by the Investigator or Sub-Investigator, and subjects who 
meet eligibility criteria will be enrolled into the study.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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
Subjects will be provided with 1 week of study drug

Week 1 telephone visit will be scheduled
6.2.
Dose Adjustment/Titration Period 
All subjects will interact weekly with the clinical site, either by telephone contact or clinic visit, 
during the dose adjustment/titration period, to evaluate safety and establish a dose of study drug 
that adequately controls dyskinesia and is well tolerated. Safety evaluations include laboratory 
testing, ECGs, monitoring for adverse events and rating scales for motor function, depression, 
cognitive function, akathisia, and somnolence. 
As all subjects will have discontinued study drug (SD-809 or placebo) for 1 week after 
completion of the parent study, they will undergo titration on SD-809 in this study. During 
titration, the Investigator, in consultation with the subject (and caregiver, if applicable), will 
determine when an adequate level of dyskinesia control has been achieved. The dose of SD-809 
should be adjusted on a weekly basis (upward or downward), in increments of 6 mg of total daily
dose, until there is adequate control of dyskinesia; the subject experiences a protocol-defined 
clinically significant adverse event (defined as related to study drug and either a) moderate or 
severe in intensity or b) meets the criteria for a serious adverse event); or the maximal allowable 
dose is reached. If a subject experiences a clinically significant adverse event attributable to 
SD-809, the Investigator will determine if a dose reduction or suspension is necessary. Subjects 
will have a telephone contact at Week 1 and a clinic visit at Week 2 to evaluate safety and 
establish a dose of study drug that adequately controls dyskinesia and is well tolerated. Although 
subjects will enter the Long-Term Treatment Period after Week 2, titration may occur through 
Week 6 to optimize dose. 
Once adequate control of dyskinesia has been achieved, the dose of SD-809 should not be 
increased further.
If a subject experiences an adverse event that is attributed to study drug, the Investigator will use 
his or her judgment to determine if a dose reduction or suspension is necessary. Dose 
adjustments should be made based on all available information including the subject’s (and 
caregiver’s, if applicable) reports of adverse events and dyskinesia control, the clinical 
assessment of safety and efficacy by the Investigator, and information from rating scales such as 
the Unified Parkinson’s Disease Rating Scale (UPDRS), the Barnes Akathisia Rating Scale 
(BARS), the HADS, the Columbia Suicide Severity Rating Scale (C-SSRS), the Epworth 
Sleepiness Scale (ESS), and the MoCA©. At the end of the dose adjustment/titration period, the 
subject’s dose will be established for the remainder of the Long-Term Treatment Period. 
6.2.1.
Weeks 1 and 2
See the Schedule of Events for a detailed summary of activities.
Telephone contact will be scheduled at Week 1 and a clinic visit at Week 2 of the study for 
evaluation of safety and SD-809 dose.
The Week 1 (±1 day) telephone contact will include the following activities:

Assessment of adverse events, dyskinesia control (in consultation with the caregiver, if 
applicable), and concomitant medication use

Evaluation of study drug dose and adjustment, if necessary

Re-order study drug

Next clinic visit will be scheduled/reconfirmed
The Week 2 (±3 day) clinic visit will include the following activities:


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
59

Assessment of adverse events, dyskinesia control (in consultation with the caregiver, if 
applicable), and concomitant medication use

Vital signs

Weight

12-lead ECG

AIMS

UPDRS Part III (motor examination)

BARS 

HADS 

C-SSRS: Since Last Visit version

ESS

Assessment of study drug accountability/compliance

Evaluation of SD-809 dose level and adjustment, if necessary, based on subject’s reports of 
adverse events and dyskinesia control (in consultation with the subject and caregiver, if 
applicable), clinical assessment of safety and efficacy, and information from the above rating 
scales.

Re-order study drug (See Operations Manual for further details)

The next telephone contact will be scheduled/reconfirmed.
6.3.
Long-Term Treatment Period (Week 3 Until the Last Dose in Part 
A)
All subjects will enter the Long-Term Treatment Period after Week 2, although dose adjustment 
should continue through Week 6. During titration, all subjects will be contacted by telephone at 
Weeks 3 and 5 and will return to the clinic at Weeks 4 and 6 for evaluation of safety and 
dyskinesia control and blood sampling for safety labs (Week 6 only). Subjects who have not 
achieved a dose that adequately controls dyskinesia and is well tolerated by the Week 6 
clinic visit should have unscheduled visits or telephone contacts to further adjust their dose 
upward or downward. Site interactions for dose adjustment should alternate between telephone 
contacts and clinic visits. 
During the remainder of the Long-Term Treatment Period, subjects will return to the clinic for 
evaluation of safety and dyskinesia once every 13 weeks, starting at Week 15 and ending at the 
last dose in Part A (completion of Part A=Week 158 or beginning of enter Part B after 
Amendment 06 implementation). Further dose adjustments of SD-809 may be made, if 
necessary, but not more often than weekly and in increments of 6 mg. Dose adjustments should 
be based on all available information, including the subject’s (and caregiver’s, if applicable) 
reports of adverse events and dyskinesia control, information from rating scales, and all safety 
evaluations. If warranted, study sites are encouraged to conduct periodic phone calls with the 
subjects to ensure adherence to the treatment regimen and retention of unused drug containers.
At Weeks 28, 54, 106, and 158, subjects will undergo a more comprehensive evaluation, 
including physical examination, complete neurological examination (Weeks 54, 106, and 158 
only), safety labs, 12-lead ECG, urine pregnancy test for women of childbearing potential, and 
performance of all rating scales. 


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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60
6.3.1.
Telephone Contacts (Week 3 ± 3 Days and Week 5 ± 3 Days)
See the Schedule of Events for a detailed summary of activities.
Telephone contacts will be scheduled during Weeks 3 and 5 to assess adverse events, dyskinesia 
control (in consultation with the caregiver, if applicable), concomitant medication use, evaluation 
of study drug dose level and adjustment, if necessary, and to schedule/confirm the next visit. 
Following the above assessments, study drug will be re-ordered according to specified 
procedures.
6.3.2.
Clinic Visits (Weeks 4, 6, 15, 41, 67, 80, 93, 106, 119, 132, and 145 [All ± 3 Days])
See the Schedule of Events for a detailed summary of activities.
Long-Term Treatment Period clinic visits include the following activities:

Assessment of adverse events, dyskinesia control (in consultation with the caregiver, if 
applicable), and concomitant medication use

Weight

Vital signs (at Week 6, include orthostatic blood pressure and pulse)

12-lead ECG (Weeks 4, 6, and 41)

Clinical laboratory tests: serum chemistry, hematology, and urinalysis (Week 6 only)

AIMS

Video recording of AIMS (Weeks 6, 15, and 41)

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS (excluding at weeks 119 and 145)

Clinical Global Impression of Change (CGIC)

PGIC

MoCA© (Weeks 6, 15, 41, 67, 80, 93, and 132)

Modified CDQ-24 (Weeks 6, 15, and 41)

Assessment of study drug accountability/compliance 

Evaluation of study drug dose level and adjustment, if necessary (through Week 6)

Re-order study drug (see Operations Manual for further details) 

Next clinic visit and/or telephone contact will be scheduled/reconfirmed 
Subjects should continue to receive their long-term treatment dose after the Week 6 clinic visit, 
although further dose adjustments are permitted if clinically indicated.
6.3.3.
Clinic Visits (Part A) (Weeks 28, 54, 106 and 158 [All ± 3 Days] or Early 
Termination)
See the Schedule of Events for a detailed summary of activities.
At Weeks 28, 54, 106, 158, or the ET visit, subjects will undergo a more comprehensive 
evaluation, including:

Assessment of adverse events, dyskinesia control (in consultation with the subject and 
caregiver, if applicable), and concomitant medication use 

Physical examination (brief physical examination only at Week 28), vital signs (including 
orthostatic blood pressure and pulse at Weeks 54, 106, and 158/ET), and weight

Complete neurological examination (Weeks 54, 106, and 158/ET only)


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
Clinical laboratory tests: serum chemistry, hematology, urinalysis, and urine pregnancy test 
(women of childbearing potential only) 

12-lead ECG

AIMS

Video recording of AIMS

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

CGIC 

PGIC 

MoCA©

Modified CDQ-24 

Assessment of study drug accountability/compliance and collection of all study drug

Re-order study drug (see Operations Manual for further details, Weeks 28 and 54 only)

The next clinic visit will be scheduled/reconfirmed 
Unless a subject discontinues the study early or opts to participate in Part B, treatment with study 
drug will stop at the Week 158 visit.
Note: If the subject discontinues from the study early, every effort should be made to complete 
the ET procedures as outlined above and in the Schedule of Events. In addition, subjects 
discontinuing prematurely from the study should have a follow-up visit 1 week after 
discontinuing therapy and a follow-up telephone contact 4 weeks after discontinuing therapy, if 
possible. The procedures outlined in Section 6.6 should be followed.
6.4.
Double-Blind, Randomized Withdrawal Period (Part B)
See the Schedule of Events for a detailed summary of activities.
At the Pre-withdrawal Visit and Post-withdrawal Visit (1 week [+3 days maximum] from the 
Pre-withdrawal Visit), the following activities should be performed:

Obtain or verify informed consent or assent (for subjects who do not have a legally 
authorized representative) after Amendment 06 implementation (Pre-withdrawal Visit only).

Randomize subject via Interactive Response Technology (IRT), and dispense study drug
(Pre-withdrawal Visit only)

Assessment of adverse events, dyskinesia control (in consultation with the subject and 
caregiver, if applicable), and concomitant medication use 

Vital signs (Pre-withdrawal Visit to include orthostatic blood pressure and pulse) and weight 

Clinical laboratory tests: serum chemistry, hematology, urinalysis, and urine pregnancy test 
(Pre-withdrawal Visit only; women of childbearing potential only) 

Single pharmacokinetic (PK) blood sample (Post-withdrawal Visit only) 

12-lead ECG

AIMS

Video recording of AIMS

UPDRS Part III (motor examination)

BARS

HADS


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
C-SSRS: Since Last Visit version

ESS

MoCA©

Assessment of study drug accountability/compliance and collection of all study drug before 
randomization into the Randomized Withdrawal Period and at the end of the Randomization 
Withdrawal Period

Subjects will be provided with a sufficient supply of study drug (blinded at Pre-withdrawal 
Visit)

The next clinic visit will be scheduled/reconfirmed. 
Clinic Visits (Part B Open-label Treatment) End of Treatment or Early Termination
See the Schedule of Events for a detailed summary of activities.
At the Part B EOT or Part B ET visit, subjects will undergo a more comprehensive evaluation, 
including:

Assessment of adverse events, dyskinesia control (in consultation with the subject and 
caregiver, if applicable), and concomitant medication use

Physical examination, vital signs (including orthostatic blood pressure and pulse), and weight

Complete neurological examination

Clinical laboratory tests: serum chemistry, hematology, urinalysis, and urine pregnancy test 
(women of childbearing potential only) 

12-lead ECG

AIMS

Video recording of AIMS

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

MoCA©

Assessment of study drug accountability/compliance and collection of all study drug

The next clinic visit will be scheduled/reconfirmed.
Unless a subject discontinues the study early, treatment with study drug will stop at the EOT 
visit.
Note: If the subject discontinues from the study early, every effort should be made to complete 
the ET procedures as outlined above and in the Schedule of Events. In addition, subjects 
discontinuing prematurely from the study should have a follow-up visit 1 week after 
discontinuing therapy and a follow-up telephone contact 4 weeks after discontinuing therapy, if 
possible. The procedures outlined in Section 6.6 should be followed.
6.5.
Reduced Burden Safety Assessments (Part C)
See the Schedule of Events for a detailed summary of activities.
At Part C Visit 1, the subjects will undergo the activities performed at the Part B EOT visit as 
described above and will sign the informed consent/assent for Part C.
At Part C Visit 2, Visit 3, Visit 4, or the EOT/ET Visit, subjects will undergo reduced burden 
safety assessments, including:


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
Physical examination, vital signs (including resting blood pressure and pulse), and weight

Complete neurological examination (Part C EOT/ET only)

Urine pregnancy test (done locally at the study site)

12-lead ECG

C-SSRS: Since Last Visit version

Assessment of study drug accountability/compliance and collection of all study drug

Assessment of AEs and concomitant meds

Re-order study drug (see Operations Manual for further details, Part C Visit 2, Visit 3, and 
Visit 4)

The next clinic visit will be scheduled/reconfirmed 
Treatment with study drug will stop at the Part C EOT Visit.
6.6.
Post-Treatment Safety Follow-up
Following discontinuation of study drug at the Week 158 visit in Part A, subjects will have a 
clinic visit at Week 159 for evaluation of safety, dyskinesia, and motor function and a telephone 
contact at Week 162 for review of adverse events and concomitant medication use since 
Week 159. 
Following discontinuation of study drug at the ET visit in Part A, subjects will have a clinic visit 
1 week later for evaluation of safety, dyskinesia, and motor function and a telephone contact 
4 weeks after the last dose for review of adverse events and concomitant medication use since 
ET. 
Following discontinuation of study drug at the EOT visit in Part B, subjects will have a 
telephone contact 4 weeks after the last dose of study drug to evaluate the adverse events and 
concomitant medication use since EOT, unless they will continue with Part C.
Following discontinuation of study drug at the ET visit in Part B, subjects will have a clinic visit 
1 week later for evaluation of safety, dyskinesia, and motor function and a telephone contact 
4 weeks after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since ET.
During the first week after stopping study drug, subjects should not take prohibited concomitant 
medications. Between the Week 158, EOT, or ET visit and the follow-up telephone contact, 
concomitant medication use is per the discretion of the Investigator.
Subjects in Part C who complete the 52 weeks of reduced burden safety assessments period will 
complete a Part C EOT Visit and a follow-up telephone contact 4 weeks after the last dose of 
study drug, to evaluate the adverse events and concomitant medication use since Part C EOT. 
Subjects who discontinue study drug in Part C will complete an ET visit, a follow-up clinic visit 
1 week later for safety evaluation, and a follow-up telephone contact 4 weeks after the last dose 
of study drug to evaluate the adverse events and concomitant medication use since ET.
6.6.1.
Clinic Visit (Week 159 ±3 Days or 1 Week after Early Termination ±3 Days)
See the Schedule of Events for a detailed summary of activities.
All subjects will return 1 week after Week 158 (Part A) or the ET visit (Part A or Part B) for 
evaluation of safety, dyskinesia, and motor function. The following activities should be 
performed:

Assessment of adverse events, dyskinesia control (in consultation with the caregiver, if 
appropriate), and concomitant medication use 

Vital signs


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
Weight

AIMS

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

Next telephone contact will be scheduled/reconfirmed 
All subjects will return 1 week after the ET visit (Part C) for evaluation of safety. The following 
activities should be performed:

Assessment of adverse events and concomitant medication use 

Vital signs

Weight

C-SSRS: Since Last Visit version

Next telephone contact will be scheduled/reconfirmed
6.6.2.
Telephone Contact (4 Weeks After EOT/ET ± 3 Days)
All subjects will have a follow-up telephone contact (4 weeks after their last dose of study drug 
[Week 158]) (Part A); or 4 weeks after the EOT visit (Part B); or 4 weeks after the ET visit (Part 
A or Part B). During the telephone contact, subjects (and caregivers, if appropriate) will be 
questioned about adverse events and concomitant medication use since the subject’s last 
evaluation.
In Part C, all subjects will have a follow-up telephone contact 4 weeks after EOT/ET Visit 
(±3 days). During the telephone contact, subjects (and caregivers, if appropriate) will be 
questioned about adverse events and concomitant medication use since the subject’s last 
evaluation.
6.7.
Unscheduled Visit(s)
See the Schedule of Events for a detailed summary of activities.
For unscheduled clinic visit(s) needed during Part A and Part B, the following activities should 
be performed, if indicated:

Assessment of adverse events, dyskinesia control (in consultation with the subject and 
caregiver), and concomitant medications

Vital signs and weight

12-lead ECG at the Investigator’s discretion

Clinical laboratory tests: serum chemistry, hematology, and urinalysis (at the Investigator’s 
discretion)

Single pharmacokinetic (PK) blood sample (for Unscheduled Visits due to serious adverse 
event, within 48 hours, if possible)

UPDRS Part III (motor examination) (at the Investigator’s discretion)

BARS (at the Investigator’s discretion)

HADS

C-SSRS: Since Last Visit version


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
ESS (at the Investigator’s discretion)

Evaluation of study drug dose level and adjustment, if necessary (at the Investigator’s 
discretion)

Re-order study drug (at the Investigator’s discretion)
For unscheduled clinic visit(s) needed during Part C, the following activities should be 
performed, if indicated:

Vital signs and weight

12-lead ECG at the Investigator’s discretion

C-SSRS: Since Last Visit version

Dispense study drug (at the Investigator discretion)

Assess AEs
6.7.1.
Unscheduled Visit(s) for Change in Antipsychotic Regimen
Subjects undergoing an increase in dose of their current antipsychotic treatment, switching to a 
new antipsychotic agent, or having an additional antipsychotic treatment added to their regimen 
will require additional ECG monitoring. In such cases, the Investigator should contact the 
Medical Monitor to review these procedures.

Subjects undergoing such a change in oral antipsychotic treatment should have an 
unscheduled visit between 1-2 weeks thereafter. 

Subjects undergoing an increase in dose of a long-acting injectable (LAI) antipsychotic, 
switching to an LAI treatment, or having an additional LAI antipsychotic treatment added to 
their regimen should have an unscheduled visit within the following timeframe, based on the 
prescribed LAI antipsychotic:
o
4-5 weeks: fluphenazine decanoate
o
8-9 weeks: risperidone LA, haloperidol decanoate, olanzapine pamoate, 
Zuclopenthixol decanoate
o
12-13 weeks: all other LAI antipsychotics
On the morning of the clinic visit, the subject should hold their SD-809 dose until they are in the 
clinic. Upon reaching the clinic, the following activities should be performed:

Administer the morning dose of SD-809 with a meal or light snack

Collect a 12-lead ECG 3 hours after SD-809 administration following at least 5 minutes of 
rest in a supine or semi-recumbent position.
o
Based on the ECG machine reading, if QTcF value is >500 msec or there is a change 
from Baseline in QTcF value of >60 msec, two additional 12-lead ECGs should be 
collected as soon as practical. There should be at least 5 minutes between ECGs.

Transmit ECGs to the central laboratory on the same day that they are collected.
6.7.2.
Unscheduled Telephone Visit(s)
For unscheduled telephone visit(s) needed during Part A and Part B, the following activities 
should be performed:

Assessment of adverse events, dyskinesia control, and concomitant medications in 
consultation with the subject and caregiver, if appropriate.


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
Evaluation of study drug dose level and adjustment, if necessary (at the Investigator’s 
discretion)

Re-order study drug (at the Investigator’s discretion) (see Operations Manual for further 
details)
For unscheduled telephone visit(s) needed during Part C, the following activities should be 
performed:

Assessment of adverse events and concomitant medications in consultation with the subject 
and caregiver, if appropriate.
6.8.
Efficacy and Quality of Life Measures
6.8.1.
Abnormal Involuntary Movement Scale
The AIMS is an assessment tool used to detect and follow the severity of TD over time. The 
AIMS was originally developed by a consortium of clinical psychopharmacology researchers 
funded by the National Institute of Mental Health’s (NIMH) Psychopharmacology Research 
Branch (Guy, 1976). While the original AIMS is widely used and accepted in clinical practice, 
the scale does not include detailed descriptors, and thus, can be difficult to implement in a 
clinical trial setting. Over the years, a number of authors have developed modifications and 
scoring conventions to help clinicians assess abnormal movements with the AIMS in a more 
uniform manner (Lane, 1985; Munetz and Benjamin, 1988).
For the present study, Auspex has proposed the use of AIMS descriptors (Appendix 2), which 
are consistent with those utilized in large trials in schizophrenia, and were developed based on 
the work of Munetz and Benjamin (Munetz and Benjamin, 1988). These descriptors have face 
validity in describing the severity of abnormal movements in TD and have been reviewed with 
key scientific experts in movement disorders and psychiatry, who uniformly agreed that they are 
appropriate for providing guidance to Investigators in grading the severity of TD in this study. 
The AIMS is composed of 12 clinician-administered and -scored items (Appendix 2). Items 1 to 
10 are rated on a 5-point anchored scale and consist of the following:

Items 1-4 assess orofacial movements

Items 5-7 deal with extremity and truncal dyskinesia

Items 8-10 deal with global severity as judged by the examiner, and the patient’s awareness 
of the movements and the distress associated with them
Items 11 through 12 are yes/no questions concerning problems associated with teeth and/or 
dentures, as such problems can be mistaken for dyskinesia.
A total score from items 1 to 7 (orofacial, extremity, and truncal movements) can be calculated 
and represent observed movements, with higher scores indicative of more severe dyskinesia. 
Item 8 can be used as an overall severity index; items 9 and 10 provide additional information 
with regard to patient incapacitation and awareness; and items 11 and 12 provide information 
that may be useful in determining lip, jaw, and tongue movements (Guy, 2000).
6.8.2.
Independent Rating of Dyskinesia
To enable a systematic evaluation of the primary endpoint, the AIMS will be digitally 
video-recorded using a standard protocol at Baseline and at Weeks 6, 15, 28, 41, 54, and 158 
(see Appendix 2). 


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The videos from Baseline and Weeks 6, 15, 28, 41, 54, 106, and 158 will be independently 
reviewed by a blinded central rater(s) who is an expert in movement disorders. 
This process will allow for a systematic assessment of dyskinesia that is not influenced by 
subject reports of tolerability or efficacy. Videos will be recorded and submitted to the central 
rater in a blinded manner with respect to visit number, site, and date of recording. A detailed 
video protocol will be included in the study operations manual. A detailed video review charter 
will be established to ensure appropriate blinding and review procedures by the central video 
raters.
6.8.3.
Clinical Global Impression of Change
The CGIC (Appendix 3) is a single-item questionnaire that asks the investigator to assess a 
subject’s TD symptoms at specific visits after initiating therapy. The CGIC uses a 7-point Likert 
Scale, ranging from very much worse (–3) to very much improved (+3), to assess overall 
response to therapy. 
6.8.4.
Patient Global Impression of Change
The PGIC (Appendix 4) is single-item questionnaire that asks the patient to assess their TD 
symptoms at specific visits after initiating therapy. The PGIC uses a 7-point Likert Scale, 
ranging from very much worse (–3) to very much improved (+3), to assess overall response to 
therapy. In general, patient-rated global measures of change have face validity and have been 
shown to correlate with disability for a number of chronic conditions (Kamper, Maher, & 
Mackay, 2009).
6.8.5.
Modified Craniocervical Dystonia Questionnaire
The CDQ-24 is a disease-specific quality of life questionnaire developed for use in patients with 
craniocervical dystonia, including both cervical dystonia (CD) and blepharospasm (BPS) 
(Muller et al, 2004). The CDQ-24 was selected for use in the present study because it includes 
domains which are relevant not only to CD and BPS, but to TD. The following domains are 
evaluated in the CDQ-24: stigma, emotional well-being, pain, activities of daily living, and 
social/family life. For the present study, the CDQ-24 has been modified (Appendix 5) such that 
the questions focus directly on the impact of TD (as opposed to CD/BPS) on quality of life. 
6.9.
Safety Evaluations
6.9.1.
Demographics and Medical History
The subject’s gender, year of birth, age, race, ethnic origin, and medical and surgical history will 
be transferred from data collected in the parent study. The subject’s medical and surgical history 
will be updated at Baseline.
6.9.2.
Physical Examination
A complete physical examination will be performed as specified in the Schedule of Events. A 
complete examination includes evaluation of the following systems/regions:

General Appearance

Skin

Head, Eyes, Ears, Nose, Throat

Neck: Lymph Nodes, pulses

Respiratory

Musculoskeletal

Abdominal

Extremities


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
Cardiovascular
A brief physical examination includes evaluation of the cardiovascular, respiratory, and 
abdominal systems.
6.9.3.
Complete Neurological Examination
A complete neurological examination will be performed as specified in the Schedule of Events. 
The neurological examination includes evaluation of the following:

Mental status 

Cranial nerves 

Motor system (strength, tone posture) 

Coordination

Gait and balance 

Tendon reflexes 

Sensation
6.9.4.
Vital Signs
Vital signs to be assessed should include resting blood pressure, heart rate, respiratory rate, and 
temperature. Heart rate and blood pressure measurements should be taken only after a subject 
has rested quietly in a sitting position for at least 5 minutes. 
6.9.5.
Orthostatic Blood Pressure and Pulse
Orthostatic blood pressure and pulse will be recorded at Weeks 6, 54, 106, 158/ET, the 
Pre-withdrawal Visit, and EOT.
Orthostatic blood pressure and pulse will be assessed in the supine and standing positions. The 
subject should be supine for at least 5 minutes before the supine blood pressure and pulse are 
measured. Subjects will then move to the sitting position briefly to ensure that no symptoms 
occur, after which they will stand for 3 minutes. Standing blood pressure and pulse will be 
obtained after the subject has been in the standing position for at least 3 minutes.
6.9.6.
Laboratory Tests
Blood and urine samples will be collected and tested for the items in Table 5 and applicable 
parameters will be calculated according to the Standard Operating Procedures (SOPs) at the 
central laboratory. If abnormal, screening labs may be repeated once to confirm the subject’s 
eligibility. As specified in Table 5, certain lab results obtained in the parent study do not need to 
be repeated at screening for Study SD-809-C-20.


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Table 5:
Laboratory Tests

Sodium

Potassium

Chloride

Bicarbonate

Magnesium

Glucose 

Blood urea nitrogen (BUN)

Creatinine 

Total calcium

Phosphate

Uric Acid

Cholesterol

Triglycerides

Total Protein

Albumin 

Total bilirubin

Direct bilirubin

Alkaline phosphatase (ALP)

Alanine aminotransferase (ALT)

Aspartate transaminase (AST)

Lactate dehydrogenase (LDH)
Hematology
Urinalysis

Hemoglobin

Hematocrit

Red blood cell count (RBC)

Mean cell volume (MCV)

Platelets

White cell count

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils

Leucocytes

Nitrites

Urobilinogen

Protein

pH

Blood

Specific gravity

Ketone

Bilirubin

Glucose

Microscopic exam (if indicated)
Labs for screening purposes
Lab results from parent study

Urine pregnancy tests (women of childbearing 
potential only)

CYP2D6 genotype (blinded)

Prothrombin Time (PT) with
International Normalized Ratio (INR)

Follicle Stimulating Hormone for post-
menopausal women only.

Hepatitis B surface antigen (HBsAg)
6.9.7.
12-lead Electrocardiogram
All ECGs will be performed after at least 5 minutes rest in a supine or semi-recumbent position. 
12-lead ECGs to assess safety will be collected according to the Schedule of Events. Heart rate 
and ECG intervals (PR, QRS, QT, and QTcF) and clinical interpretation will be assessed by the 
central reader.
6.9.8.
Detecting Adverse Events
The occurrence of adverse events should be sought by non-leading questioning of the subject and 
caregiver during the study and may also be identified when the subject and/or caregiver 
spontaneously volunteered them. Open-ended, non-leading questioning of the subject is the 
preferred method to detect adverse events. 
Suitable non-leading questions include: 

“How are you feeling?” 

“How have you been doing since your last evaluation?”

“Have you taken any new medicines since your last evaluation? If so, why?”


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Adverse events may also be detected by the medical staff through physical examination, 
evaluation of laboratory tests results, or other assessments. All adverse events occurring from 
signing of the Informed Consent Form (ICF) to the end of the study, regardless of suspected 
causal relationship to study drug, will be recorded in the source documentation and on the 
appropriate electronic Case Report Form (eCRF) page for subjects who are enrolled. 
6.9.9.
Rating Scales
Subject-completed assessments will be available in English, Spanish, Hungarian, German, 
Polish, Czech, and Slovakian.
6.9.9.1.
Unified Parkinson Disease Rating Scale Part III – Motor Examination
The UPDRS (Appendix 6) is a comprehensive instrument used to assess the signs and symptoms 
of Parkinson's disease. The UPDRS is comprised of various patient- and clinician-based 
assessments of motor, cognitive, and behavioral symptoms. UPDRS questions pertaining to 
motor function will be used to screen and monitor study subjects for Parkinsonism.
6.9.9.2.
Barnes Akathisia Rating Scale
The BARS (Appendix 7) is a widely used rating scale for evaluation of drug-induced akathisia. 
This scale includes an objective assessment, subjective measures, including self-awareness and 
distress, and a global clinical assessment (Barnes, 1989). 
6.9.9.3.
Hospital Anxiety and Depression Scale
The HADS (Appendix 8) is a self-administered instrument reliable for detecting states of 
depression and anxiety in an outpatient medical setting (Zigmond & Snaith, 1983). The HADS is 
recommended by the National Institute of Neurological Disorders & Stroke (NINDS) Common 
Data Elements for HD because it serves as a good screening measure, it has been widely used 
and it is relatively simple to complete. It focuses on subjective disturbances of mood rather than 
physical signs, and aims at distinguishing depression from anxiety. The scale consists of 14 items 
(7 each for anxiety and depression). Each item is rated on a 4-point scale ranging from 0 (not at 
all) to 3 (very often). Responses are based on the relative frequency of symptoms over the 
preceding week.
6.9.9.4.
Columbia Suicide Severity Rating Scale
The C-SSRS (Appendix 9 and Appendix 10) is a Food and Drug Administration (FDA)–
endorsed questionnaire to screen for suicidality in trials of central nervous system (CNS)–active 
compounds (The Columbia Suicide Severity Rating Scale; Guidance for Industry Suicidality: 
Prospective Assessment of Occurrence in Clinical Trials, DRAFT GUIDANCE, September 
2010). The C-SSRS is an interview by trained study personnel that should be done at Baseline 
and during the study as outlined in the Schedule of Events. The form provided at Screening 
collects the history of suicide (C-SSRS form version termed “baseline” (Appendix 9) and at 
subsequent visits uses a C-SSRS termed “Since the Last Visit” (Appendix 10).
6.9.9.5.
Epworth Sleepiness Scale
The ESS (Appendix 12) is a self-administered questionnaire composed of eight questions that 
provides a measure of a subject’s general level of daytime sleepiness (Johns, 1991). The ESS 
asks respondents to rate, on a 4-point Likert scale (0 – 3), their usual chances of dozing off or 
falling asleep in different situations or activities that most people engage in as part of their daily 


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lives. The total ESS score is the sum of 8 item-scores and can range between 0 and 24 with a 
higher score indicating a higher level of daytime sleepiness. Most people can complete the ESS, 
without assistance, in 2 or 3 minutes.
6.9.9.6.
Montreal Cognitive Assessment (MoCA©)
The MoCA© (Appendix 11) is a validated rapid screening instrument for assessing mild 
cognitive dysfunction. It assesses different cognitive domains: attention and concentration, 
executive functions, memory, language, visuoconstructional skills, conceptual thinking, 
calculations, and orientation. Time to administer the MoCA© is approximately 10 minutes. The 
total possible score is 30 points; a score of 26 or above is considered normal.
6.10.
Pharmacokinetic Evaluations
Subjects experiencing a serious adverse event should have a single blood sample collected as 
soon as possible after the serious adverse event and within 48 hours of the last dose of study drug 
for the pharmacokinetic assessment of α- and β- HTBZ, if possible. The date and time of the last 
dose of study drug should be recorded along with the date and time of the sample collection.
Subjects who have not achieved adequate control of dyskinesia during the study may have up to 
two blood samples collected for future pharmacokinetic assessment of α- and β- HTBZ. The 
pharmacokinetic sampling for inadequate efficacy must be pre-approved by the Medical 
Monitor. The date and time of the last dose of study drug should be recorded along with the date 
and time of the sample collection.
6.11.
Subject Restrictions 
6.11.1.
Concomitant Medications
Prohibited Concomitant Medications
The following products should not be used within 30 days of Baseline (unless noted below) and 
throughout the study:

Tetrabenazine (within 7 days of Baseline)

Valbenazine

AMPT

Metoclopromide, promethazine, and prochlorperazine

Stimulants (i.e., methylphenidate, amphetamine/dextroamphetamine, lisdexamphetamine, 
etc.)

MAOIs

Levodopa or dopamine agonists

Reserpine

Medications with strong anticholinergic activity (trihexyphenidyl, benztropine, orphenadrine, 
procyclidine, and biperiden)

Botulinum toxin (within 3 months of Screening)

Any investigational drug


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The drugs listed above and other drugs which are known to cause QT prolongation (see 
Appendix 14) should not be taken concomitantly with study drug. A washout period of 
5 half-lives before the Baseline visit is required. A duration less than 5 half-lives must be 
approved by the Medical Monitor.
Allowed Concomitant Medications
Stable Dosing
Subjects receiving psychoactive medications (including, but not limited to, neuroleptics [see 
Appendix 16], benzodiazepines, anticonvulsants, and mood stabilizers) must be on a stable dose 
for ≥30 days (oral medication) before Screening and in the opinion of the treating psychiatrist, no 
changes in drug or dose are expected in the next 3 months. After 3 months, changes in 
psychoactive medications are allowed if approved by the Investigator. Any changes in 
concomitant medications must be documented in the eCRF.
Antipsychotics
Considering the potential of antipsychotic drugs to prolong the QT interval, additional ECG 
monitoring is required if the Investigator 1) increases the dose of a patient’s current antipsychotic 
treatment, 2) switches the patient to a different antipsychotic treatment, or 3) adds a new 
antipsychotic treatment to the patient’s regimen. In such cases, subjects should have an 
unscheduled visit within 1-2 weeks for a change in oral antipsychotic treatment, or have an 
unscheduled visit within 4-5 weeks, 8-9 weeks, or 12-13 weeks (depending upon the prescribed 
LAI) for a change in their LAI antipsychotic treatment, to have a repeat 12-lead ECG following 
their usual SD-809 dose (see Section 6.7.1). 
Antidepressants
Subjects receiving antidepressant therapy must be on a stable dose for 45 days before Screening. 
Subjects receiving long acting (depot) medications must have been on stable therapy (dose, 
frequency) for ≥3 months before Screening. 
Other
Female subjects on hormonal contraception (approved oral, transdermal, or depot regimen) for 
birth control must be on a stable dose for at least 3 months prior to Screening and through study 
completion.
Subjects will be instructed to inform the study Investigator of the details (indication, dose, and 
dates of administration) if they do take any medication, and these details will be recorded in the 
eCRF. 
6.11.2.
Use of Alcohol or Sedating Drugs
As with other VMAT2 inhibitors (tetrabenazine, reserpine), subjects should be advised that the 
concomitant use of alcohol or other sedating drugs with SD-809 may have additive effects and 
cause or worsen somnolence. Until subjects are receiving a stable dose of SD-809 and 
understand how the drug affects them, alcohol should be used with caution. 
6.11.3.
Other Restrictions
Subjects should be advised to not drive a car or operate dangerous machinery until they 
understand how SD-809 affects them.
Use of illicit drugs is prohibited from the time of signing of the Informed Consent Form or 
Assent and throughout study participation.


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6.12.
Caregiver Responsibilities
The Investigator will assess whether the subject lives in a stable environment and has adequate 
supervision when necessary to safely participate in the trial. For those subjects needing the 
assistance of a caregiver, the caregiver must interact on a regular basis with the subject and 
oversee study drug administration. In addition, the caregiver will assure attendance at study visits 
and participate in evaluations, as required. 
The caregiver must also make him/herself available for clinic visits and telephone contacts in 
order to report dyskinesia control and adverse events to determine whether dose adjustment of 
study drug will be made. As subjects may have agnosia to dyskinesia, telephone contacts should
involve the subject and caregiver, when appropriate.
6.13.
Withdrawal Criteria
Subjects will be advised that they are free to withdraw from the study at any time for any reason. 
A subject may be withdrawn from the study for any of the following reasons:

Subject voluntarily discontinues study participation (subject withdrawal);

The need to take medication which may interfere with study measurements;

Intolerable/unacceptable adverse events (see Section 5.2.4 for QTcF discontinuation criteria);

Major violation or deviation of study protocol procedures;

Non-compliance of subject with protocol;

Subject is unable to comply with study procedures;

Withdrawal from the study is, in the Investigator’s judgment, in the subject’s best interest;

Subject is lost to follow-up;

A female subject becomes pregnant;

Study termination by the Sponsor.
All subjects to be withdrawn from the study for medical reasons should be reviewed with the 
Medical Monitor. The reasons for withdrawal will be recorded on the eCRF and included in the 
final report along with any adverse events and any necessary medical treatment. 
6.14.
Discontinued Subjects
Notification of early subject discontinuation from the study and the reason for discontinuation 
will be made to the Clinical Monitor and will be clearly documented on the appropriate eCRF 
page. If a subject is discontinued from the study early, all ET evaluations should be performed at 
the time of discontinuation, if possible. 
6.15.
Study Termination
The study may be stopped at any time by the Sponsor, IEC/IRB, and/or regulatory agencies for 
any reason. The Sponsor reserves the right to discontinue the trial at any time for any reason. 
Reasons will be provided in the event of this happening. The Investigator reserves the right to 
discontinue the study at their site for safety reasons at any time in collaboration with the 
Sponsor.


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7.
ADVERSE EVENTS
Throughout the course of the study, all adverse events will be monitored and reported on an 
adverse event CRF, including assessments of seriousness, severity, action taken, and relationship 
to study drug. If adverse events occur, the first concern will be the safety of the study 
participants. 
Adverse events will be recorded from the time of consent through the final study visit. 
Information about side effects already known about the study drug can be found in the IB and 
will be included in the subject ICF.
The Investigator and site staff are responsible for detection, recording and reporting of events 
that meet the criteria and definition of an adverse event or serious adverse event (listed below).
7.1.
Definitions
7.1.1.
Adverse Event
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An adverse event (also referred to as an adverse 
experience) therefore, can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An adverse event can arise from any use of the drug (e.g., off-label 
use, use in combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose.
Examples of an adverse event include:

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study.

Abnormal safety assessments if they lead to study drug dose modification, study drug 
discontinuation or to therapeutic intervention (e.g., low hemoglobin that requires 
transfusions).

Abnormal laboratory tests if they are associated with clinical signs, symptoms or if they lead 
to a diagnosis or therapeutic intervention.

Abnormal vital signs if they are clinically significant and lead to a diagnosis or therapeutic 
intervention. 

Abnormal ECGs if they are clinically significant and lead to therapeutic intervention or 
diagnosis. The clinical significance should be confirmed by a cardiologist.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
product or a concurrent medication.
Examples of an adverse event do not include:

A medical or surgical procedure (e.g., endoscopy); a condition that leads to the procedure is 
an adverse event.


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
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to hospital) or scheduled elective procedures like cosmetic surgery are not adverse 
events. However, if the procedure results in an unexpected complication, the complication is 
an adverse event.

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Situations where an untoward medical occurrence did not occur or when signs are not 
expressing a medical problem but rather are expressing natural physiological responses (e.g., 
dyspnea after running, limb paresthesias due to awkward position).

Signs, symptoms, or laboratory results that reflect an improvement of a past medical 
condition (e.g., sleeping better).
7.1.2.
Suspected Adverse Reaction
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of safety reporting, reasonable possibility 
means there is evidence to suggest a causal relationship between the drug and the adverse event. 
A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.
7.1.3.
Adverse Reaction
An adverse reaction means an adverse event that is caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.
7.1.4.
Unexpected Adverse Event
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
IB or is not listed at the specificity or severity that has been observed. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the IB listed only cerebral 
vascular accidents. “Unexpected”, as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
7.1.5.
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:

Results in death (i.e., the adverse event caused the death).

Is life-threatening. The term life threatening in the definition of serious refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.

Requires inpatient overnight hospitalization or prolongation of an existing hospitalization, 
unless hospitalization is for:
o
Elective or pre-planned treatment for a pre-existing condition and has not worsened 
since signing the informed consent


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o
Social reasons and/or respite care in the absence of any deterioration of the subject’s 
general condition. 
o
In general, hospitalization signifies that the subject has been detained (involving at 
least an overnight stay of at least 24 hours) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician's 
office or outpatient setting. Complications that occur during hospitalization are 
adverse events. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. 

Results in persistent or significant disability/incapacity. The term disability means a 
substantial disruption of a person’s ability to conduct normal life functions. This definition is 
not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.

Is a congenital anomaly/birth defect (i.e., an adverse finding in a child or fetus or a subject 
exposed to the study drug prior to conception or during pregnancy).

Is medically important, defined as an event that may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above, or result in 
urgent investigation. Examples of such events are malignancies, 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.
If either the Sponsor or Investigator believes the event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting.
7.2.
Recording of Adverse Events
Whenever possible, a unifying diagnosis should be recorded in the eCRF as the adverse event 
rather than individual signs or symptoms. Similarly, the unifying diagnosis should be recorded as 
the adverse event rather than the abnormal laboratory result (i.e., “anemia” instead of “low 
hemoglobin”). 
If the adverse event is a worsening of a past medical condition, the adverse event should clearly 
indicate that the past medical condition has worsened using words such as “worsening,” 
“aggravated,” or “exacerbation.” 
7.2.1.
Recording of Non-Serious Adverse Events
Collection of adverse events will begin immediately following signing of the ICF through the 
final study visit. The Investigator will monitor each subject closely and record all observed or 
volunteered adverse events. Adverse findings detected at the Screening visit (e.g., abnormalities 
on clinical laboratory testing, ECGs, physical/neurological examination) will be recorded on the 
Medical History CRF and adverse events occurring after the Screening visit but before starting 
study treatment will be recorded on the adverse event CRF and considered non-treatment 
emergent.
7.2.2.
Recording of Serious Adverse Events
Collection of serious adverse events will begin immediately following signing of the ICF 
through the final study visit. The Investigator will monitor each subject closely and record all 
observed or volunteered serious adverse events. Serious adverse events occurring after signing 


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the ICF but before starting study treatment will be considered non-treatment emergent.
If a new serious adverse event comes to the attention of the Investigator after the completion of 
the final study visit, information regarding the serious adverse event should be collected and 
reported to the Sponsor only if assessed as reasonably possibly related to the study drug(s) by the 
Investigator.
After the initial serious adverse event report, the Investigator is required to proactively follow 
each subject and provide further information to the Sponsor (or designee) on the subject’s 
condition. The Investigator will ensure that follow-up includes any supplemental investigations 
as may be indicated to elucidate the nature and/or causality of the serious adverse event. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
Serious adverse events that remain ongoing past the subject’s last protocol-specified follow-up 
visit will be evaluated by the Investigator and Sponsor. All serious adverse events will be 
followed:

Until resolution, or

For 28 days after the subject’s last follow-up visit, or

If, in the investigator’s opinion, the condition is unlikely to resolve, whichever comes first. If 
the Investigator and Sponsor agree the subject’s condition is unlikely to resolve, the 
Investigator and Sponsor will determine the follow-up requirement.
Subjects experiencing a serious adverse event should have a single blood sample collected as 
soon as possible after the serious adverse event and within 48 hours for the pharmacokinetics of 
α- and β-HTBZ, if possible. The date and time of the last dose of study drug should be recorded 
along with the date and time of the sample collection.
7.3.
Evaluation of Adverse Events (Serious and Non-Serious)
At each in-person visit and telephone contacts, occurrence of adverse events will be assessed by 
verbally asking subjects and caregivers if they have had any problems or symptoms since their 
last visit.
If the subject or caregiver reports an adverse event, the investigator/coordinator will probe 
further to determine:

Time of onset and resolution

Frequency

Causality/relation to study treatment

Intensity

Action taken regarding study drug

Outcome
7.3.1.
Severity
The Investigator will make an assessment of intensity for each adverse event and serious adverse 
event reported during the study. The assessment will be based on the Investigator’s clinical 
judgment. The intensity of each adverse event and serious adverse event recorded in the eCRF 
should be assigned to one of the following categories:

Mild: Causes minimal discomfort, but does not interfere with normal daily activities

Moderate: Causes sufficient discomfort to interfere with normal daily activities

Severe: Prevents normal daily activities
An adverse event that is assessed as severe should not be confused with a serious adverse event. 


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Severity is a category utilized for rating the intensity of an event; and both adverse events and 
serious adverse events can be assessed as severe. An event is defined as serious when it meets 
one of the pre-defined outcomes as described in Section 7.1.5.
7.3.2.
Relationship to Study Drug
The Investigator is obligated to assess the relationship between study drug and the occurrence of 
each adverse event. The Investigator will use clinical judgment to determine if there is a 
reasonable possibility that the drug caused the adverse event. The investigator’s assessment of 
the relationship of each adverse event to study drug will be recorded it in the source documents 
and the eCRF. Alternative causes, such as medical history, concomitant therapy, other risk 
factors, and the temporal relationship of the event to the study drug should be considered and 
investigated, if appropriate. The Medical Monitor’s opinion may be sought in those cases in 
which the Site Investigator is unable to make an independent judgment. The Medical Monitor 
may in turn consult with the Principal Investigator as needed. The following definitions are 
general guidelines only to help assign grade of attribution:

Unrelated: The adverse event is clearly not related to the investigational drug

Unlikely: The adverse event is doubtfully related to the investigational drug

Possible: The adverse event may be related to the investigational drug 

Probable: The adverse event is likely related to the investigational drug

Definite: The adverse event is clearly related to the investigational drug
7.3.3.
Action Taken with Study Treatment
Action taken as a result of an adverse event will be recorded on the adverse event eCRF as 
follows:

No change

Dose reduced

Drug suspended (see Section 5.2.4 for guidance in contacting Medical Monitor)

Drug permanently discontinued
7.3.4.
Treatment Required
Treatment required as a result of an adverse event will be recorded in the subject’s source 
documents, and if medication is required, on the concomitant medications log:

None

Medication Required (record on Concomitant Medications eCRF)

Hospitalization Required

Other (specify)
If a diagnosis has been entered as an adverse event, the treatment(s) recorded may represent the 
treatment(s) given for one or more sign(s) or symptoms(s) (e.g., Naproxen for the adverse event 
“fracture”, without recording “pain due to fracture” or “inflammation due to fracture” as separate 
adverse events). 
7.3.5.
Outcome
Outcome of an adverse event will be recorded on the adverse event eCRF as follows:

Recovered / Resolved 

Recovering / Resolving 

Recovered / Resolved with Sequelae


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
Not Recovered / Not Resolving 

Fatal

Unknown
7.4.
Procedures for Reporting Serious Adverse Events
All serious adverse events occurring during study participation must be reported to the Sponsor 
(or designee) and to the governing IRB/IEC as required by the IRB/IEC, local regulations, and 
the governing health authorities.
7.4.1.
Completion and Transmission of the Serious Adverse Event Report
Once an Investigator becomes aware that a serious adverse event has occurred in a study subject, 
she/he will report the information to the Sponsor (or designee) within 24 hours. The serious 
adverse event form (provided in the study Operations Manual) will always be completed as 
thoroughly as possible with all available details of the event, signed by the Investigator (or 
designee), and forwarded to the Sponsor (or designee) within the designated time frames. If the 
Investigator does not have all information regarding a serious adverse event, he/she will not wait 
to receive additional information before notifying the Sponsor (or designee) of the event and 
completing the form. The form will be updated when additional information is received
Whenever possible, the Investigator will provide an assessment of causality at the time of the 
initial report as described above.
The Sponsor will provide a list of project contacts for serious adverse event receipt. Any event 
that in the opinion of the Investigator may be of immediate or potential concern for the subject’s 
health or well-being will be reported to the Sponsor (or designee). 
7.4.2.
Regulatory Reporting Requirements for Serious Adverse Events
The Investigator must promptly (within 24 hours of awareness) report all serious adverse events 
to the Sponsor (or designee) in accordance with the procedures describe above. Prompt 
notification of serious adverse events by the Investigator to the appropriate project contact for 
serious adverse event receipt is essential so that legal obligations and ethical responsibilities 
towards the safety of other subjects are met. The Investigator will be responsible for reporting 
serious adverse events to the IRB/IEC per local regulatory requirements. 
The Sponsor (or designee) is responsible for reporting serious adverse events to the relevant 
regulatory authorities in accordance with local regulations. That is, serious adverse events which 
are determined by the Sponsor to be “Unexpected” and classified as “Suspected Adverse 
Reactions” will be reported in an expedited manner. 
7.5.
Procedures for Reporting Pregnancy Exposure and Birth Events
The Investigator must promptly report all pregnancies in female study subjects to the Sponsor (or 
designee) in accordance with the Operations Manual. While the pregnancy itself is not 
considered to be an adverse event or serious adverse event, any pregnancy complications should 
be recorded as adverse events or serious adverse events. Any pregnancy will be followed through 
its conclusion for observation of any serious adverse events including congenital anomalies/birth 
defects.


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8.
STATISTICAL PROCEDURES AND DATA ANALYSIS
This section describes the statistical analysis strategy and procedures for the study. Summary 
statistics will be provided by prior treatment (in parent study) and for the overall population. 
Descriptive statistics will be calculated for quantitative data and frequency counts and 
percentages will be provided for categorical data. Details of the data analysis will be described in 
a separate Statistical Analysis Plan.
8.1.
Analysis Populations
Safety Population: The Safety Population will include all subjects who were administered any 
study drug. Subjects who are assigned a subject number but withdrew prior to dosing will not be 
included in the Safety Population. If relevant, details of their participation and reason for 
withdrawal will be listed separately in the study report. 
All summaries of safety endpoints in will be summarized descriptively in the Safety Population.
Intent-to-Treat (ITT) Population: The ITT Population will include all enrolled subjects in the 
study. All efficacy measures in Part A will be summarized using the ITT Population.
Randomized Withdrawal ITT Population: The Randomized Withdrawal ITT Population will 
include all subjects enrolled to Part B of the study. 
Randomized Withdrawal Modified Intent-to-Treat (mITT) Population: The Randomized 
Withdrawal mITT Population will include all subjects enrolled to Part B who receive study drug 
during the Randomized Withdrawal Period and have a centrally read AIMS score at both the 
Pre-withdrawal Visit and the Post-withdrawal Visit. All efficacy measures in the Randomized 
Withdrawal Period will be analyzed using the Randomized Withdrawal mITT Population.
8.2.
Demographics and Baseline Data
Demographic information will be presented for each subject. Medical/surgical history data at 
baseline will be listed, as will physical examination data. 
8.3.
Safety Analyses
Safety and tolerability will be assessed throughout the study by monitoring the following 
parameters:

Adverse events 

Clinical laboratory tests 

Physical examination 

Vital signs

12- lead ECGs

UPDRS – Motor Examination

BARS 

HADS

C-SSRS

ESS

MoCA©
Safety data will be summarized descriptively for the overall population and based on prior 
treatment (SD-809 or placebo) in the parent study. Descriptive statistics will be calculated for 
quantitative data and frequency counts and percentages will be provided for categorical data. 
Descriptive statistics of change-from-baseline will use the Baseline from the present study 
(SD-809-C-20 Baseline).
The nature, frequency, and severity of adverse events will be tabulated for all subjects combined 
and by treatment. Baseline, within study, end of study, and change-from-baseline values for 


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clinical laboratory evaluations and vital signs will be summarized as appropriate.
Treatment-emergent adverse events and laboratory, vital sign, and ECG parameters will be 
summarized. In addition, change from baseline will be summarized for laboratory and vital sign 
parameters. Shift tables will be provided for clinical laboratory results. ECG results will be 
classified as normal and abnormal and summarized.
8.4.
Safety Endpoints
The following safety endpoints will be assessed in Part A:

Incidence of adverse events, serious adverse events, severe adverse events, drug-related 
adverse events, adverse events leading to withdrawal during the following periods:
o
Overall
o
During titration 
o
During long-term treatment 

Observed values and changes from baseline in clinical laboratory parameters (hematology, 
chemistry, and urinalysis)

Observed values and changes from baseline in vital signs

Observed values in ECG parameters and abnormal findings

Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms, or a change 
from Baseline in QTcF of >30 ms or >60 ms

Observed values and changes in UPDRS Part III (motor examination), BARS, HADS, 
C-SSRS, ESS, and MoCA©

Duration of time to achieve stable dosing of SD-809
The following secondary safety endpoints will be assessed in Part B:

Incidence of adverse events, serious adverse events, severe adverse events, drug-related 
adverse events, and adverse events leading to withdrawal

Observed values and changes from start of randomized withdrawal in clinical laboratory 
parameters (hematology, chemistry, and urinalysis)

Observed values and changes from start of randomized withdrawal in vital signs

Observed values in ECG parameters and abnormal findings

Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms, or a change 
from Baseline in QTcF of >30 ms or >60 ms

Observed values and changes in UPDRS Part III (motor examination), BARS, HADS, C-
SSRS, ESS, and MoCA©
The following secondary safety endpoints will be assessed in Part C:

Secondary safety endpoints:
o
Incidence of adverse events, serious adverse events, severe adverse events, 
drug-related adverse events, and adverse events leading to withdrawal from start 
of Part C
o
Observed values and changes in vital signs from start of Part C
o
Observed values and changes in C-SSRS from start of Part C
o
Observed values in ECG parameters and abnormal findings from start of Part C


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o
Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms, 
or a change from Baseline in QTcF of >30 ms or >60 ms from start of Part C
8.5.
Efficacy Measures
The following efficacy measures will be assessed during Part A:

The change in AIMS score (items 1 through 7) from Baseline of this study at each visit that 
this is measured, as assessed by the site rating.

The proportion of subjects who are a treatment success based on the CGIC at each visit that 
this is measured. A treatment success is defined as Much or Very Much Improved on the 
CGIC from Baseline of this study. 

The proportion of subjects who have a 50% or greater reduction in AIMS score from 
Baseline of this study at each visit that this is measured.

The change in the modified CDQ-24 score from Baseline of this study at each visit that this 
is measured.

The proportion of subjects who are a treatment success based on the PGIC at each visit that 
this is measured. A treatment success is defined as Much or Very Much Improved on the 
PGIC from Baseline of this study.

The percent change in AIMS score from Baseline of this study at each visit that this is 
measured.
The following efficacy measure will be assessed during Part B (Randomized Withdrawal 
Period):

Primary efficacy endpoint: change from Pre-withdrawal Visit AIMS scores (items 1 through 
7) as assessed by blinded central video rating to the Post-withdrawal Visit between subjects 
treated with SD-809 and subjects treated with placebo.
8.6.
Efficacy Analysis (Randomized Withdrawal Period; Part B)
Analysis of the change in centrally read AIMS score (items 1 through 7) during the Randomized 
Withdrawal Period (from the Pre-withdrawal Visit to the Post-withdrawal Visit) will use an 
analysis of covariance (ANCOVA) model with the change in AIMS score as the dependent 
variable. The model will include randomized withdrawal treatment group, AIMS score at the 
Pre-withdrawal Visit, and DRA status at the Pre-withdrawal Visit as fixed effects. The least 
squares means of the change in AIMS score will be compared between the SD-809 treatment and 
placebo groups using a 2-sided test at the alpha=0.05 level of significance. In addition, actual 
values and changes in AIMS score will be summarized using descriptive statistics.
The primary efficacy analysis will be tested at the α=0.05 level. If less than 135 subjects are 
enrolled into the randomized withdrawal portion of the study, inferential statistics will not be 
provided as the study will be insufficiently powered to detect a treatment effect given the sample 
size assumptions.
8.7.
Sample Size
Because this is an open-label safety study, the sample size is not based on statistical 
considerations. 
During the Randomized Withdrawal Period in Part B, there will be up to 194 subjects 
randomized (SD-809 or placebo). It is estimated that approximately 91 subjects per arm will 
enable a power of at least 90% to detect a beneficial effect of 1.4 points or more in the change 


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from pre-withdrawal to post-withdrawal in centrally read AIMS when the SD-809 arm is 
compared to placebo, assuming a standard deviation of 2.9 and a 2-sided type I error rate of 5%.
Approximately 102 subjects may enroll in Part C conducted in the EU countries.
8.8.
Protocol Deviations and Violations
The Investigator is responsible for ensuring that the study is conducted in accordance with the 
protocol. No modifications to the protocol, other than those that are deemed necessary to protect 
the safety, rights, or welfare of subjects by the Investigator are to be made without prior, written 
approval by the Sponsor. The nature and reasons for the protocol deviation will be recorded 
where appropriate and indicated. The Sponsor must be notified of all protocol 
deviations/violations. Significant protocol deviations/violations (e.g., inclusion/exclusion 
criteria) will be reported to the Sponsor and to the IRB/IEC in accordance with its reporting 
policy.
8.9.
Data Recording
Source data will be transcribed onto source document worksheets and will then be entered into 
an eCRF. An Electronic Data Capture (EDC) system with eCRFs will be used for this trial. 
Instructions for eCRF completion will be provided in a separate document. Source data 
collection and entry into the eCRF will be completed by authorized study site personnel 
designated by the investigator. Appropriate training and security measures will be completed 
with the investigator and all authorized study site personnel prior to the study being initiated and 
before any data is entered into the eCRF system for any study subjects.
8.10.
Data Quality Assurance
Steps to assure the accuracy and reliability of data include the selection of qualified clinical 
Investigators and appropriate study sties, review of protocol procedures with the clinical 
Investigator and associated personnel prior to the study, and periodic monitoring visits by the 
Sponsor. The Sponsor (or designee) will review data accuracy and completeness during and after
the study, and any discrepancies will be resolved with the clinical investigator or designee as 
appropriate.
8.11.
Data Management
The data will be entered into a validated EDC system that complies with Title 21 of the Code of 
Federal Regulations part 11, maintained by the Sponsor or designee. The data management 
group will be responsible for data processing, in accordance with agreed procedures. The 
Principal Investigator will electronically sign and date the appropriate eCRF page when 
instructed to do so by the study CRA. This signature will indicate that the Principal Investigator 
inspected or reviewed the data in the database, the data queries, and the site notifications, and 
agrees with the content.
The standard procedures for handling and processing eCRF records will be followed per Good 
Clinical Practice (GCP) and the Sponsor’s (or designee’s) SOPs. 
Complete details of data management will be described in a separate Data Management Plan.


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9.
ADMINISTRATIVE ISSUES
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines including the International Conference on Harmonization (ICH) Guideline on GCP.
The clinical trial will be conducted in accordance with the applicable regulations of the local 
regulatory authority.
9.1.
Investigator Obligations
9.1.1.
Independent Ethics Committee/Institutional Review Board Approval
Prior to initiation of the study, the written IEC/IRB approval of the protocol and Study 
Information Forms/Informed Consent Forms based on the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) will be received. This approval will be on 
the Institutional letterhead and will refer to the Study Information Forms/Informed Consent 
Forms and to the study by title and protocol number given on page 1 of the protocol. A copy of 
the signed and dated letter of approval will be provided to Auspex and designee prior to study 
commencement. Any written information and/or advertisements to be used for volunteer 
recruitment will be approved by the IEC/IRB prior to use. 
9.1.2.
Written Informed Consent
Informed consent will be obtained before the subject can participate in the study. If subject lacks 
the capacity to provide informed consent, a LAR must provide written informed consent and the 
subject must provide assent. The contents and process of obtaining informed consent will be in 
accordance with all applicable regulatory requirements.
It is the responsibility of the Investigator or designee to obtain written informed consent, using 
the most current informed consent form approved by the IRB/IEC and Sponsor, from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study. The Investigator or designee must also explain to the subjects 
that they are completely free to refuse to enter the study or to withdraw from it at any time. 
Appropriate forms for documenting written consent will be provided by the Investigator or 
designee.
For this study, each eligible subject will be required to provide written informed consent 
utilizing: Consent to participation in the study (Information Form/Informed Consent Form).
All eligible subjects and caregivers will have the study explained by the Investigator or designee. 
They will receive a full explanation, in lay terms, of the aims of the study, the discomfort, risks, 
and benefits in taking part as well as of insurance and other procedures for compensation in case 
of injury. It will be explained that the study is for research purposes only and is not expected to 
provide any therapeutic benefit to the individual. It will be pointed out that they can withdraw 
from the study at any time without prejudice. Each subject will acknowledge receipt of this 
information by giving written informed consent for participation in the study. The subject and 
caregiver will be given a copy of the signed Information Form/Informed Consent Form to retain.
Part B Double-Blind, Randomized Withdrawal Period
Part B will begin after Amendment 06 implementation. Subjects who decline to participate in the 
Randomized Withdrawal Period (Part B) (i.e., sign written informed consent) will continue in 
Part A until Week 158.


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Part C Reduced Burden Safety Assessments
Part C will begin after Amendment 07 implementation. Subjects who decline to participate in 
Part C (i.e., do not sign written informed consent) will complete the study at the Part B 
Follow-up Call.
9.1.3.
Emergency Contact with Investigator
Suitable arrangements will be made for subjects to make contact with the Investigator or a 
medically qualified designee in the event of an emergency.
9.1.4.
Ethical Considerations
This study will be carried out in accordance with the principles of ICH GCP which build upon 
the ethical codes contained in the Declaration of Helsinki.
The investigational site and the Sponsor agree to abide by the applicable guidelines for 
compensation for injury resulting from participating in a company-sponsored research project. 
Compensation will only be provided on the understanding that the provision of compensation 
does not amount to an admission of legal liability.
9.1.5.
Privacy Rule
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the Sponsor. Only the subject number and/or 
randomization number will be recorded on the source documents and eCRF. If the subject name 
appears on any other document (e.g., pathologist report), it must be redacted before a copy of the 
document is supplied to the Sponsor. Study findings stored on a computer will be stored in 
accordance with local data protection laws. The subjects will be informed in writing that 
representatives of the Sponsor, IEC/IRB, or Regulatory Authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in the strictest confidence and in accordance with local data protection 
laws. Laboratory specimens, including CAG repeat testing, will be destroyed after testing is 
complete in accordance with each laboratory’s standard procedures. 
Digital video data is considered identifiable data (contains faces). Subjects will be informed in 
writing that video data will be analyzed by specific TD experts, and may be reviewed by the 
FDA. Sponsor medical personnel may access video data for review and analysis; however, 
videos will not be used by sponsor for any commercial, advertising or promotional purposes. 
Copies of the digital video data compiled and held for purposes of conducting this study will be 
handled in the strictest confidence and stored in accordance with local data protection laws. 
If the results of the study are published, the identity of all subjects will remain confidential.
The Investigator will maintain a list of the subject identification number to enable subjects’ 
records to be identified.
9.2.
Protocol Amendments
Any amendments to the protocol must be agreed upon by the Sponsor. Protocol amendments, if 
any, will be formalized and submitted to the IRB/IEC, per local rules, for written approval before 
implementation. The expedited review procedure for an amendment is appropriate only if subject 
safety is not an issue.


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9.3.
Records Retention
Following closure of the study, the Investigator must maintain all site study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., audit or inspection) and whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems and staff. The Sponsor will 
inform the Investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that site for the study, as dictated by any institutional requirements or local laws or 
regulations, or the Sponsor’s standards/procedures; otherwise, the retention period will default to 
the time period specified in 21 CFR Part 312.57: 2 years after a marketing application is 
approved for the drug; or, if an application is not approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is discontinued and FDA has been so 
notified.
9.4.
Study Monitoring
The Sponsor (or designee) is responsible for assuring the proper conduct of the study with regard 
to protocol adherence and validity of the data recorded on the eCRFs. Subject confidentiality will 
be maintained.
In accordance with applicable regulations, GCP, and Sponsor (or designee) procedures, the 
clinical trial coordination center (CTCC) will contact the site prior to the subject enrollment to 
review the protocol and data collection procedures with site staff. In addition, the monitor will 
periodically contact the site, including conducting on-site visits. The extent, nature and 
frequency of on-site visits will be based on such considerations as the study objective and/or 
endpoints, the purpose of the study, study design complexity, and enrolment rate. The visits will 
be conducted in accordance with the Sponsor’s (or designee’s) SOP and study monitoring plan.
In general, the Investigator agrees to fully cooperate with the monitor, allow the monitor direct 
access to all relevant documents, to allocate his/her time and the time of his/her staff to the 
monitor to discuss any findings and any relevant issues as needed.
9.5.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies. Examples of a clinical product complaint 
include but are not limited to the following: 

Suspected contamination

Questionable stability (e.g., color change, flaking, crumbling, etc)

Defective or incorrect packaging/labels

Missing or extra units (e.g., primary container is received at the site with more or less than 
the designated number of units inside)

Unexpected or unanticipated taste or odor or both
9.5.1.
Product Complaint Reporting and Documentation
Each investigational site is responsible for reporting a suspected clinical product complaint to the 
Sponsor as soon as feasible and, if possible, within 48 hours of becoming aware of the issue. The 
following information should be provided to the Sponsor:

Investigational site number, principal investigator name, and clinical protocol number


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
Date of and name of person receiving the complaint

Name, phone number, and address of the source of the complaint

Product name and strength

Description or nature of complaint

Subject identifier and corresponding visit number, if applicable

Subject number, bottle, and kit numbers (if applicable)

Product available for return: Yes/No

Product was taken or used according to protocol: Yes/No

Associated serious adverse event: Yes/No
Note: Reporting a complaint must not be delayed if any of the above required information is not 
known within 48 hours of becoming aware of the complaint. The Sponsor will collaborate with 
the Investigator to obtain any outstanding information.
The Investigator will record in the source documentation a description of the clinical product 
complaint and any actions taken to resolve the complaint and to preserve the safety of the 
subject.
9.5.2.
Handling the Suspect Study Drug at the Investigational Site
The Investigator must retain the product in question in a location separate from the Investigator’s 
clinical study supplies. The Sponsor may request that the Investigator return the product for 
further evaluation and/or analysis.
The integrity of the randomization code and corresponding blinded clinical supplies must be 
maintained whenever possible.
9.5.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event, the protocol should be followed.
9.5.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor (or 
designee) may conduct a Quality Assurance audit. Regulatory agencies may also conduct a 
regulatory inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection is requested, the Investigator and institution 
agree to immediately notify the Sponsor, to allow the auditor/inspector direct access to all 
relevant documents, and allocate his/her time and the time of his/her staff to the auditor/inspector 
to discuss findings and any relevant issues and remedies.


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10.
INFORMATION DISCLOSURE AND INVENTIONS
10.1.
Ownership
All information provided by Auspex, and all data and information generated by a study site 
and/or by Auspex’s contractors and subcontractors as part of the study (other than a study 
subject’s medical records), are the sole property of Auspex.
All rights, title and interests in any inventions, discoveries, know-how and other intellectual or 
industrial property rights which are conceived or reduced to practice during the course of or as a 
result of the study are the sole property of Auspex and are hereby assigned to Auspex.
If any written contract is executed between Auspex and the study site for the conduct of the 
study, or between Auspex and a contractor for support of the study, and such contract includes 
ownership provisions that are inconsistent with or otherwise differ from the foregoing sentence, 
then with respect to such inconsistency or difference, that contract’s ownership provisions 
regarding inventions and other intellectual or industrial property rights shall control.
10.2.
Confidentiality
All information provided by Auspex and all data and information generated by the site as part of 
the study, (other than a subject’s medical records), will be kept confidential by the Investigator 
and other site staff. The Investigator or other site personnel will not use this information and data 
for any purpose other than conducting the study. These restrictions do not apply to: 
(1) information which becomes publicly available through no fault of the Investigator or site 
staff; (2) information which it is necessary to disclose in confidence to an IEC solely for the 
evaluation of the study; (3) information which it is necessary to disclose in order to provide 
appropriate medical care to a study subject; or (4) study results which may be published as 
described in the next paragraph. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement.
10.3.
Publication
Auspex recognizes the importance of communicating medical study data and therefore 
encourages publication in peer-reviewed scientific journals and at seminars or conferences. The 
details of the processes of producing and reviewing reports, manuscripts and presentations based 
on the data from this trial are described in the Clinical Trial Agreement.


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11.
REFERENCES
American Psychiatric Association. (2000). Diagnostic criteria from DSM-IV-TR. Washington, 
D.C.: American Psychiatric Association.
Baillie, T. A. (1981). The use of stable isotopes in pharmacological research. Pharmacol Rev, 
33(2), 81-132. 
Barnes, T. R. (1989). A rating scale for drug-induced akathisia. Br J Psychiatry, 154, 672-676. 
Bhidayasiri, R., Fahn, S., Weiner, W. J., Gronseth, G. S., Sullivan, K. L., Zesiewicz, T. A., & 
American Academy of, N. (2013). Evidence-based guideline: treatment of tardive 
syndromes: report of the Guideline Development Subcommittee of the American 
Academy of Neurology. Neurology, 81(5), 463-469.
Blagojevic, N., Storr, G., & Allen, J. B. (1994). Role of heavy water in boron neutron capture 
therapy. In R. Zamenhof, G. Solares & O. Harling (Eds.), Dosimetry and treatment 
planning for neutron capture therapy. Madison, WI.
Brandrup, E. (1961). Tetrabenacine treatment in persisting dyskinesia caused by 
psychopharmaca. Am J Psychiatry, 118, 551-552. 
Chang, R. (2007). Chemistry, 9th Ed.: McGraw-Hill.
Chouinard, G., Annable, L., Ross-Chouinard, A., & Mercier, P. (1988). A 5-year prospective 
longitudinal study of tardive dyskinesia: factors predicting appearance of new cases. J 
Clin Psychopharmacol, 8(4 Suppl), 21S-26S. 
Collins, M. L., Eng, S., Hoh, R., & Hellerstein, M. K. (2003). Measurement of mitochondrial 
DNA synthesis in vivo using a stable isotope-mass spectrometric technique. J Appl 
Physiol, 94(6), 2203-2211. 
The Columbia Suicide Severity Rating Scale. Retrieved May 18, 2012, from 
http://www.cssrs.columbia.edu/about_cssrs.html
Correll, C. U., Rummel-Kluge, C., Corves, C., Kane, J. M., & Leucht, S. (2009). Antipsychotic 
combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled 
trials. Schizophr Bull, 35(2), 443-457.
Di Costanzo, L., Moulin, M., Haertlein, M., Meilleur, F., & Christianson, D. W. (2007). 
Expression, purification, assay, and crystal structure of perdeuterated human arginase I. 
Arch Biochem Biophys, 465(1), 82-89.
Fisher, S. J., & Helliwell, J. R. (2008). An investigation into structural changes due to 
deuteration. Acta Crystallogr A, 64(Pt 3), 359-367.
Gerlach, J., & Hansen, L. (1992). Clozapine and D1/D2 antagonism in extrapyramidal functions. 
Br J Psychiatry Suppl(17), 34-37. 
Godwin-Austen, R. B., & Clark, T. (1971). Persistent phenothiazine dyskinesia treated with 
tetrabenazine. Br Med J, 4(5778), 25-26. 
Guidance for Industry Suicidality: Prospective Assessment of Occurrence in Clinical Trials, 
DRAFT GUIDANCE. (September 2010).
Guy, W. (1976). AIMS: ECDEU Assessment Manual for Psychopharmacology. Washington, 
DC: Government Printing Office.
Guy, W. (2000). Abnormal Involuntary Movement Scale (AIMS). In A. J. Rush, H. A. Pincus, 
M. B. First, D. Blacker, J. Eundicott, S. J. Keith, K. A. Phillips, N. D. Ryan, G. R. Smith, 
M. T. Tsuang, T. A. Widiger & D. A. Zarin (Eds.), Handbook of Psychiatric Measures
(pp. 166-168). Washington, DC: American Psychiatric Association.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
90
Guyton, A. C. (1991) Textbook of Medical Physiology, 8th Ed. (pp. 274). Philadelphia, PA: W.B. 
Saunders.
Hellerstein, M. K., Hoh, R. A., Hanley, M. B., Cesar, D., Lee, D., Neese, R. A., & McCune, J. 
M. (2003). Subpopulations of long-lived and short-lived T cells in advanced HIV-1 
infection. J Clin Invest, 112(6), 956-966. 
Jankovic, J., & Beach, J. (1997). Long-term effects of tetrabenazine in hyperkinetic movement 
disorders. Neurology, 48(2), 358-362. 
Jankovic, J., & Clarence-Smith, K. (2011). Tetrabenazine for the treatment of chorea and other 
hyperkinetic movement disorders. Expert Rev Neurother, 11(11), 1509-1523.
Jankovic, J., Hunter, C. B., Mejia, N., & Vuong, K. (2004). Tetrabenazine: Effective treatment 
for tardive dyskinesia. Movement Disorders, 19(Suppl. 9), S73. 
Jankovic, J., & Orman, J. (1988). Tetrabenazine therapy of dystonia, chorea, tics, and other 
dyskinesias. Neurology, 38(3), 391-394. 
Johns, M. W. (1991). A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep, 14(6), 540-545.
Jones, P.B., Barnes, T.R.E, Davies, L., Dunn, G., Lloyd, H., Hayhurst, K.P., . . . Lewis, S.,W. 
(2006). Randomized controlled trial of the effect on quality of life of second- vs first-
generation antipsychotic drugs in schizophrenia. Arch Gen Psychiatry, 63, 1079-1087.
Kamper, S. J., Maher, C. G., & Mackay, G. (2009). Global rating of change scales: a review of 
strengths and weaknesses and considerations for design. J Man Manip Ther, 17(3), 
163-170. 
Kane, J. M. (2004). Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence 
and incidence. J Clin Psychiatry, 65 Suppl 9, 16-20. 
Kassis, A. N., & Jones, P. J. (2008). Changes in cholesterol kinetics following sugar cane 
policosanol supplementation: a randomized control trial. Lipids Health Dis, 7(1), 17. 
Kazamatsuri, H., Chien, C., & Cole, J. O. (1972). Treatment of tardive dyskinesia. I. Clinical 
efficacy of a dopamine-depleting agent, tetrabenazine. Arch Gen Psychiatry, 27(1), 
95-99. 
Kenney, C., Hunter, C., & Jankovic, J. (2007). Long-term tolerability of tetrabenazine in the 
treatment of hyperkinetic movement disorders. Mov Disord, 22(2), 193-197.
Kushner, D. J., Baker, A., & Dunstall, T. G. (1999). Pharmacological uses and perspectives of 
heavy water and deuterated compounds. Can J Physiol Pharmacol, 77(2), 79-88. 
Lane, R. D., Glazer, W. M., Hansen, T. E., Berman, W. H., & Kramer, S. I. (1985). Assessment 
of tardive dyskinesia using the abnormal involuntary movement scale. J of Nervous and 
Mental Disease, 173(6), 353-357.
Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A., Perkins, D.O., 
Hsiao, J.K. (2005). Effectiveness of Antipsychotic drugs in patients with chronic 
schizophrenia. New Eng J Med, 353 (12), 1206-1223.
Leitch, C. A., & Jones, P. J. (1993). Measurement of human lipogenesis using deuterium 
incorporation. J Lipid Res, 34(1), 157-163. 
Leucht, S., Wahlbeck, K., Hamann, J., & Kissling, W. (2003). New generation antipsychotics 
versus low-potency conventional antipsychotics: a systematic review and meta-analysis. 
The Lancet, 361(9369), 1581-1589. 
Lohr, J. B. (2008). Commentary: Is Tardive Dyskinesia Disappearing? Drug Induced Movement 
Disorders (pp. 302-310): Blackwell Publishing Inc.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
91
MacCullum, W.A.G. (1970). Tetrabenazine for Extra-Pyramidal Movement Disorders. British 
Medical Journal, 760. 
Muller, J., Wissel, J., Kemmler, G., Voller, B., Bodner, T., Schneider, A., Poewe, W. (2004) 
Craniocervical Dystonia Questionnaire (CDQ-24): Development and Validation of a 
Disease-specific Quality of Life Instrument. J Neurol Neurosurg Psychiatry, 75: 
749-753.
Munetz, M. R. and Benjamin, S. (1988) How to Examine Patients Using the Abnormal 
Involuntary Movement Scale. Hospital and Community Psychiatry, 39(11), 1172-1177.
Neese, R. A., Misell, L. M., Turner, S., Chu, A., Kim, J., Cesar, D., Hellerstein, M. K. (2002). 
Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the 
deoxyribose moiety of DNA. Proc Natl Acad Sci U S A, 99(24), 15345-15350. 
Ondo, W. G., Hanna, P. A., & Jankovic, J. (1999). Tetrabenazine treatment for tardive 
dyskinesia: assessment by randomized videotape protocol. Am J Psychiatry, 156(8), 
1279-1281. 
Paleacu, D., Giladi, N., Moore, O., Stern, A., Honigman, S., & Badarny, S. (2004). 
Tetrabenazine treatment in movement disorders. Clin Neuropharmacol, 27(5), 230-233. 
Stacy, M., Cardoso, F., & Jankovic, J. (1993). Tardive stereotypy and other movement disorders 
in tardive dyskinesias. Neurology, 43(5), 937-941. 
Strawford, A., Antelo, F., Christiansen, M., & Hellerstein, M. K. (2004). Adipose tissue 
triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured 
with 2H2O. Am J Physiol Endocrinol Metab, 286(4), E577-588. 
Tardive Dyskinesia Task Force. (1980). Tardive dyskinesia: summary of a Task Force Report of 
the American Psychiatric Association. By the Task Force on Late Neurological Effects of 
Antipsychotic Drugs. Am J Psychiatry, 137(10), 1163-1172. 
Tarsy, D. (1983). History and definition of tardive dyskinesia. Clin Neuropharmacol, 6(2), 
91-99. 
Tarsy, D., & Baldessarini, R. J. (1984). Tardive dyskinesia. Annu Rev Med, 35, 605-623.
Tarsy, D., & Baldessarini, R. J. (2006). Epidemiology of tardive dyskinesia: is risk declining 
with modern antipsychotics? Mov Disord, 21(5), 589-598.
Teo, J. T., Edwards, M. J., & Bhatia, K. (2012). Tardive dyskinesia is caused by maladaptive 
synaptic plasticity: a hypothesis. Mov Disord, 27(10), 1205-1215. 
Trugman, J. M. (1998). Tardive Dyskinesia: Diagnosis, Pathogenesis, and Management. The 
Neurologist, 4(4), 180-187. 
Ware, J. E., Jr. (2000). SF-36 health survey update. [Research Support, Non-U.S. Gov't Review]. 
Spine (Phila Pa 1976), 25(24), 3130-3139. 
Ware, J. E., Jr., & M., k. (September 20, 1996 (updates September 27, 1997)). The SF-36 Health 
Survey (Version 2.0) Technical Note. Boston MA: Health Assessment Lab. 
Zigmond, A. S., & Snaith, R. P. (1983). The hospital anxiety and depression scale. Acta 
Psychiatr Scand, 67(6), 361-370. 


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12.
APPENDICES
Appendix 1: Site Investigator Signature Page

I agree to implement and conduct this study diligently and in strict compliance with 
the protocol, good clinical practices and all applicable laws and regulations.

I have read and agree to comply with the Investigator obligations stated in this 
protocol. Any changes in procedure will only be made if necessary to protect the 
safety, rights or welfare of subjects.

I agree to conduct in person or to supervise the trial.

I agree to ensure that all that assist me in the conduct of the study are aware of their 
obligations.

I agree to maintain all information supplied by Auspex Pharmaceuticals, Inc. in 
confidence and, when this information is submitted to an Institutional Review Board 
(IRB), Independent Ethics Committee (IEC) or another group, it will be submitted 
with a designation that the material is confidential.
I have read and understand Protocol SD-809-C-20 Amendment 07 in its entirety and I 
agree to all aspects.
Investigator:
Print Name
Signature
Date


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Appendix 2: 
 
 
 
 
 
 
 
 
 
                                                
h Guy W. AIMS: ECDEU Assessment Manual for Psychopharmacology. Washington, DC: Government Printing 
Office; 1976.


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Appendix 3: 
 


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Appendix 4:
 
 


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Appendix 5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 6: Unified Parkinson’s Disease Rating Scale (UPDRS) PART III: Motor 
Examinationi
 
                                                
 


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20c. Tremor at rest – Left hand
 


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Appendix 12: 


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Appendix 13: Strong CYP2D6 Inhibitors

Bupropion

Fluoxetine

Paroxetine
The maximum total daily dose of SD-809 for subjects with body weight less than 100 kg 
receiving any of the above strong CYP2D6 inhibitors is 36 mg per day. For subjects with body 
weight of 100 kg or more, receiving any of the above strong CYP2D6 inhibitors, the maximum 
total daily dose of SD-809 is 42 mg per day.


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Appendix 14: Prohibited or Restricted QT Prolonging Drugs
Generic
Brand Name Class/Clinical Use
Prohibited 
or 
Restricted
Note
Amiodarone
Cordarone®, 
Pacerone®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Arsenic trioxide Trisenox®
Anti-cancer / Leukemia
Prohibited
Azithromycin
Zithromax®
Antibiotic / bacterial infection
Prohibited
Bepridil
Vascor®
Anti-anginal / heart pain
Prohibited
Chloroquine
Aralen®
Anti-malarial / malaria infection
Prohibited
Citalopram
Celexa®
Anti-depressant / depression
Restricted
See Appendix 16 for 
dosing information
Clarithromycin
Biaxin®
Antibiotic / bacterial infection
Prohibited
Disopyramide
Norpace®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Dofetilide
Tikosyn®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Domperidone
Motilium®
Anti-nausea / nausea
Prohibited Not available in U.S.
Droperidol
Inapsine®
Sedative; Anti-nausea/anesthesia 
adjunct, nausea
Prohibited
Erythromycin
E.E.S.®, 
Erythrocin®
Antibiotic; GI stimulant; GI motility
Prohibited
Escitalopram
Lexapro®, 
Cipralex®
Anti-depressant / Anxiety disorders
Restricted
See Appendix 16 for 
dosing information
Flecainide
Tambocor®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Halofantrine
Halfan®
Anti-malarial / malaria infection
Prohibited
Ibutilide
Corvert®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Levomethadyl
Orlaam®
Opiate agonist/pain control, narcotic 
dependence
Prohibited Not available in U.S.
Methadone
Dolophine®
Opiate agonist/pain control, narcotic 
dependence
Prohibited
Methadone
Methadose®
Opiate agonist/pain control, narcotic 
dependence
Prohibited
Moxifloxacin
Avelox®
Antibiotic / bacterial infection
Prohibited
Pentamidine
NebuPent®, 
Pentam®
Anti-infective / pneumocystis 
pneumonia
Prohibited
Probucol
Lorelco®
Antilipemic / Hypercholesterolemia
Prohibited Not available in U.S.
Procainamide
Pronestyl®, 
Procan®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Quinidine
Quinaglute, 
Cardioquin
Anti-arrhythmic / abnormal heart rhythm Prohibited
Sevoflurane
Ulane®, 
Sojourn®
Anesthetic, general / anesthesia
Prohibited
Sotalol
Betapace®
Anti-arrhythmic / abnormal heart rhythm Prohibited
Sparfloxacin
Zagam®
Antibiotic / bacterial infection
Prohibited Not available in U.S.
Thioridazine
Mellaril®
Antipsychotic
Prohibited
Vandetanib
Caprelsa®
Anti-cancer / Thyroid cancer
Prohibited
Vardenafil
Levitra®
Phosphodiesterase inhibitor / vasodilator Prohibited


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Appendix 15: Dopamine Receptor Antagonists 
Typical/First 
Generation 
Antipsychotics
Typical Dosing
Atypical/Second 
Generation 
Antipsychotics
Typical Dosing
Chlorpromazine 
(Thorazine, Largactil)
30-800 mg/day (usual 
dose: 200-600 mg/day)
Aripiprazole (Abilify)
Usual dose:10-15 mg/day; 
up to 30 mg/day
Fluphenazine (Prolixin)
Initial: 2.5-10 mg/day; 
maintenance: 1-5 mg/day 
(up to 40 mg/day in some 
cases)
Asenapine Maleate 
(Saphris)
5 mg 2 times/day; up to 10 
mg 2 times/day
Haloperidol (Haldol, 
Serenace)
0.5-5 mg/day 2-3 
times/day; maximum: 30 
mg/day
Clozapine (Clozaril)
Initial: 12.5 mg 1-2 
times/day; target dose: 300-
450 mg/day; maximum 
dose: 900 mg/day
Loxapine (Loxapac, 
Loxitane)
Initial: 10 mg 2 times/day; 
maintenance: 60-100 
mg/day (maximum: 250 
mg/day)
Iloperidone (Fanapt)
Initial: 1 mg 2 times/day; 
recommended range: 6-12 
mg 2 times/day
Molindone (Moban; not 
available in US)
Initial: 50-75 mg/day; up to 
225 mg/day
Lurasidone (Latuda)
Initial: 20 mg/day; 
maximum: 120 mg/day
Perphenazine (Trilafon)
Initial: 4-8 mg/day; up to 
24 mg/day (up to 64
mg/day in hospitalized 
patients)
Olanzapine (Zyprexa)
Initial: 5-10 mg/day; 
maintenance: 10-20 mg/day 
(maximum: 30 mg/day for 
acute agitation)
Pimozide (Orap)
Initial: 1-2 mg/day; up to 
10 mg/day (or 0.2 
mg/kg/day)
Olanzapine/Fluoxetine 
(Symbyax)
Initial: 6 mg/25 mg per day; 
usual dose: 6-12 mg/25-50 
mg per day
Thioridazine (Mellaril)
Prohibited
Paliperidone (Invega)
Usual dose: 6 mg/day; 
maximum: 12 mg/day
Thiothixene (Navane)
Initial: 2 mg 3 times/day; 
usual dose: 15 mg/day; 
maximum 60 mg/day for 
severe symptoms
Quetiapine (Seroquel)
Initial: 25 mg 2 times/day; 
Usual range: 150-750 
mg/day
Trifluoperazine (Stelazine)
1-2 mg 2 times/day; up to 
40 mg/day in hospitalized 
patients
Risperidone 
(Risperdal)
Initial: 2 mg 1-2 times/day; 
Recommended range: 4-8 
mg/day
Ziprasidone (Geodon)
Initial: 20 mg 2 times/day; 
maintenance: 20-100 mg 2 
times/day
Other Agents
Metaclopramide (Reglan)
10 mg 4 times/day
Prochlorperazine 
(Compazine)
5-10 mg, 3-4 times/day; 
(usual maximum: 40 
mg/day)
Promethazine (Phenergan) 
containing compounds
12.5-50 mg/dose every 4-6 
hours 


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Appendix 16: Citalopram and Escitalopram Dosing Information
Citalopram (Celexa) is allowed with the following restrictions:
a) If the subject is a known CYP2C19 poor metabolizer, Celexa is not allowed.
b) If the subject is > 60 years old or is receiving cimetidine, omeprazole, esomeprazole, 
fluconazole, fluoxetine or ticlopidine, the maximum allowed dose is 20 mg/day.
c) If the subject is ≤ 60 years old and is not receiving any of the medications in (b) above, 
the maximum allowed dose is 40 mg.
The following flowchart may be used to determine the maximum allowable dose of Celexa:
Escitalopram (Lexapro or Cipralex) is allowed with the following restrictions:
Age
Maximum daily dose
< 65 years
20 mg
≥ 65 years
10 mg


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Appendix 17: Protocol Summary of Changes, Original Protocol (Dated 24 March 2014) to Amendment 01 (Dated 28 May 
2014)
Section 
Original Protocol, dated 24 March 2014
Amendment 01, dated 28 May 2014
Reason for Change
Study Contacts,
Medical Monitor
 
 
Update
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
2.
Subject has received any of the following 
medications within 30 days of Baseline: 

Reserpine, α-methyl-p-tyrosine 
(AMPT), anticholinergics, amantadine, 
or memantine

Metoclopraomide, stimulants, or 
monoamine oxidase inhibitors (MAOI)
2. Subject has received any of the following medications 
within 30 days of Baseline: 

Reserpine, α-methyl-p-tyrosine (AMPT), 
botulinum toxin (within 3 months of Baseline), 
anticholinergics, amantadine, or memantine

Metoclopramide, stimulants, or monoamine 
oxidase inhibitors (MAOIs)

Levodopa or dopamine agonists
Botulinum toxin may 
confound assessments 
of the dyskinesia; 
correct inconsistency 
between exclusion 
criteria and prohibited 
concomitant 
medications
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
15. Subject has participated in an 
investigational drug or device trial (other 
than Study SD-809-C-18) and received 
study drug within 30 days (or 5 drug half-
lives) of Screening, whichever is longer
15. Subject has participated in an investigational drug or 
device trial (other than Study SD-809-C-18) and 
received study drug within 30 days (or 5 drug half-
lives) of Baseline, whichever is longer
Correct inconsistency 
between exclusion 
criteria and prohibited 
concomitant 
medications
Section 3, 
Investigational Plan
The study will be conducted at approximately 30 
centers in the U.S., Canada, and possibly other 
regions. 
The study will be conducted at approximately 30 centers 
in the U.S. and possibly other regions. 
Clarification
Section 6.9.1,
Concomitant 
Medications
Prohibited Concomitant Medications
The following products should not be used within 
4 weeks of Screening and throughout the study:
•
Metoclopromide 
•
MAO Inhibitors
•
Levodopa or dopamine agonists
•
Reserpine
•
Amantadine
•
Memantine
Prohibited Concomitant Medications
The following products should not be used within 30 days 
of Baseline (unless noted below) and throughout the study:
•
Tetrabenazine (within 7 days of Baseline)
•
AMPT
•
Metoclopromide 
•
MAOIs
•
Levodopa or dopamine agonists
•
Reserpine
•
Anticholinergics
•
Amantadine
•
Memantine
•
Botulinum toxin (within 3 months of Screening)
•
Any investigational drug
Correct inconsistency 
between exclusion 
criteria and prohibited 
concomitant 
medications


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Section 
Original Protocol, dated 24 March 2014
Amendment 01, dated 28 May 2014
Reason for Change
Section 6.9.1,
Concomitant 
Medications
No text
After 3 months, changes in psychoactive medications are 
allowed if approved by the Investigator. Any changes in 
concomitant medications must be documented in the 
eCRF.
Clarification
Section 8,
Statistical 
Procedures and Data 
Analysis
Summary statistics will be provided by treatment.
Summary statistics will be provided by prior treatment (in 
Study SD-809-C-18) and for the overall population. 
Clarification
Section 8.3,
Safety Analysis
Descriptive statistics of change-from-baseline 
will use the Baseline from Study SD-809-C-18 
(C-18 Baseline) and the Baseline from the 
present study (C-20 Baseline), as appropriate, 
and will be specified in the Statistical Analysis 
Plan.
Descriptive statistics of change-from-baseline will use the 
Baseline from the present study (SD-809-C-20 Baseline).
Clarification
Appendix 2, 
Abnormal 
Involuntary 
Movement Scale 
(AIMS)
No Text
Scoring Criteria for Items 1 through 7
Clarification
Appendix 2, 
Abnormal 
Involuntary 
Movement Scale 
(AIMS)
Complete Examination Procedures before 
making ratings.
Movement Ratings:
Rate highest severity observed in category I, 
II, III
Complete Examination Procedures before making 
ratings.
Rate highest severity observed in category I, II, III
Clarification
Appendix 2, 
Abnormal 
Involuntary 
Movement Scale 
(AIMS)
8. Severity of abnormal movements 
8. Severity of abnormal movements 
None, normal = 0
Minimal = 1
Mild = 2
Moderate = 3
Severe = 4
Clarification
Appendix 2, 
Abnormal 
Involuntary 
Movement Scale 
(AIMS)
9. Incapacitation due to abnormal movements
9. Incapacitation due to abnormal movements
None, normal = 0
Minimal = 1
Mild = 2
Moderate = 3
Severe = 4
Clarification


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Section 
Original Protocol, dated 24 March 2014
Amendment 01, dated 28 May 2014
Reason for Change
Appendix 6, Unified 
Parkinson’s Disease 
Rating Scale 
(UPDRS) Part III: 
Motor Examination
Updated numbers of UPDRS to begin at 18 to better 
match Part III (Motor Examination) of the UPDRS.
Clarification
Appendix 17, 
Protocol Summary 
of Changes, Original 
Protocol (dated 24 
March 2014) to 
Amendment 01 
(dated 28 May 2014)
No Text
Addition of Appendix
Summarize changes in 
Amendment 01
Global
investigational product
study drug
Clarification
Global
Dates, section numbers, and tables of contents updated; 
typos and minor errors corrected
Clarification


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Appendix 18: Protocol Summary of Changes, Amendment 01 (dated 28 May 2014) to Amendment 02 (dated 08 July 2014)
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Global
dutetrabenazine
deutetrabenazine
Change in generic name
Cover Page
No text
EUDRACT No.: 2014-001891-73
Addition of EUDRACT 
number for European study 
sites
Study Contacts
Administrative change
Protocol 
Synopsis, Study 
Design
This is an open-label, single-arm study in which 
subjects with moderate to severe TD who have 
successfully completed the SD-809-C-18 study 
will be invited to participate.
Informed consent/assent will be obtained before 
any study procedures are performed. Subjects 
may have informed consent/assent obtained up to 
30 days in advance of subject’s SD-809-C-18 
Week 13 Visit/TD-Long Term Safety (LTS) 
Baseline Visit. 
This is an open-label, single-arm study in which 
subjects with moderate to severe TD who have 
successfully completed a parent study (SD-809-C-18 
study or any other controlled study of SD-809 for the 
treatment of moderate to severe TD) will be invited to 
participate.
Informed consent/assent will be obtained before any 
study procedures are performed. Subjects may have 
informed consent/assent obtained up to 30 days in 
advance of subject’s parent study Week 13 Visit/TD-
Long Term Safety (LTS) Baseline Visit.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, Study 
Design
Subjects who have successfully completed Study 
SD-809-C-18 may be eligible to enroll into this 
study after they complete a 1-week washout 
period and Week 13 evaluation from Study 
SD-809-C-18. To reduce subject burden, after 
obtaining informed consent/assent, some data 
collected in Study SD-809-C-18 will be used in 
Study SD-809-C-20 and will provide some of the 
baseline data for Study SD-809-C-20 (see 
Schedule of Events). In addition to assessments 
completed for the SD-809-C-18 Week 13 visit, 
evaluations required as part of the SD-809-C-20 
study will be completed on the same day as the 
Week 13 visit. 
Subjects who have successfully completed a parent 
study may be eligible to enroll into this study after they 
complete a 1-week washout period and the final 
evaluation in the parent study. To reduce subject 
burden, after obtaining informed consent/assent, some 
data collected in the parent study will be used in Study 
SD-809-C-20 and will provide some of the baseline 
data for Study SD-809-C-20 (see Schedule of Events). 
For example, in addition to assessments completed for 
the SD-809-C-18 Week 13 visit, evaluations required 
as part of the SD-809-C-20 study will be completed on 
the same day as the Week 13 visit. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.


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Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Protocol 
Synopsis, Study 
Design
Titration Period (up to 6 weeks): As subjects 
will have discontinued study drug (SD-809 or 
placebo) for 1 week at completion of the SD-809-
C-18 study, they will undergo SD-809 dose 
titration in this study. 
Titration Period (up to 6 weeks): As subjects will 
have discontinued study drug (SD-809 or placebo) for 
1 week at completion of the parent study, they will 
undergo SD-809 dose titration in this study. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, Dose 
Regimen
Once the Investigator determines that a stable 
dose has been reached, SD-809 will be supplied 
in 30-count bottles.
During long-term treatment, SD-809 will be supplied 
in 30-count bottles.
Clarification
Protocol 
Synopsis, Dose 
Regimen

The starting dose will be SD-809 12 mg/day 
(6 mg BID) regardless of previous treatment 
in the SD-809-C-18 trial. Prior treatment 
assignment from Study SD-809-C-18 will 
remain blinded.

The starting dose will be SD-809 12 mg/day (6 mg 
BID) regardless of previous treatment in the parent 
trial. Prior treatment assignment from the parent 
trial will remain blinded.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, 
Sample Size
Approximately 80 subjects (eligible subjects who 
completed SD-809-C-18 may enroll)
Approximately 260 subjects (eligible subjects who 
completed SD-809-C-18 or any other controlled study 
of SD-809 for treatment of moderate to severe TD may 
enroll)
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, 
Inclusion Criteria
Section 4.2, 
Inclusion Criteria
2.
Subject has successfully completed Study 
SD-809-C-18a
2.
Subject has successfully completed a Study SD-
809-C-18 or another controlled study of SD-809 
for treatment of moderate to severe TD
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Footnotes “a” 
and “d”
Successful completion of Study SD-809-C-18 is 
defined as (1) study participation through Week 
13 (2) the subject has generally been compliant 
with study drug and procedures, in the opinion of 
the investigator, and (3) the subject has no 
ongoing AEs that are serious or severe in 
intensity or are expected to interfere with safety 
evaluations in this study.
Successful completion is defined as (1) study 
participation through Week 13 (2) the subject has 
generally been compliant with study drug and 
procedures, in the opinion of the investigator, and (3) 
the subject has no ongoing AEs that are serious or 
severe in intensity or are expected to interfere with 
safety evaluations in this study.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.


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Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Protocol 
Synopsis, 
Exclusion 
Criteria
Section 4.3, 
Exclusion 
Criteria
2.
Subject has received any of the following 
medications within 30 days of Screening or 
Baseline: 
a.
Tetrabenazine, reserpine, α-methyl-p-
tyrosine (AMPT), botulinum toxin 
(within 3 months of Screening), 
anticholinergics, amantadine, or 
memantine
b.
Metoclopramide, stimulants, or 
monoamine oxidase inhibitors (MAOIs)

Levodopa or dopamine agonists
2.
Subject has received any of the following 
medications within 30 days of Screening or 
Baseline: 

Tetrabenazine, reserpine, α-methyl-p-tyrosine 
(AMPT), botulinum toxin (within 3 months of 
Screening), and medications with strong 
anticholinergic activity (trihexyphenidyl, 
benztropine, orphenadrine, procyclidine, and 
biperiden)

Metoclopramide, promethazine, and 
prochlorperazine 

Stimulants (i.e., methylphenidate, 
amphetamine/dextroamphetamine, 
lisdexamphetamine, etc.), or monoamine 
oxidase inhibitors (MAOIs)

Levodopa or dopamine agonists
Modified to better reflect 
medications likely to have 
significant interactions with 
SD-809 and/or directly oppose 
the effects of SD-809 based 
on known mechanism of 
action. In addition, additional 
guidance on specific 
anticholinergics and 
stimulants considered 
exclusionary is provided
Protocol 
Synopsis, 
Exclusion 
Criteria
Section 4.3, 
Exclusion 
Criteria
6.
Subject has history of any of the following 
within 5 years of Baseline:

Previous intent to act on suicidal 
ideation with a specific plan (positive 
answer to question 5 on C-SSRS), 
irrespective of level of ambivalence at 
the time of suicidal thought

Previous preparatory acts to commit 
suicide or suicidal behavior

A previous actual, interrupted or aborted 
suicide attempt
6.
Subject has history of any of the following within 
6 months of Baseline:

Previous intent to act on suicidal ideation with
a specific plan (positive answer to question 5 
on C-SSRS), irrespective of level of 
ambivalence at the time of suicidal thought

Previous preparatory acts to commit suicide or 
suicidal behavior

A previous actual, interrupted or aborted 
suicide attempt
Time frame modified from 5 
years to 6 months, as this time 
frame is considered more 
clinically relevant to 
accurately determine 
eligibility for this trial.
Protocol 
Synopsis, 
Exclusion 
Criteria
Section 4.3, 
Exclusion 
Criteria
14. Subject has known allergy to any of the 
components of study drug
14. Subject has known allergy to tetrabenazine or to 
any of the components of SD-809.
Clarification


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Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
128
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Protocol 
Synopsis, 
Exclusion 
Criteria
Section 4.3, 
Exclusion 
Criteria
15. Subject has participated in an investigational 
drug or device trial (other than Study SD-
809-C-18) and received study drug within 30 
days (or 5 drug half-lives) of Baseline, 
whichever is longer.
15. Subject has participated in an investigational drug 
or device trial (other than Study SD-809-C-18 or 
any other eligible SD-809 parent study) and 
received study drug within 30 days (or 5 drug 
half-lives) of Baseline, whichever is longer.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, 
Statistics
Safety data will be summarized descriptively for 
the overall population and based on prior 
treatment (SD-809 or placebo) in Study SD-809-
C-18. 
Safety data will be summarized descriptively for the 
overall population and based on prior treatment (SD-
809 or placebo) in the parent study. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Protocol 
Synopsis, 
Statistics
Descriptive statistics of change-from-baseline 
will utilize the Baseline from Study SD-809-C-18 
(C-18 Baseline) and the Baseline from the 
present study (C-20 Baseline), as appropriate, 
and will be specified in the Statistical Analysis 
Plan. 
Descriptive statistics of change-from-baseline will use 
the Baseline from the present study and will be 
specified in the Statistical Analysis Plan. 
Correct inconsistency between 
synopsis and main text
Protocol 
Synopsis, 
Statistics
Descriptive statistics will be used to summarize 
efficacy measures for the overall population and 
based on prior treatment (SD-809 or placebo) 
from Study SD-809-C-18.
Descriptive statistics will be used to summarize 
efficacy measures for the overall population and based 
on prior treatment (SD-809 or placebo) in the parent 
study.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Schedule of 
Events (Global 
change)
Study SD-809-C-18
Parent study
Subjects previously 
participating in another study 
of SD-809 for the treatment of
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Schedule of 
Events
MoCA© at Week 4 and Week 55 visits.
MoCA© deleted at Week 4 and Week 55
Reduce subject burden and 
decrease potential for practice 
effects.
Schedule of 
Events
Return Study Drug at Visit 54
Procedure deleted
Remove duplication of 
assessment of study drug 
accountability/compliance


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
129
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Schedule of 
Events
Footnote 7
Subjects who experience an SAE should have a 
single blood sample collected for metabolites of 
SD-809 within 48 hours of SAE, if possible.
Subjects who experience an SAE should have a blood 
sample collected for pharmacokinetic assessment as 
soon as possible after the SAE and within 48 hours of 
the last dose of study drug, if possible.
Clarification
Protocol 
Approval Page
No text
Added signature for Principal Investigator
Added Investigator signatures 
for European study sites.
Section 3, 
Investigational 
Plan
Approximately 80 subjects who have 
successfully completed the Phase 2/3 SD-809-C-
18 efficacy study will be enrolled. 
Approximately 260 subjects who have successfully 
completed a parent study (Phase 2/3 SD-809-C-18 
efficacy study or any other SD-809 study for treatment 
of moderate to severe TD) will be enrolled. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 3.1, 
Study Design
This is an open-label, single-arm study in which 
subjects with moderate to severe drug-induced 
TD who have successfully completed the SD-
809-C-18 efficacy study will be invited to 
participate. Successful completion of Study SD-
809-C-18 is defined as (1) study participation 
through Week 13 (2) the subject has generally 
been compliant with study drug and procedures, 
in the opinion of the investigator and (3) the 
subject has no ongoing AEs that that are serious 
(SAE)c, severe in intensity or are expected to 
interfere with their participation in this study.
Informed consent/assent will be obtained before 
any study procedures are performed. Subjects 
may have informed consent/assent obtained up to 
30 days in advance of subject’s SD-809-C-18 
Week 13 Visit/TD-Long Term Safety (LTS) 
Baseline Visit.
Subjects who have successfully completed Study 
SD-809-C-18 may be eligible to rollover directly 
into this study after they complete a 1-week 
washout period and the Week 13 evaluation of 
Study SD-809-C-18. To reduce subject burden, 
after obtaining informed consent/assent, some 
data collected in the SD-809-C-18 study will be 
used in the SD-809-C-20 study and will provide 
some of the baseline data for SD-809-C-20 (see 
This is an open-label, single-arm study in which 
subjects with moderate to severe drug-induced TD who 
have successfully completed a parent study will be 
invited to participate. Successful completion of a 
parent study is defined as (1) study participation 
through Week 13 (2) the subject has generally been 
compliant with study drug and procedures, in the 
opinion of the investigator and (3) the subject has no 
ongoing AEs that that are serious (SAE)c, severe in 
intensity or are expected to interfere with their 
participation in this study. 
Informed consent/assent will be obtained before any 
study procedures are performed. Subjects may have 
informed consent/assent obtained up to 30 days in 
advance of subject’s parent study Week 13 Visit/TD-
Long Term Safety (LTS) Baseline Visit. 
Subjects who have successfully completed a parent 
study may be eligible to rollover directly into this 
study after they complete a 1-week washout period and 
the Week 13 evaluation of the parent study. To reduce 
subject burden, after obtaining informed 
consent/assent, some data collected in the parent study 
will be used in the SD-809-C-20 study and will 
provide some of the baseline data for SD-809-C-20 
(see Schedule of Events). In addition to assessments 
completed for the parent study Week 13 visit, 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
130
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Schedule of Events). In addition to assessments 
completed for the SD-809-C-18 Week 13 visit, 
evaluations required as part of the SD-809-C-20 
study will be completed on the same day as the 
Week 13 visit.
Titration Period (up to 6 weeks): As all 
subjects will have discontinued study drug (SD-
809 or placebo) for 1 week at completion of the 
SD-809-C-18 study, they will undergo titration 
on SD-809 in this study. 
evaluations required as part of the SD-809-C-20 study 
will be completed on the same day as the Week 13 
visit.
Titration Period (up to 6 weeks): As all subjects will 
have discontinued study drug (SD-809 or placebo) for 
1 week at completion of the parent study, they will 
undergo titration on SD-809 in this study. 
Section 3.2, 
Rationale for 
Study Design
Subjects who successfully complete the placebo-
controlled efficacy study (SD-809-C-18) will be 
eligible to enroll. 
Subjects who successfully complete a placebo-
controlled efficacy study (SD-809-C-18 or any other 
controlled study of SD-809 as treatment for moderate 
to severe TD) will be eligible to enroll. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 3.2, 
Rationale for 
Study Design
The present investigation is an open-label safety 
study of up to 54 weeks treatment with SD-809 at 
a pharmacologically active dose and will enroll 
subjects with drug-induced dyskinesia associated 
with TD who were either previously exposed to 
SD-809 or placebo (from Study SD-809-C-18).
The US prescribing information for tetrabenazine 
indicates that CYP2D6 genotyping should be 
performed at doses higher than 50 mg, although 
genotyping is often not performed in clinical 
practice as the drug is titrated. In the present 
study, CYP2D6 genotyping will have been 
performed in a blinded manner in the previous 
study (SD-809-C-18) to allow evaluation of the 
effect of phenotype on safety parameters at the 
conclusion of the study.
The present investigation is an open-label safety study 
of up to 54 weeks treatment with SD-809 at a 
pharmacologically active dose and will enroll subjects 
with drug-induced dyskinesia associated with TD who 
were previously exposed to either SD-809 or placebo 
in a parent study.
The US prescribing information for tetrabenazine 
indicates that CYP2D6 genotyping should be 
performed at doses higher than 50 mg, although 
genotyping is often not performed in clinical practice 
as the drug is titrated. In the present study, CYP2D6 
genotyping will have been performed in a blinded 
manner in the parent study to allow evaluation of the 
effect of phenotype on safety parameters at the 
conclusion of the study.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 4.1, 
Population 
Characteristics
Male and female adult subjects with TD who 
have successfully completed the SD-809-C-18 
efficacy study and meet eligibility criteria will be 
enrolled.
Male and female adult subjects with TD who have 
successfully completed the parent study (Study SD-
809-C-18 or any other controlled study of SD-809 for 
treatment of moderate to severe TD) efficacy study and 
meet eligibility criteria will be enrolled.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
131
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Section 5.1, 
Study Drug
Once the Investigator determines that a stable 
dose has been reached, SD-809 will be 
supplied in 30 count bottles and labeled 
according to applicable regulatory guidelines.
During long-term treatment, SD-809 will be 
supplied in 30 count bottles and labeled according 
to applicable regulatory guidelines.
Clarification
Section 5.2.1, 
General 
Guidelines
• The starting dose will be SD-809 12 mg/day 
(6 mg BID) regardless of previous treatment in 
the SD-809-C-18 trial. Prior treatment 
assignment from Study SD-809-C-18 will 
remain blinded.

The starting dose will be SD-809 12 mg/day (6 
mg BID) regardless of previous treatment in the 
parent study. Prior treatment assignment from the 
parent study will remain blinded.
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 6.1.1
6.1.1
Prior Data from Study SD-809-C-18
6.1.1
Prior Data from the Parent Study
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 6.1.1, 
Prior Data from 
the Parent Study
See Schedule of Events for data to be imported 
from SD-809-C-18 after informed consent/assent.
Subjects who have successfully completed Study 
SD-809-C-18 may be eligible to rollover directly 
into this study after they complete a 1-week 
washout period and the Week 13 (visit window 
up to 10 days) evaluation of Study SD-809-C-18. 
To reduce subject burden, after obtaining 
informed consent/assent, some data collected in 
the SD-809-C-18 study will be used in the SD-
809-C-20 study and provide some of the baseline 
data for SD-809-C-20 (see Schedule of Events). 
In addition to assessments completed for the SD-
809-C-18 Week 13 visit, evaluations required as 
part of the SD-809-C-20 study will be completed 
on the same day as the Week 13 visit. All 
subjects participating in SD-809-C-20 are 
expected to rollover to SD-809-C-20 at the Week 
13 visit of SD-809-C-18. 
See Schedule of Events for data to be imported from 
the parent study after informed consent/assent.
Subjects who have successfully completed a parent 
study may be eligible to rollover directly into this 
study after they complete a 1-week washout period and 
the Week 13 (visit window up to 10 days) evaluation 
of the parent study. To reduce subject burden, after 
obtaining informed consent/assent, some data collected 
in the parent study will be used in the SD-809-C-20 
study and provide some of the baseline data for SD-
809-C-20 (see Schedule of Events). In addition to 
assessments completed for the parent study Week 13 
visit, evaluations required as part of the SD-809-C-20 
study will be completed on the same day as the Week 
13 visit. All subjects participating in SD-809-C-20 are 
expected to rollover to SD-809-C-20 at the Week 13 
visit of the parent study. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study
SD-809-C-20.


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
132
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Section 6.2, Dose 
Adjustment 
Period
As all subjects will have discontinued study drug 
(SD-809 or placebo) for 1 week after completion 
of the SD-809-C-18 study, they will undergo 
titration on SD-809 in this study. 
As all subjects will have discontinued study drug (SD-
809 or placebo) for 1 week after completion of the 
parent study, they will undergo titration on SD-809 in 
this study. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 6.4.1, 
Clinic Visit 
(Week 55 ± 3 
days)

MoCA©
Text deleted.
Reduce subject burden and 
decrease potential for practice 
effects.
Section 6.7.1, 
Demographic 
and Medical 
History
The subject’s gender, date of birth, race, ethnic 
origin, and medical and surgical history will be 
transferred from data collected in Study SD-809-
C-18. 
The subject’s gender, year of birth, age, race, ethnic 
origin, and medical and surgical history will be 
transferred from data collected in the parent study. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 6.7.6, 
Laboratory Tests
Screening Labs
Labs for Screening Purposes
Clarification that these 
laboratory evaluations are for 
screening purposes, but may 
occur at a visit other than 
Screening
Section 6.7.6, 
Laboratory Tests

CAG repeat (blinded)
Text deleted
CAG repeat evaluation not 
relevant to this study
Section 6.7.7, 12-
lead 
Electrocardio-
gram
12-lead ECGs to assess safety will be recorded 
according to the Schedule of Events and 
interpreted by a cardiologist. Heart rate and ECG 
intervals (PR, QRS, QT, and QTcF) and clinical 
interpretation will be assessed by the cardiologist 
and recorded in the CRF.
12-lead ECGs to assess safety will be collected 
according to the Schedule of Events. Heart rate and 
ECG intervals (PR, QRS, QT, and QTcF) and clinical 
interpretation will be assessed by the central reader.
Clarification
Section 6.8,
Pharmaco-kinetic 
Evaluations
Subjects experiencing an SAE should have a 
single blood sample collected as soon as possible 
after the SAE and within 48 hours for the 
pharmacokinetics of α- and β- HTBZ, if possible. 
The date and time of the last dose of study drug 
should be recorded along with the date and time 
of the sample collection.
Subjects experiencing an SAE should have a single 
blood sample collected as soon as possible after the 
SAE and within 48 hours of the last dose of study drug 
for the pharmacokinetic assessment of α- and β-
HTBZ, if possible. The date and time of the last dose 
of study drug should be recorded along with the date 
and time of the sample collection.
Clarification


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
133
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Section 6.9.1,
Concomitant 
Medications
Prohibited Concomitant Medications
The following products should not be used within 
30 days of Baseline (unless noted below) and 
throughout the study:
•
Tetrabenazine (within 7 days of baseline)
•
AMPT
•
Metoclopromide 
•
MAOIs
•
Levodopa or dopamine agonists
•
Reserpine
•
Anticholinergics
•
Amantadine
•
Memantine
•
Botulinum toxin (within 3 months of 
Screening)
•
Any investigational drug
Prohibited Concomitant Medications
The following products should not be used within 30 
days of Baseline (unless noted below) and throughout 
the study:
•
Tetrabenazine (within 7 days of Baseline) 
•
AMPT
•
Metoclopromide, promethazine, and 
prochlorperazine
•
Stimulants (i.e., methylphenidate, 
amphetamine/dextroamphetamine, 
lisdexamphetamine, etc.)
•
MAOIs
•
Levodopa or dopamine agonists
•
Reserpine
•
Medications with strong anticholinergic activity 
(trihexyphenidyl, benztropine, orphenadrine, 
procyclidine, and biperiden)
•
Botulinum toxin (within 3 months of Screening)
•
Any investigational drug
Modified to better reflect 
medications likely to have 
significant interactions with 
SD-809 and/or directly oppose 
the effects of SD-809 based 
on known mechanism of 
action. In addition, additional 
guidance on specific 
anticholinergics and 
stimulants considered 
exclusionary is provided.
Section 6.13, 
Study 
Termination
The Investigator reserves the right to discontinue 
the study for safety reasons at any time in 
collaboration with the Sponsor.
The Investigator reserves the right to discontinue the 
study at their site for safety reasons at any time in 
collaboration with the Sponsor.
Clarification
Section 7.4.2, 
Regulatory 
Reporting 
Requirements for 
SAEs
The Investigator must promptly report all SAEs 
to the Sponsor in accordance with the procedures 
describe above. 
The Investigator must promptly (within 24 hours of 
awareness) report all SAEs to the Sponsor (or 
designee) in accordance with the procedures describe 
above. 
Clarification
Section 8, 
Statistical 
Procedures and 
Data Analysis
Summary statistics will be provided by prior 
treatment (in Study SD-809-C-18) and for the 
overall population. 
Summary statistics will be provided by prior treatment 
(in parent study) and for the overall population. 
Subjects previously 
participating in another study 
of SD-809 for the treatment of 
moderate to severe TD will be 
allowed to participate in Study 
SD-809-C-20.
Section 8.3, 
Safety Analysis
Safety data will be summarized descriptively for 
the overall population and based on prior 
treatment (SD-809 or placebo). 
Safety data will be summarized descriptively for the 
overall population and based on prior treatment (SD-
809 or placebo) in the parent study. 
Clarification


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
134
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Section 9.4.1, 
Safety 
Monitoring 
Committee 
(SMC)
9.4.1
Safety Monitoring Committee (SMC)
An independent Safety Monitoring committee 
(SMC) will be established prior to study start, 
with an appropriate charter to direct decisions 
and communications, maintain a firewall to 
preserve the blinding and integrity of the study, 
and monitor the trial safety results at intervals 
throughout the study. The SMC will be 
comprised of at least two clinicians, at least one 
of which is experienced in treating patients with 
movement disorders such as TD, and a 
statistician not otherwise associated with the trial.
The main purpose of the SMC will be to protect 
the interests of the subjects enrolled in the trial. 
The SMC will determine the data necessary for 
monitoring and the intervals for formal review 
and discussion (e.g., after certain percentage of 
enrolled subjects complete treatment), and this 
information will be specified in the SMC charter.
The SMC will make recommendations to the 
Sponsor as to whether the trial should continue as 
planned or whether modifications should be 
made to safety monitoring. Minutes will be kept 
of all meetings but those referring to unblinded 
data will not be made available outside of the 
SMC until the trial is complete.
The final decision on whether the protocol should 
be amended or the study should be terminated 
will be the responsibility of the Sponsor. Any 
decision to stop will be communicated to 
investigators and regulatory agencies.
Text deleted
Safety monitoring committee 
not required for this open-
label study.
Appendix 1, Site 
Investigator 
Signature Page 
I have read and understand Protocol SD-809-
C-20 in its entirety and I agree to all aspects.
I have read and understand Protocol SD-809-C-20 
Amendment 02 in its entirety and I agree to all 
aspects.
Clarification
Appendix 1, Site 
Investigator 
Signature Page
Principal Investigator
Investigator
Clarification


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
135
Section 
Amendment 01, dated 28 May 2014
Amendment 02, dated 08 July 2014
Reason for Change
Appendix 18, 
Protocol 
Summary of 
Changes, 
Protocol 
Amendment 01 
(dated 28 May 
2014) to 
Amendment 02 
(dated 08 July 
2014) to 
No Text
Addition of Appendix 18
Summarize changes in 
Amendment 02
Global
Not applicable
Dates, section numbers, and tables of contents 
updated; typos and minor errors corrected
Clarification


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
136
Appendix 19: Protocol Summary of Changes, Amendment 02 (dated 08 July 2014) to Amendment 03 (dated 14-Oct-2015)
Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Study Contacts
Administrative change
Protocol Synopsis, 
No. Sites
Section 3, 
Investigational 
Plan
Approximately 30
Approximately 80
Update to number of 
study sites
Protocol Synopsis, 
Study Population
Male and female adult subjects with moderate to 
severe drug-induced TD who have successfully 
completed the SD-809-C-18 efficacy study 
(approximately 80 subjects) will be enrolled.
Male and female adult subjects with moderate to severe 
drug-induced TD who have successfully completed a 
previous placebo-controlled efficacy study of SD-809 for 
the treatment of TD with the Sponsor will be enrolled.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Protocol Synopsis,
Study Population
This is an open-label, single-arm study in which 
subjects with moderate to severe TD who have 
successfully completed a parent study (SD-809-C-18 
study or any other controlled study of SD-809 for the 
treatment of moderate to severe TD) will be invited to 
participate.
This is an open-label, single-arm study in which subjects 
with moderate to severe TD who have successfully 
completed a parent study (Study SD-809-C-18, Study 
SD-809-C-23, or any other controlled study of SD-809 
for the treatment of moderate to severe TD) will be 
invited to participate.
Clarification that 
subjects who complete
any eligible parent 
study of SD-809 for 
TD may be enrolled


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
137
Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Protocol Synopsis, 
Study Design
Section 3.1, Study 
Design
Section 6.3, Long-
Term Treatment 
Period
Long-Term Treatment Period (up to 52 weeks): 
During long-term treatment, subjects will continue
titration through Week 6. During this period, all 
subjects will be contacted by telephone at Week 3 (the 
first week of the Long-Term Treatment Period) and 
Week 5 and will return to the clinic at Weeks 4, 6, 15, 
28, 41, and 54 for evaluation of safety and dyskinesia 
control. Subjects who have not achieved a dose level 
that adequately controls dyskinesia and is well 
tolerated by the Week 6 visit should have unscheduled 
visits or telephone contacts to further adjust their dose 
upward or downward. Interactions with the clinical 
site for dose adjustment should alternate between 
telephone contacts and clinic visits. During long-term 
treatment, further dose adjustments of SD-809 may be 
made, if necessary, but not more often than weekly 
and only in increments of 6 mg per day. Dose 
adjustments should be based on all available 
information, including the subject’s and caregiver’s (if 
appropriate) reports of AEs and dyskinesia control, as 
well as information from rating scales and safety 
evaluations, when available. 
Long-Term Treatment Period (up to 2 years): During 
long-term treatment, subjects will continue titration 
through Week 6. During titration, all subjects will be 
contacted by telephone at Week 3 (the first week of the 
Long-Term Treatment Period) and Week 5 and will 
return to the clinic at Week 4 and Week 6 for evaluation 
of safety and dyskinesia control. Subjects who have not 
achieved a dose level that adequately controls dyskinesia 
and is well tolerated by the Week 6 visit should have 
unscheduled visits or telephone contacts to further adjust 
their dose upward or downward. Interactions with the 
clinical site for dose adjustment should alternate between 
telephone contacts and clinic visits. During the 
remainder of the Long-Term Treatment Period, subjects 
will return to the clinic for evaluation of safety and 
dyskinesia once every 13 weeks, starting at Week 15 and 
ending at Week 106 (i.e., after 2 years of Long-Term 
Treatment Period). During long-term treatment, further 
dose adjustments of SD-809 may be made, if necessary, 
but not more often than weekly and only in increments of 
6 mg per day. Dose adjustments should be based on all 
available information, including the subject’s and 
caregiver’s (if appropriate) reports of AEs and dyskinesia 
control, as well as information from rating scales, and 
safety evaluations, when available. If warranted, study 
sites are encouraged to conduct periodic phone calls with 
the subjects to ensure adherence to the treatment regimen 
and retention of unused drug containers.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years and addition 
of clinic visits during 
the extension
Protocol Synopsis, 
Study Design
Post-Treatment Safety Follow Up: All subjects will 
discontinue study drug at the Week 54 visit and return 
for their final clinic visit at Week 55 for evaluation of 
safety, dyskinesia control, and motor function. During 
this 1-week washout period, subjects should not take 
prohibited concomitant medications. Subjects will 
also have a follow-up telephone contact at Week 58, 
4 weeks after their last dose of study drug, to evaluate 
AEs and concomitant medication usage.
Post-Treatment Safety Follow-up: All subjects will 
discontinue study drug at the Week 106 visit and return 
for their final clinic visit at Week 107 for evaluation of 
safety, dyskinesia control, and motor function. During 
this 1-week washout period, subjects should not take 
prohibited concomitant medications. Subjects will also 
have a follow-up telephone contact at Week 110, 
4 weeks after their last dose of study drug, to evaluate 
AEs and concomitant medication usage.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
138
Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Protocol Synopsis, 
Sample Size
Approximately 260 subjects (eligible subjects who 
completed SD-809-C-18 or another controlled study 
of SD-809 for treatment of moderate to severe TD 
may enroll)
Approximately 330 subjects (eligible subjects who 
completed a previous controlled study of SD-809 for 
treatment of moderate to severe TD) may enroll.
Update to number of 
subjects based on 
current enrollment for 
Study SD-809-C-18 
and Study SD-809-C-
23
Protocol Synopsis, 
Inclusion Criteria
Section 4.2, 
Inclusion Criteria
2. Subject has successfully completed Study SD-809-
C-18 or any other controlled study of SD-809 for 
treatment of moderate to severe TD
2. Subject has successfully completed Study SD-809-
C-18, SD-809-C-23, or any other controlled study of 
SD-809 for treatment of moderate to severe TD.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD, including Study
SD-809-C-23, may be 
enrolled
Protocol Synopsis, 
Inclusion Criteria
Section 4.2, 
Inclusion Criteria
5. For subjects with underlying psychiatric illness
... 
• Subject has a mental health provider who is 
aware of the subject’s participation in the trial 
and does not anticipate any changes to the 
subject’s treatment regimen (drug, dose, 
frequency) in the next 3 months. 
5. For subjects with underlying psychiatric illness
... 
• Subject has a health care provider who is aware of 
the subject’s participation in the trial and does not 
anticipate any changes to the subject’s treatment 
regimen (drug, dose, frequency) in the next 
3 months. 
Clarification
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
6. Subject has a history of any of the following within 
6 months of Baseline:
• Previous intent to act on suicidal ideation with 
a specific plan (positive answer to question 5 
on the Columbia Suicide Severity Rating Scale 
[C-SSRS]), irrespective of level of ambivalence 
at the time of suicidal thought
...
6.
Subject has a history of any of the following within 
6 months of Screening:
• Previous intent to act on suicidal ideation with a 
specific plan, irrespective of level of ambivalence 
at the time of suicidal thought
...
Clarification
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
12. Subject has evidence of hepatic impairment at 
Screening, as indicated by:
...

Prothrombin time >4 seconds prolonged.
...
12. Subject has evidence of hepatic impairment at 
Screening of the parent study, as indicated by:
...

Prothrombin time >17 seconds (i.e., 
prothrombin time prolonged >4 seconds over 
the ULN).
...
Clarification


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
13. Subject has evidence of significant renal 
impairment at Screening, indicated by...
13. Subject has evidence of significant renal impairment 
at Screening of the parent study, indicated by...
Clarification
Protocol Synopsis, 
Exclusion Criteria
Section 4.3, 
Exclusion Criteria
15. Subject has participated in an investigational drug 
or device trial (other than Study SD-809-C-18 or 
any other eligible SD-809 parent study) and 
received study drug within 30 days (or 5 drug 
half-lives) of Baseline, whichever is longer.
15. Subject has participated in an investigational drug or 
device trial (other than Study SD-809-C-18, Study 
SD-809-C-23, or any other eligible SD-809 parent 
study) and received study drug within 30 days (or 
5 drug half-lives) of Baseline, whichever is longer.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Protocol Synopsis, 
Efficacy Measures
Section 8.5, 
Efficacy Measures
The change in Abnormal Involuntary Movement 
Scale (AIMS) score (items 1 through 7) from 
Baseline of this study to end of long-term therapy 
(Week 54) as assessed by blinded central video 
rating.

The proportion of subjects who are a treatment 
success at the end of long-term therapy (Week 54), 
based on the Clinical Global Impression of Change 
(CGIC). A treatment success is defined as Much or 
Very Much Improved on the CGIC from Baseline 
of this study to end of long-term therapy. 
Change in the modified Craniocervical Dystonia 
(CDQ-24) score from Baseline of this study to the 
end of long-term therapy (Week 54).
The proportion of subjects who have a 50% or 
greater reduction in AIMS score from Baseline of 
this study to the end of long term therapy (Week 
54)
The proportion of subjects who are a treatment 
success at the end of long-term therapy (Week 54), 
based on the Patient Global Impression of Change 
(PGIC). A treatment success is defined as Much or 
Very Much Improved on the PGIC from Baseline 
of this study to end of long-term therapy.
The percent change in AIMS score from Baseline 

The change in Abnormal Involuntary Movement 
Scale (AIMS) score (items 1 through 7) from 
Baseline of this study at each visit that this is 
measured, as assessed by blinded central video rating.

The change in AIMS score (items 1 through 7) from 
Baseline of this study at each visit that this is 
measured, as assessed by the site rating.

The proportion of subjects who are a treatment 
success based on the Clinical Global Impression of 
Change (CGIC) at each visit that this is measured. A 
treatment success is defined as Much or Very Much 
Improved on the CGIC from Baseline of this study. 

The change in the modified Craniocervical Dystonia 
(CDQ-24) score from Baseline of this study at each 
visit that this is measured.

The proportion of subjects who have a 50% or greater 
reduction in AIMS score from Baseline of this study 
at each visit that this is measured.

The proportion of subjects who are a treatment 
success based on the Patient Global Impression of 
Change (PGIC) at each visit that this is measured. A 
treatment success is defined as Much or Very Much 
Improved on the PGIC from Baseline of this study.

The percent change in AIMS score from Baseline of 
this study at each visit that this is measured.
Efficacy measures 
from throughout the 
study will now be 
analyzed, not just at 
the end of 1 year of 
long-term treatment


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
of this study to the end of long term therapy (Week 
54).
Based on the change in AIMS score from Baseline 
of this study to the end of long-term therapy (Week 
54), as assessed by blinded central video rating, the 
cumulative proportion of responders ranging from 
a 10% improvement from Baseline to a 90% 
improvement from Baseline in steps of 10 
percentage points.

Based on the change in AIMS score from Baseline of 
this study at each visit that this is measured, as 
assessed by blinded central video rating, the 
cumulative proportion of responders ranging from a 
10% improvement from Baseline to a 90% 
improvement from Baseline in steps of 10 percentage 
points.
Schedule of 
Events
Not applicable
Addition of quarterly clinic visits at Weeks 67, 80, 93, 
and 106/ET. Change of Follow-up Period clinic visit to 
Week 107 and telephone contact to Week 110.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years and addition 
of clinic visits during 
the extension
Protocol Approval 
Page
Update of title and 
affiliation
Section 3, 
Investigational 
Plan
This is an open-label, single-arm study designed to 
evaluate the long-term safety and tolerability of SD-
809 for the treatment of subjects with moderate to 
severe drug-induced TD over a 54-week period. 
Approximately 260 subjects who have successfully 
completed a parent study (Phase 2/3 SD-809-C-18 
efficacy study or any other SD-809 study for 
treatment of moderate to severe TD) will be enrolled. 
The study will be conducted at approximately 
30 centers in the U.S. and possibly other regions. The 
study is divided into a Screening Period, a Titration 
Period, a Long-Term Treatment Period, and a 
Post-Treatment Safety Follow-up Period. For subjects 
who complete the study, overall study participation 
will be up to 58 weeks.
This is an open-label, single-arm study designed to 
evaluate the long-term safety and tolerability of SD-809 
for the treatment of subjects with moderate to severe 
drug-induced TD for up to 2 years (106 weeks). 
Approximately 330 subjects who have successfully 
completed a parent study (Study SD-809-C-18, Study 
SD-809-C-23, or any other SD-809 study for treatment 
of moderate to severe TD) will be enrolled. The study 
will be conducted at approximately 80 centers in the 
U.S., Europe, and possibly other regions. The study is 
divided into a Screening Period, a Titration Period, a 
Long-Term Treatment Period, and a Post-Treatment 
Safety Follow-up Period. For subjects who complete the 
study, overall study participation will be up to 110 
weeks.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Update to number of 
subjects
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Update to number of 
study sites


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Section 3.1, Study 
Design
Titration Period (up to 6 weeks): As all subjects will 
have discontinued study drug (SD-809 or placebo) for 
1 week at completion of the SD-809-C-18 study, they 
will undergo titration on SD-809 in this study.
Titration Period (up to 6 weeks): As all subjects will 
have discontinued study drug (SD-809 or placebo) for 
1 week at completion of the parent study, they will 
undergo titration on SD-809 in this study.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Section 3.1, Study 
Design
Post-Treatment Safety Follow Up: All subjects will 
discontinue study drug at the Week 54 visit and return 
for their final clinic visit at Week 55 for evaluation of 
safety, dyskinesia control, and motor function. During 
this one week washout, subjects should not take 
prohibited concomitant medications. Between the 
Week 55 visit and the Week 58 telephone contact, 
concomitant medication use is per the discretion of 
the Investigator. Subjects will also have a follow-up 
telephone contact at Week 58, 4 weeks after their last 
dose of study drug, to evaluate adverse events and 
concomitant medication usage.
Post-Treatment Safety Follow-up: All subjects will 
discontinue study drug at the Week 106 visit and return 
for their final clinic visit at Week 107 for evaluation of 
safety, dyskinesia control, and motor function. During 
this 1-week washout, subjects should not take prohibited 
concomitant medications. Subjects will also have a 
follow-up telephone contact at Week 110, 4 weeks after 
their last dose of study drug, to evaluate adverse events 
and concomitant medication usage. Between the Week 
107 visit and the Week 110 telephone contact, 
concomitant medication use is per the discretion of the 
Investigator.
Extension of Long-
Term Treatment
Period from 1 year to 
2 years
Section 3.2, 
Rationale for 
Study Design
Subjects who successfully complete a placebo-
controlled efficacy study (SD-809-C-18 or any other 
controlled study of SD-809 as treatment for moderate 
to severe TD) will be eligible to enroll.
Subjects who successfully complete a placebo-controlled 
efficacy study (Study SD-809-C-18, Study SD-809-C-
23, or any other controlled study of SD-809 as treatment 
for moderate to severe TD) will be eligible to enroll.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Section 3.2, 
Rationale for 
Study Design
The present investigation is an open-label safety study 
of up to 54 weeks of treatment with SD-809...
The present investigation is an open-label safety study of 
up to 106 weeks of treatment with SD-809...
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Section 4.1, 
Population 
Characteristics
Male and female adult subjects with TD who have 
successfully completed the parent study (Study SD-
809-C-18 or any other controlled study of SD-809 for 
treatment of moderate to severe TD) efficacy study 
and meet eligibility criteria will be enrolled.
Male and female adult subjects with TD who have 
successfully completed the parent efficacy study (Study 
SD-809-C-18, Study SD-809-C-23, or any other 
controlled study of SD-809 for treatment of moderate to 
severe TD) and meet eligibility criteria will be enrolled.
Clarification that 
subjects who complete 
any eligible parent 
study of SD-809 for 
TD may be enrolled
Section 5, Study 
Treatment
The initial drug supply will be provided in the clinic 
at the Baseline visit.
The initial drug supply will be provided to the subject in 
the clinic at the Baseline visit.
Clarification
Section 5.2.2 
(heading changed)
Dosing in Long-Term Treatment (Weeks 3-54)
Dosing in Long-Term Treatment (Weeks 3 to 106)
Extension of Long-
Term Treatment 


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Period from 1 year to 
2 years
Section 6.1.1 
(heading changed)
Prior Data from Study SD-809-C-18
Prior Data from Subject’s Parent Study
Subjects who 
complete any eligible 
parent study of SD-
809 for TD may be 
enrolled, and their 
prior data will then be 
used for this study
Section 6.1.2, 
Baseline Visit
Obtain informed consent or assent
Obtain or verify informed consent or assent
Clarification
Section 6.3, Long-
Term Treatment 
Period
At the end of the Long-Term Treatment Period 
(Week 54), subjects will undergo a comprehensive 
evaluation, including physical and complete 
neurological exam, safety labs, 12-lead ECG, and 
performance of all rating scales.
At Weeks 28, 54, and 106, subjects will undergo a more 
comprehensive evaluation, including physical exam, 
complete neurological exam (Weeks 54 and 106 only), 
safety labs, 12-lead ECG, urine pregnancy test for 
women of childbearing potential, and performance of all 
rating scales.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years and addition 
of clinic visits during 
the extension
Section 6.3.2 
(heading changed)
Clinic Visits (Weeks 4, 6, 15, 28, and 41 [all ± 3 
days])
...

Brief physical examination (Week 28 only)
...

12-lead ECG (Weeks 4, 6, and 41)

Clinical laboratory tests: serum chemistry, 
hematology, and urinalysis (Weeks 6 and 28)

Urine pregnancy test (women of child-bearing 
potential only; Week 28 only)

AIMS

Video recording of AIMS (Weeks 6, 15, 28, and 
41)
...

MoCA© (Weeks 6, 15, 28, 41)

Modified CDQ-24 (Weeks 6, 15, 28, 41)

Next clinic visit and telephone contact (Week 4) 
Clinic Visits (Weeks 4, 6, 15, 41, 67, 80, and 93 [all ± 3 
days])
...

Deleted bullet
...

12-lead ECG (Weeks 4, 6, and 41)

Clinical laboratory tests: serum chemistry, 
hematology, and urinalysis (Week 6 only)

Deleted bullet

AIMS

Video recording of AIMS (Weeks 6, 15, and 41)
...

MoCA© (Weeks 6, 15, 41, 67, 80, 93)

Modified CDQ-24 (Weeks 6, 15, 41)
...

Next clinic visit and/or telephone contact will be 
scheduled/reconfirmed
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years and addition 
of clinic visits during 
the extension. Moved 
the more 
comprehensive Week 
28 visit activities from 
Section 6.3.2 to 
Section 6.3.3.


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Protocol SD-809-C-20 Amendment 07
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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
will be scheduled/reconfirmed
Section 6.3.3 
(heading changed)
Clinic Visit (Week 54 ± 3 days or Early 
Termination)
See the Schedule of Events for a detailed summary of 
activities.
All subjects will stop study drug at the Week 54 visit. 
Subjects will return to the clinic for the following 
Week 54/Early Termination (ET) end-of-long term 
treatment period assessments:
...
Physical examination, vital signs (including 
orthostatic blood pressure and pulse), and weight
Complete neurological examination
...
No text
...
No text
Clinic Visits (Weeks 28, 54, and 106 [all ± 3 days] or 
Early Termination)
See the Schedule of Events for a detailed summary of 
activities.
At Weeks 28, 54, and 106 or at the Early Termination 
Visit, subjects will undergo a more comprehensive 
evaluation, including:
...

Physical examination (brief physical examination 
only at Week 28), vital signs (including orthostatic 
blood pressure and pulse at Weeks 54 and 106/ET), 
and weight

Complete neurological examination (Weeks 54 and 
106/ET only)
...

Re-order study drug (see Operations Manual for 
further details, Weeks 28 and 54 only)
...
Unless a subject discontinues the study early, treatment 
with study drug will stop at the Week 106 visit.
Addition of clinic visit 
during extension of 
Long-Term Treatment 
Period from 1 year to 
2 years. Moved the 
more comprehensive 
Week 28 visit 
activities from Section 
6.3.2 to Section 6.3.3.
Section 6.4, Post-
Treatment Safety 
Follow-up
Following discontinuation of study drug at the Week 
54 visit, subjects will have a clinic visit at Week 55 
for evaluation of safety, dyskinesia and motor 
function, and a telephone contact at Week 58 for 
review of AEs and concomitant medication use since 
Week 55. During the first week after stopping study 
drug (i.e., through the Week 55 visit), subjects should 
not take prohibited concomitant medications. Between 
the Week 55 visit and the Week 58 telephone contact, 
concomitant medication use is per the discretion of 
the Investigator.
Following discontinuation of study drug at the Week 106 
visit, subjects will have a clinic visit at Week 107 for 
evaluation of safety, dyskinesia, and motor function and 
a telephone contact at Week 110 for review of AEs and 
concomitant medication use since Week 107. During the 
first week after stopping study drug (i.e., through the 
Week 107 visit), subjects should not take prohibited 
concomitant medications. Between the Week 107 visit 
and the Week 110 telephone contact, concomitant 
medication use is per the discretion of the Investigator.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Section 6.4.1 
(heading changed)
Clinic Visit (Week 55 ± 3 days)
...
All subjects will return one week after the Week 54 or 
Clinic Visit (Week 107 ± 3 days)
...
All subjects will return 1 week after the Week 106 or 
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change
Early Termination visit...
Early Termination visit...
Section 6.4.2 
(heading changed)
Telephone Contact (Week 58 ± 3 days)
All subjects will have a follow-up telephone contact at 
Week 58, 3 weeks after the Week 55 visit (4 weeks 
after their last dose of study drug [Week 54]), or 
3 weeks after the Early Termination visit.
Telephone Contact (Week 110 ± 3 days)
All subjects will have a follow-up telephone contact at 
Week 110, 3 weeks after the Week 107 visit (4 weeks 
after their last dose of study drug [Week 106]), or 
4 weeks after the Early Termination visit.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Section 6.6.2, 
Independent 
Rating of 
Dyskinesia
To enable a systematic evaluation of the primary 
endpoint, the AIMS will be digitally video-recorded 
using a standard protocol at Baseline and at Weeks 6, 
15, 28, 41, and 54 (see Appendix 2).
The videos from Baseline and Weeks 6, 15, 28, 41, 
and 54 will be independently reviewed by a blinded 
central rater(s) who is an expert in movement 
disorders.
To enable a systematic evaluation of the primary 
endpoint, the AIMS will be digitally video-recorded 
using a standard protocol at Baseline and at Weeks 6, 15, 
28, 41, 54, and 106 (see Appendix 2).
The videos from Baseline and Weeks 6, 15, 28, 41, 54, 
and 106 will be independently reviewed by a blinded 
central rater(s) who is an expert in movement disorders.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Section 6.7.5, 
Orthostatic Blood 
Pressure and Pulse
Orthostatic blood pressure and pulse will be recorded 
at Week 6 and Week 54/ET.
Orthostatic blood pressure and pulse will be recorded at 
Weeks 6, 54, and 106/ET.
Extension of Long-
Term Treatment 
Period from 1 year to 
2 years
Section 6.7.6, 
Laboratory Tests
Blood and urine samples will be collected and 
analyzed, and applicable parameters calculated 
according to the Standard Operating Procedures 
(SOPs) at the central laboratory. If abnormal, 
screening labs may be repeated once to confirm the 
subject’s eligibility.
Blood and urine samples will be collected and tested for 
the items in Table 3, and applicable parameters will be 
calculated according to the Standard Operating 
Procedures (SOPs) at the central laboratory. If abnormal, 
screening labs may be repeated once to confirm the 
subject’s eligibility. As specified in Table 3, certain lab 
results obtained in the parent study do not need to be 
repeated at screening for Study SD-809-C-20.
Table 3: Laboratory Tests
Indicate that certain 
labs from parent study 
do not need to be 
repeated; clarification
Section 6.7.6, 
Laboratory Tests
Labs for Screening Purposes

Urine and serum pregnancy tests (women of 
childbearing potential only)

Follicle Stimulating Hormone for post-
menopausal women only.

Hepatitis B surface antigen (HBsAg)
Other
Labs for Screening Purposes

Urine pregnancy tests (women of childbearing 
potential only)
Lab Results from Parent Study

CYP2D6 genotype (blinded)

Prothrombin Time (PT) with International 
Normalized Ratio (INR)
Specify which labs 
from parent study do 
not need to be 
repeated for Study 
SD-809-C-20


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Section 
Amendment 02, dated 08 July 2014
Amendment 03, dated 14 Oct 2015
Reason for Change

CYP2D6 genotype (blinded)

Prothrombin Time (PT) with International 
Normalized Ratio (INR)

Follicle Stimulating Hormone for post-menopausal 
women only.

Hepatitis B surface antigen (HBsAg)
Section 6.7.9, 
Rating Scales
Subject completed assessments will be available in 
English, Spanish, and French.
Subject-completed assessments will be available in 
English, Spanish, Hungarian, German, Polish, Czech, 
and Slovakian.
Update of translations 
available for subject-
completed 
assessments
Section 9.5, 
Clinical Product 
Complaints 
(section added)
Not applicable
Section added
(renumbering of subsequent sections)
Insertion of 
standardized language 
regarding any 
problems with the 
physical quality or 
characteristics of 
clinical drug supplies
Appendix 1, Site 
Investigator 
Signature Page 
I have read and understand Protocol SD-809-C-20 
Amendment 02 in its entirety and I agree to all 
aspects.
I have read and understand Protocol SD-809-C-20 
Amendment 03 in its entirety and I agree to all 
aspects.
Clarification
Appendix 19, 
Summary of 
Changes, 
Amendment 02 
(dated 08 July 
2014) to 
Amendment 03 
(dated 14 Oct 
2015) 
Not applicable
Appendix added
Summarize protocol 
changes in 
Amendment 03
Global
Not applicable
Updated dates, section numbers, and tables of contents. 
Corrected typos; errors in punctuation, grammar, and 
formatting; and inconsistencies in style.


Auspex Pharmaceuticals, Inc.
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Appendix 20: Protocol Summary of Changes, Amendment 03 (dated 14 Oct 2015) to Amendment 04 (dated 27 Sept 2016)
Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
Study Contacts:
Sponsor
 
 
 
Administrative 
changes
Study Contacts:
Medical 
Monitor
Protocol 
Synopsis: Study 
Design
Titration Period (up to 6 weeks): As subjects will 
have discontinued study drug (SD-809 or placebo) for 
1 week at completion of the parent study, they will 
undergo SD-809 dose titration in this study. During 
titration, the Investigator, in consultation with the 
subject, will determine when an adequate level of 
dyskinesia control has been achieved. The dose of 
SD-809 should be adjusted (upward or downward), in 
increments of 6 mg per day (up to once per week), 
until there is adequate control of dyskinesia, the 
subject experiences a protocol-defined clinically 
significant adverse event (defined as related to study 
drug and either a) moderate or severe in intensity or b) 
meets the criteria for a serious adverse event [SAE]), 
Titration Period (up to 6 weeks): As subjects will have 
discontinued study drug (SD-809 or placebo) for 1 week at 
completion of the parent study, they will undergo SD-809 dose 
titration in this study. During titration, the Investigator, in 
consultation with the subject, will determine when an adequate 
level of dyskinesia control has been achieved. The dose of 
SD-809 should be adjusted (upward or downward), in 
increments of 6 mg per day (up to once per week), until there is 
adequate control of dyskinesia, the subject experiences a 
protocol-defined clinically significant adverse event (defined as 
related to study drug and either a) moderate or severe in 
intensity or b) meets the criteria for a serious adverse event 
[SAE]), or the maximal allowable dose is reached. If a subject 
experiences a clinically significant AE attributable to SD-809, 
Clarification of 
the procedure 
for dose 
suspension or 
withdrawal


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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
or the maximal allowable dose is reached. If a subject 
experiences a clinically significant AE attributable to 
SD-809, the Investigator will determine if a dose 
reduction or, suspension, is necessary. Subjects will 
have a telephone contact at Week 1 and a clinic visit at 
Week 2 to evaluate safety and establish a dose of study 
drug that adequately controls dyskinesia and is well 
tolerated. Although subjects will enter the long-term 
treatment period after Week 2, titration should 
continue through Week 6 to optimize dose. 
the Investigator will determine if a dose reduction, dose 
suspension, or withdrawal from the study is necessary. Prior to 
withdrawing a subject from the study, the reasons for doing so 
should be discussed with the Medical Monitor or Sponsor 
Clinician. Subjects will have a telephone contact at Week 1 and 
a clinic visit at Week 2 to evaluate safety and establish a dose of 
study drug that adequately controls dyskinesia and is well 
tolerated. Although subjects will enter the long-term treatment 
period after Week 2, titration should continue through Week 6 
to optimize dose. 
Protocol 
Synopsis: Study 
Design
Long-Term Treatment Period (up to 2 years):
During long-term treatment, subjects will continue 
titration through Week 6. During titration, all subjects 
will be contacted by telephone at Week 3 (the first 
week of the Long-Term Treatment Period) and Week 5 
and will return to the clinic at Week 4 and Week 6 for 
evaluation of safety and dyskinesia control. Subjects 
who have not achieved a dose level that adequately 
controls dyskinesia and is well tolerated by the Week 6 
visit should have unscheduled visits or telephone 
contacts to further adjust their dose upward or 
downward. Interactions with the clinical site for dose 
adjustment should alternate between telephone 
contacts and clinic visits. During the remainder of the 
Long-Term Treatment Period, subjects will return to 
the clinic for evaluation of safety and dyskinesia once 
every 13 weeks, starting at Week 15 and ending at 
Week 106 (i.e., after 2 years of Long-Term Treatment 
Period). During long-term treatment, further dose 
adjustments of SD-809 may be made, if necessary, but 
not more often than weekly and only in increments of 
6 mg per day. Dose adjustments should be based on all 
available information, including the subject’s and 
caregiver’s (if appropriate) reports of AEs and 
dyskinesia control, as well as information from rating 
scales and safety evaluations, when available. If 
warranted, study sites are encouraged to conduct 
periodic phone calls with subjects to ensure adherence 
Long-Term Treatment Period (up to 3 years): During long-
term treatment, subjects will continue titration through Week 6. 
During titration, all subjects will be contacted by telephone at 
Week 3 and Week 5 and will return to the clinic at Week 4 and 
Week 6 for evaluation of safety and dyskinesia control. Subjects 
who have not achieved a dose level that adequately controls 
dyskinesia and is well tolerated by the Week 6 visit should have 
unscheduled visits or telephone contacts to further adjust their 
dose upward or downward. Interactions with the clinical site for 
dose adjustment should alternate between telephone contacts and 
clinic visits. During the remainder of the Long-Term Treatment 
Period, subjects will return to the clinic for evaluation of safety 
and dyskinesia once every 13 weeks, starting at Week 15 and 
ending at Week 158 (i.e., after 3 years of Long-Term Treatment 
Period). During long-term treatment, further dose adjustments of 
SD-809 may be made, if necessary, but not more often than 
weekly and only in increments of 6 mg per day. Dose 
adjustments should be based on all available information, 
including the subject’s and caregiver’s (if appropriate) reports of 
AEs and dyskinesia control, as well as information from rating 
scales and safety evaluations, when available. If warranted, 
study sites are encouraged to conduct periodic phone calls with 
subjects to ensure adherence to the treatment regimen and 
retention of unused drug containers.
Update to 
clarify Study 
Design 
extension


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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
to the treatment regimen and retention of unused drug 
containers.
Protocol 
Synopsis, 
Section: Study 
Design Post-
Treatment 
Safety Follow-
up
Post-Treatment Safety Follow-up: All subjects will 
discontinue study drug at the Week 106 visit and 
return for their final clinic visit at Week 107 for 
evaluation of safety, dyskinesia control, and motor 
function. During this 1-week washout period, subjects 
should not take prohibited concomitant medications. 
Subjects will also have a follow-up telephone contact 
at Week 110, 4 weeks after their last dose of study 
drug, to evaluate AEs and concomitant medication 
usage.
Post-Treatment Safety Follow-up: All subjects will discontinue 
study drug at the Week 158 visit and return for their final clinic 
visit at Week 159 for evaluation of safety, dyskinesia control, 
and motor function. During this 1-week washout period, subjects 
should not take prohibited concomitant medications. Subjects 
will also have a follow-up telephone contact at Week 162, 4 
weeks after their last dose of study drug, to evaluate AEs and 
concomitant medication usage.
Update to post 
treatment 
follow-up 
schedule
Protocol 
Synopsis,
Dose Regimen
Study drug will be administered as follows:
All treatment regimens will be administered twice 
daily (BID) with meals, approximately 10 hours apart 
during the day.
The starting dose will be SD-809 12 mg/day (6 mg 
BID) regardless of previous treatment in the parent 
trial. Prior treatment assignment from the parent trial 
will remain blinded.
The maximum total daily dose of SD-809 is 48 mg/day 
(24 mg BID) unless the subject is on a strong CYP2D6 
inhibitor (paroxetine, fluoxetine, or bupropion), in 
which case the maximum total daily dose is 36 
mg/day.
Daily doses up to 36 mg/day will be given as one 
tablet BID whereas daily doses of 42 mg/day and 48 
mg/day will be given as two tablets BID.
Study drug will be administered as follows:
All treatment regimens will be administered twice daily (BID) 
with meals, approximately 10 hours apart during the day.
The starting dose will be SD-809 12 mg/day (6 mg BID) 
regardless of previous treatment in the parent trial. Prior 
treatment assignment from the parent trial will remain blinded.
The maximum total daily dose of SD-809 is based on body 
weight:
o
If body weight <100 kg, the maximum daily dose is 48 
mg/day (24 mg BID) unless the subject is on a strong 
CYP2D6 inhibitor (paroxetine, fluoxetine, or 
bupropion), in which case the maximum total daily 
dose is 36 mg/day. 
o
If body weight ≥100 kg the maximum daily dose is 60 
mg/day (30 mg BID) unless the subject is on a strong 
CYP2D6 inhibitor (paroxetine, fluoxetine, or 
bupropion), in which case the maximum daily dose is 
42 mg/day.
Daily doses up to 36 mg/day will be given as one tablet BID 
whereas daily doses of 42 mg/day, 48 mg/day, 54 mg/day and 60 
mg/day will be given as two tablets BID.
Changes in 
maximum daily 
dose
Schedule of 
Events
8 Subjects who have not achieved adequate control of 
dyskinesia during the study may have up to two blood 
Schedule Events (Year 3)
Study week: 119, 132, 145, & 158/ET
Follow-up: 159 & 162
8 Subjects who have not achieved adequate control of dyskinesia 
during the study may have up to two blood samples collected 
Update to 
Schedule of 
Events table to 
extend study for 
another year


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
samples collected for future pharmacokinetic 
assessment of α- and β- HTBZ. 
within 48 hours of the last dose of study drug for future 
pharmacokinetic assessment of α- and β- HTBZ. The 
pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor
3.0 
Investigational 
Plan
This is an open-label, single-arm study designed to 
evaluate the long-term safety and tolerability of SD-
809 for the treatment of subjects with moderate to 
severe drug-induced TD for up to 2 years (106 weeks). 
Approximately 330 subjects who have successfully 
completed a parent study (Study SD-809-C-18, Study 
SD-809-C-23, or any other SD-809 study for treatment 
of moderate to severe TD) will be enrolled. The study 
will be conducted at approximately 80 centers in the 
U.S., Europe, and possibly other regions. The study is 
divided into a Screening Period, a Titration Period, a 
Long-Term Treatment Period, and a Post-Treatment 
Safety Follow-up Period. For subjects who complete 
the study, overall study participation will be up to 110 
weeks.
This is an open-label, single-arm study designed to evaluate the 
long-term safety and tolerability of SD-809 for the treatment of 
subjects with moderate to severe drug-induced TD for up to 
3 years (158 weeks). Approximately 330 subjects who have 
successfully completed a parent study (Study SD-809-C-18, 
Study SD-809-C-23, or any other SD-809 study for treatment of
moderate to severe TD) will be enrolled. The study will be 
conducted at approximately 80 centers in the U.S., Europe, and 
possibly other regions. The study is divided into a Screening 
Period, a Titration Period, a Long-Term Treatment Period, and a 
Post-Treatment Safety Follow-up Period. For subjects who 
complete the study, overall study participation will be up to 162 
weeks.
3.1-
Investigational 
Plan
Long-Term Treatment Period (up to 2 years): During 
the Long-Term Treatment Period, subjects will 
continue titration through Week 6. During titration, all 
subjects will be contacted by telephone at Week 3 (the 
first week of the Long-Term Treatment Period) and 
Week 5 and will return to the clinic at Week 4 and 
Week 6 for evaluation of safety and dyskinesia 
control. Subjects who have not achieved a stable dose 
by the Week 6 visit may have unscheduled visits or 
telephone contacts to further adjust their dose upward 
or downward. Site interactions for dose adjustment 
should alternate between telephone contacts and clinic 
visits. During the remainder of the Long-Term 
Treatment Period, subjects will return to the clinic for 
evaluation of safety and dyskinesia once every 13 
weeks, starting at Week 15 and ending at Week 106 
(i.e., after 2 years of Long-Term Treatment Period). 
During long-term treatment, further dose adjustments 
of SD-809 may be made, if necessary, but not more 
Long-Term Treatment Period (up to 3 years): During the Long-
Term Treatment Period, subjects will continue titration through 
Week 6. During titration, all subjects will be contacted by 
telephone at Week 3 (the first week of the Long-Term Treatment 
Period) and Week 5 and will return to the clinic at Week 4 and 
Week 6 for evaluation of safety and dyskinesia control. Subjects 
who have not achieved a stable dose by the Week 6 visit may 
have unscheduled visits or telephone contacts to further adjust 
their dose upward or downward. Site interactions for dose 
adjustment should alternate between telephone contacts and 
clinic visits. During the remainder of the Long-Term Treatment 
Period, subjects will return to the clinic for evaluation of safety 
and dyskinesia once every 13 weeks, starting at Week 15 and 
ending at Week 158 (i.e., after 3 years of Long-Term Treatment 
Period). During long-term treatment, further dose adjustments of 
SD-809 may be made, if necessary, but not more often than 
weekly and in increments of 6 mg per day. Dose adjustments 
should be based on all available information, including the 
subject’s and caregiver’s reports of adverse events and 
Update to Long-
Term Treatment 
Period from 2 to 
3 years


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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
often than weekly and in increments of 6 mg per day. 
Dose adjustments should be based on all available 
information, including the subject’s and caregiver’s 
reports of adverse events and dyskinesia control, 
information from rating scales, and all safety 
evaluations. If warranted, study sites are encouraged to 
conduct periodic phone calls with the subjects to 
ensure adherence to the treatment regimen and 
retention of unused drug containers.
dyskinesia control, information from rating scales, and all safety 
evaluations. If warranted, study sites are encouraged to conduct 
periodic phone calls with the subjects to ensure adherence to the 
treatment regimen and retention of unused drug containers.
Protocol 
3.1 
Investigational 
Plan
Post-Treatment Safety Follow-up: All subjects will 
discontinue study drug at the Week 106 visit and 
return for their final clinic visit at Week 107 for 
evaluation of safety, dyskinesia control, and motor 
function. During this 1-week washout, subjects should 
not take prohibited concomitant medications. Subjects 
will also have a follow-up telephone contact at Week 
110, 4 weeks after their last dose of study drug, to 
evaluate adverse events and concomitant medication 
usage. Between the Week 107 visit and the Week 110 
telephone contact, concomitant medication use is per 
the discretion of the Investigator.
Post-Treatment Safety Follow-up: All subjects will discontinue 
study drug at the Week 158 visit and return for their final clinic 
visit at Week 159 for evaluation of safety, dyskinesia control, 
and motor function. During this 1-week washout, subjects 
should not take prohibited concomitant medications. Subjects 
will also have a follow-up telephone contact at Week 162, 4 
weeks after their last dose of study drug, to evaluate adverse 
events and concomitant medication usage. Between the Week 
159 visit and the Week 162 telephone contact, concomitant 
medication use is per the discretion of the Investigator.
Update to post-
treatment safety 
follow-up
Protocol 
3.2 Rationale 
for Study 
Design
The present investigation is an open-label safety study 
of up to 106 weeks of treatment with SD-809 at a 
pharmacologically active dose and will enroll subjects 
with drug-induced dyskinesia associated with TD who 
were previously exposed to either SD-809 or placebo 
in a parent study.
The present investigation is an open-label safety study of up to 
158 weeks of treatment with SD-809 at a pharmacologically 
active dose (or until SD-809 has a regulatory approval for 
treatment of TD) and will enroll subjects with drug-induced 
dyskinesia associated with TD who were previously exposed to 
either SD-809 or placebo in a parent study.
Clarification of 
Study Design 
rationale
Protocol 
3.3 Rationale 
for Dose 
Selection
No text
For subjects with a body weight less than 100 kg, the maximum 
total daily dose of SD-809 is 48 mg/day (24 mg BID), unless the 
subject is receiving a strong CYP2D6 inhibitor (e.g., paroxetine; 
see Appendix 13), in which case the maximum total daily dose is 
36 mg/day. For subjects with a body weight of 100 kg, or more, 
the maximum total daily dose of SD-809 is 60 mg/day (30 mg 
BID), unless the subject is on a strong CYP2D6 inhibitor 
(paroxetine, fluoxetine, or bupropion), in which case the 
maximum daily dose is 42 mg/day.
Update for dose 
selection 
rationale


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Protocol SD-809-C-20 Amendment 07
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
5.2.1 General 
Guidelines

If a subject experiences a clinically significant AE 
attributable to SD-809, the Investigator will 
determine if a dose reduction or suspension is 
necessary. 

For subjects with body weight less than100 kg, the 
maximum total daily dose of SD-809 is 48 mg/day (24 mg 
BID), unless the subject is on a strong CYP2D6 inhibitor 
(paroxetine, fluoxetine, or bupropion), in which case the 
maximum daily dose is 36 mg/day. For subjects with body 
weight 100 kg or more, the maximum total daily dose of 
SD-809 is 60 mg/day (30 mg BID), unless the subject is on 
a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or 
bupropion), in which case the maximum daily dose is 42 
mg/day.
Table 2 Maximum Daily Dose Level During the Maintenance 
Period
Body 
weight 
(kg)*
Target dose (schedule)
Not 
CYP2D6 
impaired
On strong CYP2D6 inhibitor
<100 
kg
48 mg/day 
(24 mg 
BID)
36 mg/day (18 mg BID)
≥100 
kg
60 mg/day 
(30 mg 
BID)
42 mg/day (21 mg BID)

Daily doses up to 36 mg/day will be given as 1 tablet BID, 
whereas daily doses of 42, 48, 54 and 60 mg/day will be 
given as 2 tablets BID 

If a subject experiences a clinically significant AE 
attributable to SD-809, the Investigator will determine if a 
dose reduction or dose suspension, or withdrawal from the 
study is necessary. Prior to withdrawing a subject from the 
study, the reasons for doing so should be discussed with the 
Medical Monitor or Sponsor Clinician
Clarification of 
the treatment 
regiments
Protocol:
5.2.3 Dose 
Reduction or 
Suspension
5.2.3
Dose Reduction or Suspension
If a subject experiences a clinically significant AE (see 
Section 7) that is attributed to SD-809, the Investigator 
will use his or her judgment to determine if a dose 
reduction, dose suspension or withdrawal from the 
study is necessary. Prior to withdrawing a subject from 
5.2.3
Dose Reduction or Suspension
If a subject experiences a clinically significant AE (see Section 
7) that is attributed to SD-809, the Investigator will use his or 
her judgment to determine if a dose reduction, dose suspension 
or withdrawal from the study is necessary. Prior to withdrawing 
a subject from the study, the reasons for doing so should be 
Clarification of 
the procedures 
if a dose 
reduction, 
suspension or 
withdrawal is 


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Protocol SD-809-C-20 Amendment 07
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Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
the study, the reasons for doing so should be discussed 
with the Medical Monitor or Sponsor Clinician. Dose 
adjustments should be made based on all available 
information including the subject’s and caregiver’s 
reports of AEs and dyskinesia control, the clinical 
assessment of safety and efficacy by the investigator 
and information from rating scales.
discussed with the Medical Monitor or Sponsor Clinician. Dose 
adjustments should be made based on all available information 
including the subject’s and caregiver’s reports of AEs and 
dyskinesia control, the clinical assessment of safety and efficacy 
by the investigator and information from rating scales.
necessary
Protocol:
5.2.3 Dose 
Reduction or 
Suspension
Suspensions for more than 7 days must be reviewed by 
the Medical Monitor. If the subject restarts study drug 
within 7 days of suspension, the full dose of SD-809 
may be resumed without titration. If subject restarts 
study drug greater than 7 days following a suspension, 
retitration will be required. 
Suspensions for more than 7 days must be reviewed by the 
Medical Monitor. If the subject restarts study drug within 7 days 
of suspension, the full dose of SD-809 may be resumed without 
titration. If subject restarts study drug greater than 7 days 
following a suspension, re-titration will be required. Dose re-
titrations will necessitate additional unscheduled visits and 
telephone contacts which will be needed to ensure that the 
subject reaches the appropriate maintenance dose safely and 
without undue delay, and to ensure adherence to the treatment 
regimen and retention of any unused drug materials.
Clarifying dose 
re-titration 
procedures
Protocol:
6.3 Long Term 
Treatment 
Period (up to 3 
years)
During the remainder of the Long-Term Treatment 
Period, subjects will return to the clinic for evaluation 
of safety and dyskinesia once every 13 weeks, starting 
at Week 15 and ending at Week 106 (i.e., after 2 years 
of Long-Term Treatment Period). Further dose 
adjustments of SD-809 may be made, if necessary, but 
not more often than weekly and in increments of 6 mg. 
Dose adjustments should be based on all available 
information, including the subject’s (and caregiver’s, if 
applicable) reports of AEs and dyskinesia control, 
information from rating scales, and all safety 
evaluations. If warranted, study sites are encouraged to 
conduct periodic phone calls with the subjects to 
ensure adherence to the treatment regimen and 
retention of unused drug containers.
At Weeks 28, 54, and 106, subjects will undergo a 
more comprehensive evaluation, including physical 
exam, complete neurological exam (Weeks 54 and 106 
only), safety labs, 12 lead ECG, urine pregnancy test 
for women of childbearing potential, and performance 
of all rating scales. 
During the remainder of the Long-Term Treatment Period, 
subjects will return to the clinic for evaluation of safety and 
dyskinesia once every 13 weeks, starting at Week 15 and ending 
at Week 158 (i.e., after 3 years of Long-Term Treatment Period). 
Further dose adjustments of SD-809 may be made, if necessary, 
but not more often than weekly and in increments of 6 mg. Dose 
adjustments should be based on all available information, 
including the subject’s (and caregiver’s, if applicable) reports of 
AEs and dyskinesia control, information from rating scales, and 
all safety evaluations. If warranted, study sites are encouraged to 
conduct periodic phone calls with the subjects to ensure 
adherence to the treatment regimen and retention of unused drug 
containers.
At Weeks 28, 54, and 158, subjects will undergo a more 
comprehensive evaluation, including physical examination, 
complete neurological exam (Weeks 54 and 158 only), safety 
labs, 12 lead ECG, urine pregnancy test for women of 
childbearing potential, and performance of all rating scales.
Update on the 
long term 
treatment period


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Protocol SD-809-C-20 Amendment 07
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
Protocol:
6.3.2 Clinic 
Visits
Clinic Visits (Weeks 4, 6, 15, 41, 67, 80, and 93 [all 
± 3 days])
See the Schedule of Events for a detailed summary of 
activities.
Long-Term Treatment Period clinic visits include the 
following activities:

Assessment of AEs, dyskinesia control (in 
consultation with the caregiver, if applicable), and 
concomitant medication use

Weight

Vital signs (at Week 6, include orthostatic blood 
pressure and pulse)

12-lead ECG (Weeks 4, 6, and 41)

Clinical laboratory tests: serum chemistry, 
hematology, and urinalysis (Week 6 only)

AIMS

Video recording of AIMS (Weeks 6, 15, and 41)

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

CGIC

PGIC

MoCA© (Weeks 6, 15, 41, 67, 80, 93)

Modified CDQ-24 (Weeks 6, 15, 41)

Assessment of study drug 
accountability/compliance 

Evaluation of study drug dose level and 
adjustment, if necessary (through Week 6)

Re-order study drug (see Operations Manual for 
further details) 

Next clinic visit and/or telephone contact will be 
scheduled/reconfirmed 
Subjects should continue to receive their long-term 
treatment dose after the Week 6 clinic visit, although 
further dose adjustments are permitted if clinically 
Clinic Visits (Weeks 4, 6, 15, 41, 67, 80, 93, 119, 132, and 145 
[all ± 3 days])
See the Schedule of Events for a detailed summary of activities.
Long-Term Treatment Period clinic visits include the following 
activities:

Assessment of AEs, dyskinesia control (in consultation 
with the caregiver, if applicable), and concomitant 
medication use

Weight

Vital signs (at Week 6, include orthostatic blood 
pressure and pulse)

12-lead ECG (Weeks 4, 6, and 41)

Clinical laboratory tests: serum chemistry, hematology, 
and urinalysis (Week 6 only)

AIMS

Video recording of AIMS (Weeks 6, 15, and 41)

UPDRS Part III (motor examination)

BARS 

HADS

C-SSRS: Since Last Visit version

ESS (excluding at weeks 119 & 145)

CGIC

PGIC

MoCA© (Weeks 6, 15, 41, 67, 80, 93 & 132)

Modified CDQ-24 (Weeks 6, 15, 41)

Assessment of study drug accountability/compliance 

Evaluation of study drug dose level and adjustment, if 
necessary (through Week 6)

Re-order study drug (see Operations Manual for further 
details) 

Next clinic visit and/or telephone contact will be 
scheduled/reconfirmed 
Subjects should continue to receive their long-term treatment 
dose after the Week 6 clinic visit, although further dose 
adjustments are permitted if clinically indicated.
Update to clinic 
visits schedule


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Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
indicated.
Protocol:
6.3.3 Clinic 
Visits or Early 
Termination
6.3.3 Clinic Visits (Weeks 28, 54, and 106 [all ± 3 
days] or Early Termination)
See the Schedule of Events for a detailed summary of 
activities.
At Weeks 28, 54, and 106, or at the Early Termination 
Visit, subjects will undergo a more comprehensive 
evaluation, including:
Assessment of AEs, dyskinesia control (in consultation 
with the subject and caregiver, if applicable), and 
concomitant medication use 
Physical examination (brief physical exam only at 
Week 28), vital signs (including orthostatic blood 
pressure and pulse at Weeks 54, 106/ET, and weight
Complete neurological examination (Weeks 54, 
106/ET only)
Clinical laboratory tests: serum chemistry, 
hematology, urinalysis, and urine pregnancy test 
(women of childbearing potential only) 
12-lead ECG
AIMS
Video recording of AIMS
UPDRS Part III (motor examination)
BARS
HADS
C-SSRS: Since Last Visit version
ESS
CGIC
PGIC
MoCA©
Modified CDQ-24
Assessment of study drug accountability/compliance 
and collection of all study drug
Re-order study drug (see Operations Manual for 
further details, Weeks 28 and 54 only)
The next clinic visit will be scheduled/reconfirmed 
Unless a subject discontinues the study early, 
treatment with study drug will stop at the Week 106 
6.3.3 Clinic Visits (Weeks 28, 54, 106 and 158 [all ± 3 days] or 
Early Termination)
See the Schedule of Events for a detailed summary of activities.
At Weeks 28, 54, 106 and 158, or at the Early Termination Visit, 
subjects will undergo a more comprehensive evaluation, 
including:
Assessment of AEs, dyskinesia control (in consultation with the 
subject and caregiver, if applicable), and concomitant 
medication use 
Physical examination (brief physical examination only at Week 
28), vital signs (including orthostatic blood pressure and pulse at 
Weeks 54, 106, 158/ET), and weight
Complete neurological examination (Weeks 54, 106, and 
158/ET only)
Clinical laboratory tests: serum chemistry, hematology, 
urinalysis, and urine pregnancy test (women of childbearing 
potential only) 
12-lead ECG
AIMS
Video recording of AIMS
UPDRS Part III (motor examination)
BARS
HADS
C-SSRS: Since Last Visit version
ESS
CGIC
PGIC
MoCA©
Modified CDQ-24
Assessment of study drug accountability/compliance and 
collection of all study drug
Re-order study drug (see Operations Manual for further details, 
Weeks 28 and 54 only)
The next clinic visit will be scheduled/reconfirmed 
Unless a subject discontinues the study early, treatment with 
study drug will stop at the Week 158 visit.
Note: If the subject discontinues from the study early, every 
Update to the 
Clinic visits or 
early 
termination


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Protocol SD-809-C-20 Amendment 07
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
visit.
Note: If the subject discontinues from the study early, 
every effort should be made to complete the early 
termination procedures as outlined above and in the 
Schedule of Events. In addition, subjects discontinuing 
prematurely from the study should have a follow-up 
visit 1 week after discontinuing therapy and a follow-
up telephone contact 4 weeks after discontinuing 
therapy, if possible. The procedures outlined in 
Section 6.4 should be followed.
effort should be made to complete the early termination 
procedures as outlined above and in the Schedule of Events. In 
addition, subjects discontinuing prematurely from the study 
should have a follow-up visit 1 week after discontinuing therapy 
and a follow-up telephone contact 4 weeks after discontinuing 
therapy, if possible. The procedures outlined in Section 6.4 
should be followed.
Protocol:
6.4 Post-
Treatment 
Safety Follow-
up
6.4 Post-Treatment Safety Follow-up
Following discontinuation of study drug at the Week 
106 visit, subjects will have a clinic visit at Week 107 
for evaluation of safety, dyskinesia, and motor 
function and a telephone contact at Week 110 for 
review of AEs and concomitant medication use since 
Week 107. During the first week after stopping study 
drug (i.e., through the Week 107 visit), subjects should 
not take prohibited concomitant medications. Between 
the Week 107 visit and the Week 110 telephone 
contact, concomitant medication use is per the 
discretion of the Investigator.
6.4 Post-Treatment Safety Follow-up
Following discontinuation of study drug at the Week 158 visit, 
subjects will have a clinic visit at Week 159 for evaluation of 
safety, dyskinesia, and motor function and a telephone contact at 
Week 162 for review of AEs and concomitant medication use 
since Week 159. During the first week after stopping study drug 
(i.e., through the Week 159 visit), subjects should not take 
prohibited concomitant medications. Between the Week 159 
visit and the Week 162 telephone contact, concomitant 
medication use is per the discretion of the Investigator.
Update to the 
post treatment 
follow-up visit 
schedule
Protocol:
6.4.1 Clinical 
Visit
6.4.2 Telephone 
Contact
6.4.1 Clinical Visit (Week 107 ± 3 days)
See the Schedule of Events for a detailed summary of 
activities.
All subjects will return 1 week after the Week 106 or 
Early Termination visit for evaluation of safety, 
dyskinesia, and motor function. The following 
activities should be performed:
Assessment of AEs, dyskinesia control (in consultation 
with the caregiver, if appropriate), and concomitant 
medication use 
Vital signs
Weight
AIMS
UPDRS Part III (motor examination)
BARS
HADS
6.4.1 Clinical Visit (Week 159 ± 3 days)
See the Schedule of Events for a detailed summary of activities.
All subjects will return 1 week after the Week 158 or Early 
Termination visit for evaluation of safety, dyskinesia, and motor 
function. The following activities should be performed:
Assessment of AEs, dyskinesia control (in consultation with the 
caregiver, if appropriate), and concomitant medication use 
Vital signs
Weight
AIMS
UPDRS Part III (motor examination)
BARS
HADS
C-SSRS Since Last Visit version
ESS
Next telephone contact will be scheduled/reconfirmed 
Update visit 
weeks for 
clinical and 
telephone


Auspex Pharmaceuticals, Inc.
Protocol SD-809-C-20 Amendment 07
CONFIDENTIAL
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Section 
Amendment 03, dated 14 Oct 2015
Amendment 04, dated 27 Sept 2016
Reason for 
Change
C-SSRS Since Last Visit version
ESS
Next telephone contact will be scheduled/reconfirmed 
6.4.2 Telephone Contact (Week 110 ± 3 days)
All subjects will have a follow-up telephone contact at 
Week 110, 3 weeks after the Week 107 visit (4 weeks 
after their last dose of study drug [Week 106]), or 4 
weeks after the Early Termination visit. During the 
telephone contact, subjects (and caregivers, if 
appropriate) will be questioned about AEs and 
concomitant medication use since the subject’s last 
evaluation.
6.4.2 Telephone Contact (Week 162 ± 3 days)
All subjects will have a follow-up telephone contact at Week 
162, 3 weeks after the Week 159 visit (4 weeks after their last 
dose of study drug [Week 158]), or 4 weeks after the Early 
Termination visit. During the telephone contact, subjects (and 
caregivers, if appropriate) will be questioned about AEs and 
concomitant medication use since the subject’s last evaluation.
Protocol:
6.8 
Pharmacokinetic 
Evaluations
No text
6.8 Pharmacokinetic Evaluations
Subjects who have not achieved adequate control of dyskinesia 
during the study may have up to two blood samples collected for 
future pharmacokinetic assessment of α- and β- HTBZ. The 
pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor. The date and time of the last 
dose of study drug should be recorded along with the date and 
time of the sample collection.
Clarify 
pharmacokinetic 
procedures
Appendix 13:
Strong CYP2D6 
Inhibitor
After the Screening visit, addition of the above strong 
CYP2D6 inhibitors is prohibited.
Subject’s receiving any of the above strong CYP2D6 
inhibitors will have a maximal dose of SD-809 of 36 
mg per day.
The maximum total daily dose of SD-809 for subjects with body 
weight less than 100 kg receiving any of the above strong 
CYP2D6 inhibitors is 36 mg per day. For subjects with body 
weight of 100 kg or more, receiving any of the above strong 
CYP2D6 inhibitors, the maximum total daily dose of SD-809 is 
42 mg per day.
Update 
Appendix 13
Appendix 20, 
Summary of 
Changes, 
Amendment 03 
(dated 14 Oct 
2015) to 
Amendment 04 
(dated 27 Sept 
2016) 
Not applicable
Appendix added
Summarize 
protocol 
changes in 
Amendment 04
Global
Not applicable
Updated amendment number, dates, section numbers, and tables 
of contents. Corrected typos; errors in punctuation, grammar, 
and formatting; and inconsistencies in style.


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Appendix 21: Protocol Summary of Changes, Amendment 04 (dated 27 Sept 2016) to Amendment 05 (dated 08 Feb 2017)
Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
Study Contacts: 
Sponsor
Medical Monitor
(US)
(EU)
 
 
Not applicable.
 
 
Update to contacts and/or 
telephone numbers.
Addition of EU Medical Monitor 
and back-up
Schedule of Events
Not applicable
Addition of footnote #9 to the “12-lead ECG” 
activity row, under the unscheduled visits 
assessment column
9
Subjects undergoing an increase in 
dose of their current antipsychotic treatment, 
switching to a new antipsychotic agent, or 
having an additional antipsychotic treatment 
added to their regimen will require additional 
ECG monitoring (see Section 6.5.1).
To direct the reader to 
Section 6.5.1, which details the 
additional ECG monitoring per 
the protocol.
Protocol Approval Page 
 
Principal Investigator for the Study 
Date
Date
 
Date
Removal of the signature for 
multiple PIs/coordinating 
investigators. 
 
is no longer required to sign off. 


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Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
5.2.3 Dose Reduction, 
Suspension, or 
Discontinuation
5.2.3
Dose Reduction or Suspension
Dose reductions should generally occur in 
increments of 6 mg/day, except in the case of 
addition of a strong CYP2D6 inhibitor (i.e., 
paroxetine, fluoxetine, bupropion), in which 
case a greater dose reduction may be 
required. Dose reductions in this context 
should be reviewed with the Medical 
Monitor. A dose reduction of 6 mg/day can 
be made by requesting that the next lowest 
dose level be shipped directly to the subject.
Suspension of study drug for up to 1 week, if 
warranted, is allowed. 
Suspensions of study drug for AEs must be 
reviewed with the Medical Monitor before 
therapy is restarted. If study drug is 
restarted after a suspension for an AE, a 
dose reduction of 6 mg or more is 
permitted.
Suspensions for more than 7 days must be 
reviewed by the Medical Monitor. If the 
subject restarts study drug within 7 days of 
suspension, the full dose of SD-809 may be 
resumed without titration. If subject restarts 
study drug greater than 7 days following a 
suspension, retitration will be required. Dose 
re-titrations will necessitate additional 
unscheduled visits and telephone contacts 
which will be needed to ensure that the 
subject reaches the appropriate maintenance 
dose safely and without undue delay, and to 
ensure adherence to the treatment regimen 
and retention of any unused drug materials.
5.2.3
Dose Reduction, Suspension, or 
Discontinuation
Dose Reduction
Dose reduction should generally occur in 
increments of 6 mg/day, except in the case of 
addition of a strong CYP2D6 inhibitor (i.e., 
paroxetine, fluoxetine, bupropion), in which 
case a greater dose reduction may be 
required. Dose reductions in this context 
should be reviewed with the Medical 
Monitor. A dose reduction of 6 mg/day can 
be made by requesting that the next lowest 
dose level be assigned through the Interactive 
Response Technology system.
Suspension
Suspension of study drug for up to 1 week, if
warranted, is allowed.
Suspensions of study drug for AEs must be 
reviewed with the Medical Monitor before 
therapy is restarted. If study drug is 
restarted after a suspension for an AE, a dose 
reduction of 6 mg or more is permitted.
If a subject’s serum potassium or magnesium 
falls below the lower limit of normal, study 
drug must be suspended. The Medical 
Monitor must be contacted to determine the 
appropriate investigation and treatment. 
SD-809 may only be restarted once serum 
potassium or magnesium have normalized.
Suspensions for more than 7 days must be 
reviewed by the Medical Monitor. If the 
subject restarts study drug within 7 days of 
suspension, the full dose of SD-809 may be 
resumed without titration. If subject restarts 
study drug greater than 7 days following a 
suspension, re-titration will be required. Dose 
re-titrations will necessitate additional 
Clarify that a dose reduction is 
operationalized through the 
Interactive Response Technology 
system
As hypokalemia and 
hypomagnesiam may contribute 
to QT prolongation, criteria for 
suspending treatment have been 
added in case a subject’s 
potassium or magnesium levels
fall below the lower limit of 
normal.


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Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
The reason for a dose reduction or 
suspension must be clearly documented.
unscheduled visits and telephone contacts 
which will be needed to ensure that the 
subject reaches the appropriate maintenance 
dose safely and without undue delay, and to 
ensure adherence to the treatment regimen 
and retention of any unused drug materials.
Discontinuation
Discontinue study drug and complete an early 
termination visit if, based on readings of 
12-lead ECGs interpreted in the central ECG 
laboratory, the subject meets either of the 
following criteria:
•
a meanf QTcF value >500 msec or 
•
a meanf change in QTcF of >60 
msec from Baseline
The reason for a dose reduction, 
suspension, or discontinuation must be 
clearly documented.
Addition of subject 
discontinuation criteria regarding 
clinically significant QTc 
observations.
6.5.1 Unscheduled 
Visit(s) for Change in 
Antipsychotic Regimen
Not applicable
6.5.1
Unscheduled Visit(s) for Change in 
Antipsychotic Regimen
Subjects undergoing an increase in dose of 
their current antipsychotic treatment, 
switching to a new antipsychotic agent, or 
having an additional antipsychotic treatment 
added to their regimen will require additional 
ECG monitoring. In such cases, the 
Investigator should contact the Medical 
Monitor to review these procedures.
•
Subjects undergoing such a change 
in oral antipsychotic treatment should have 
an unscheduled visit between 1-2 weeks 
thereafter. 
•
Subjects undergoing an increase in 
dose of a long-acting injectable (LAI) 
antipsychotic, switching to LAI treatment, or 
having an additional LAI antipsychotic 
Given the potential for many 
antipsychotics to prolong the QT 
interval, additional ECG 
monitoring will be added if a 
patient increases antipsychotic 
dose, switches to a new 
antipsychotic, or has a new 
antipsychotic treatment added to 
their regimen.


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Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
treatment added to their regimen should have 
an unscheduled visit within the following 
timeframe, based on the prescribed LAI 
antipsychotic:
o
4-5 weeks: fluphenazine decanoate
o
8-9 weeks: risperidone LA, 
haloperidol decanoate, olanzapine pamoate, 
Zuclopenthixol decanoate
o
12-13 weeks: all other LAI 
antipsychotics
On the morning of the clinic visit, the subject 
should hold their SD-809 dose until they are 
in the clinic. Upon reaching clinic, the 
following activities should be performed:
•
Administer the morning dose of SD-
809 with a meal or light snack
•
Collect a 12-lead ECG 3 hours after 
SD-809 administration following at least 5 
minutes of rest in a supine or semi-recumbent 
position.
o
Based on the ECG machine reading, 
if QTcF value is >500 msec or there is a 
change from Baseline in QTcF value of >60 
msec, two additional 12-lead ECGs should be 
collected as soon as practical. There should 
be at least 5 minutes between ECGs.
•
Transmit ECGs to the central 
laboratory on the same day that they are 
collected.
6.5.2 Unscheduled 
Telephone Visit(s)
Not applicable
6.5.2
Unscheduled Telephone Visits
Addition of section head to 
enhance protocol structure
6.7.7 12-Lead 
Electrocardiogram
All ECGs will be performed after at least 5 
minutes rest in a supine or semi-supine 
position.
All ECGs will be performed after at least 5 
minutes rest in a supine or semi-recumbent 
position.
Update to ECG position 
terminology
6.9.1 Concomitant 
Medications
Allowed Concomitant Medications
Subjects receiving psychoactive medications 
(including, but not limited to, neuroleptics 
[see Appendix 16], benzodiazepines, 
Allowed Concomitant Medications
Stable dosing
Subjects receiving psychoactive medications 
(including, but not limited to, neuroleptics 
Increased breakdown of allowed 
concomitant medications.
Addition of “antipsychotics” 
subsection to clarify the 


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Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
anticonvulsants, and mood stabilizers) must 
be on a stable dose for ≥30 days (oral 
medication) before Screening and in the 
opinion of the treating psychiatrist, no 
changes in drug or dose are expected in the 
next 3 months. After 3 months, changes in 
psychoactive medications are allowed if 
approved by the Investigator. Any changes in 
concomitant medications must be 
documented in the eCRF.
Subjects receiving antidepressant therapy 
must be on a stable dose for 45 days before 
Screening. Subjects receiving long acting 
(depot) medications must have been on stable 
therapy (dose, frequency) for ≥3 months 
before Screening. 
Female subjects on hormonal contraception 
(approved oral, transdermal, or depot 
regimen) for birth control must be on a stable 
dose for at least 3 months prior to Screening 
and through study completion.
Subjects will be instructed to inform the study 
Investigator of the details (indication, dose, 
and dates of administration) if they do take 
any medication, and these details will be 
recorded in the eCRF.
[see Appendix 16], benzodiazepines, 
anticonvulsants, and mood stabilizers) must 
be on a stable dose for ≥30 days (oral 
medication) before Screening and in the 
opinion of the treating psychiatrist, no 
changes in drug or dose are expected in the 
next 3 months. After 3 months, changes in 
psychoactive medications are allowed if 
approved by the Investigator. Any changes in 
concomitant medications must be 
documented in the eCRF.
Antipsychotics
Considering the potential of antipsychotic 
drugs to prolong the QT interval, additional 
ECG monitoring is required if the 
Investigator 1) increases the dose of a 
patient’s current antipsychotic treatment, 
2) switches the patient to a different 
antipsychotic treatment, or 3) adds a new 
antipsychotic treatment to the patient’s 
regimen. In such cases, subjects should have 
an unscheduled visit within 1-2 weeks for a 
change in oral antipsychotic treatment, or 
have an unscheduled visit within 4-5 weeks, 
8-9 weeks, or 12-13 weeks (depending upon 
the prescribed LAI) for a change in their LAI 
antipsychotic treatment, to have a repeat 
12-lead ECG following their usual SD-809 
dose (see Section 6.5.1). 
Antidepressants
Subjects receiving antidepressant therapy 
must be on a stable dose for 45 days before 
Screening. Subjects receiving long acting 
(depot) medications must have been on stable 
therapy (dose, frequency) for ≥3 months 
before Screening.
Other
Female subjects on hormonal contraception 
(approved oral, transdermal, or depot 
additional ECG monitoring that 
will take place due to the 
potential for antipsychotic drugs 
to prolong the QT interval


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Section 
Amendment 04 (dated 27 Sept 2016)
Amendment 05, dated 08 Feb 2017
Reason for Change
regimen) for birth control must be on a stable 
dose for at least 3 months prior to Screening 
and through study completion.
Subjects will be instructed to inform the study 
Investigator of the details (indication, dose, 
and dates of administration) if they do take 
any medication, and these details will be 
recorded in the eCRF.
6.11 Withdrawal Criteria
•
Intolerable/unacceptable adverse 
events; 
•
Intolerable/unacceptable adverse 
events (see Section 5.2.3 for QTcF 
discontinuation criteria);
Addition of cross-reference to 
newly inserted rules on QTcF 
discontinuation criteria
Appendices 7 - 12
Appendices 7 - 12 were in advertently left out 
of Amendment 04 
Appendices 7 - 12 have now been inserted 
back into the protocol 
Fix/update
Appendix 14 Prohibited or 
Restricted QT Prolonging 
Drugs
Not applicable
Addition of the drug, Thioridazine, to 
Appendix 14
Thioridazine is categorized as a 
prohibited QT prolonging drug
Appendix 15 Dopamine 
Receptor Antagonists
Thioridazine “Typical Dosing” column: 
Initial: 50-100 mg 3 times/day; up to 800 
mg/day
Thioridazine “Typical Dosing” column: 
Prohibited
Update to the drug, Thioridazine, 
in the list of Dopamine Receptor 
Antagonists. Dosing with 
Thioridazine is now prohibited
Appendix 21, Summary of 
Changes, Amendment 04 
(dated 27 Sept 2016) to 
Amendment 05 (dated 
08 Feb 2017) 
Not applicable
Appendix added
Summarize protocol changes in 
Amendment 05
Global
Not applicable
Updated amendment number, dates, section 
numbers, and tables of contents. Corrected 
typos; errors in punctuation, grammar, and 
formatting; and inconsistencies in style.


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Appendix 22: Protocol Summary of Changes, Amendment 05 (dated 08 Feb 2017) to Amendment 06 (dated 23 Jan 2018)
Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
Study Contacts: 
Sponsor
Medical Monitor (US)
Medical Monitor (EU)
Auspex Pharmaceuticals, Inc.
3333 N. Torrey Pines Court, Suite 400
La Jolla, CA 92037
USA
Tel: 
Fax
Vice President, Clinical Development, 
Teva USA
Tel: +
Email: 
 
Sr Mgr, Global Clinical Project Mgmt 
Global Clinical Operations, CNS & Pain
Tel: 
 
E-mail: 
C-20 Study Phone
Tel: 
 
E-mail: 
c
E-mail
Email: 
Auspex Pharmaceuticals, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
USA
Vice President, TA Head, Specialty R&D
Tel: 
E-mail: 
Sr Mgr, Global Clinical Project Mgmt
Global Clinical Operations, CNS & Pain
Tel: +
E-mail:
Study SD-809-C-20 Phone
E-mail: 
E-mail: 
Email: 
Updated to Sponsor contacts 
and/or telephone numbers.
Updated C-20 Study Phone to 
Study SD-809-C-20 Phone 
Schedule of Events
Not applicable
First table designated as Part A and footnotes 
updated to reflect optional move to Part B; 
additional table created for Part B table. Columns 
Updated to designate Part A and 
Part B and create Randomization 
Withdrawal Period


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
include Part B Pre-withdrawal Visit, Part B Post-
withdrawal Visit, EOT/ET visit, Follow-up visit 
(ET only), Follow-up Call, and Unscheduled. 
Study Schematic Diagram
Not applicable
Study Schematic Diagram (Parts A and B)
Added study schematic diagram 
for Parts A and B
Protocol Approval Page 
Vice President, Clinical Development
Teva USA
Date
Vice President, TA Head, Specialty R&D
Teva Pharmaceuticals
Date
Updated to the sponsor’s clinical 
signatory
List of Abbreviations
Not applicable
Updated
Updated to include abbreviations 
required in new amendment text
1.4 Introduction SD-809 
(Deutetrabenazine)
The safety and pharmacokinetics of oral 
SD-809 have been evaluated in five 
Phase 1 studies in healthy adult 
volunteers. Additionally, two Phase 3 
studies in adult patients with chorea 
associated with HD, and one Phase 1b 
study in adolescent patients with tics 
associated with Tourette syndrome are 
ongoing at this time.
The safety and pharmacokinetics of oral SD-809 
have been evaluated in five Phase 1 studies in 
healthy adult volunteers. Additionally, two Phase 3 
studies in adult patients with chorea associated 
with HD and one Phase 1b study in adolescent 
patients with tics associated with Tourette
syndrome have been completed.
Updated study statuses
Protocol Synopsis, 
Objectives
Section 2 Study Objectives
The objectives of this study are: 

Evaluate the safety and tolerability 
of long-term maintenance therapy 
with SD-809

Evaluate the efficacy of long-term 
maintenance therapy of SD-809 to 
reduce the severity of abnormal 
involuntary movements of TD
The objectives of this study are: 

Evaluate the safety and tolerability of long-
term maintenance therapy with SD-809

Evaluate the efficacy of long-term 
maintenance therapy of SD-809 to reduce the 
severity of abnormal involuntary movements 
of TD

Evaluate the persistence of the therapeutic 
effect of SD-809
Added objective for Part B
Section 3 Investigational 
Plan
This is an open-label, single-arm study 
designed to evaluate the long-term 
safety and tolerability of SD-809 for the 
treatment of subjects with moderate to 
severe drug-induced TD for up to 
3 years (158 weeks). Approximately 
330 subjects who have successfully 
completed a parent study (Study SD-
809-C-18, Study SD-809-C-23, or any 
other SD-809 study for treatment of 
moderate to severe TD) will be enrolled. 
This is an open-label, single-arm study designed to 
evaluate the long-term safety and tolerability of 
SD-809 for the treatment of subjects with moderate 
to severe drug-induced TD. Approximately 330 
subjects who have successfully completed a parent 
study (Study SD-809-C-18, Study SD-809-C-23, or 
any other SD-809 study for treatment of moderate 
to severe TD) will be enrolled. The study will be 
conducted at approximately 80 centers in the U.S., 
Europe, and possibly other regions. The study is 
divided into 2 parts, Part A and Part B. These parts 
Updated study parts to include 
Randomization Withdrawal 
Period (Part B)


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
The study will be conducted at 
approximately 80 centers in the U.S., 
Europe, and possibly other regions. The 
study is divided into a Screening Period, 
a Titration Period, a Long-Term 
Treatment Period, and a Post-Treatment 
Safety Follow-up Period. For subjects 
who complete the study, overall study 
participation will be up to 162 weeks.
include a Screening Period (Part A), a Titration 
Period (Part A), a Long-Term Treatment Period 
(Part A), a Double-Blind, Randomized Withdrawal 
Period (Part B), treatment after completion of the 
Randomized Withdrawal Period (Part B), and a 
Post-Treatment Safety Follow-up Period (Part A 
and Part B).
Section 3.1 Study Design
Section 5.2.1 General 
Guidelines
5.2.4 Dose Reduction, 
Suspension, or 
Discontinuation
Prior to withdrawing a subject from the 
study, the reasons for doing so should 
be discussed with the Medical Monitor 
or Sponsor Clinician.
Prior to withdrawing a subject from the study, the 
reasons for doing so should be discussed with the 
Medical Monitor or Sponsor Clinician.
Removed requirement for 
discussion with Medical Monitor 
or Sponsor clinician
Protocol Synopsis, Study 
Design
Section 3.1 Study Design
Informed consent/assent will be 
obtained before any study procedures 
are performed. Subjects may have 
informed consent/assent obtained up to 
30 days in advance of subject’s parent 
study Week 13 Visit/TD-Long Term 
Safety (LTS) Baseline Visit. Subjects 
who meet the selection criteria will be 
eligible to participate. 
Informed consent/assent (Part A) will be obtained 
before any study procedures are performed. 
Subjects may have informed consent/assent 
obtained up to 30 days in advance of subject’s 
parent study Week 13 Visit/TD-Long Term Safety 
(LTS) Baseline Visit. Subjects who meet the 
selection criteria will be eligible to participate. 
Informed consent/assent for Part B will be obtained 
after Amendment 06 implementation and before 
any study procedures related to Part B are 
performed.
Updated to include informed 
consent for Part B
Protocol Synopsis, Study 
Design
Section 3.1 Study Design
Long-Term Treatment Period (up to 
3 years)
During the remainder of the Long-Term 
Treatment Period, subjects will return to 
the clinic for evaluation of safety and 
dyskinesia once every 13 weeks, 
starting at Week 15 and ending at 
Week 158 (i.e., after 3 years of Long-
Term Treatment Period). During long-
term treatment, further dose adjustments 
of SD-809 may be made, if necessary, 
Long-Term Treatment Period (Week 3 until the 
last dose in Part A)
During the remainder of the Long-Term Treatment 
Period, subjects will return to the clinic for 
evaluation of safety and dyskinesia once every 13 
weeks, starting at Week 15 and ending at the last 
dose in Part A (completion of Part A=Week 158 or 
beginning of Part B after Amendment 06 
implementation). During long-term treatment, 
further dose adjustments of SD-809 may be made, 
if necessary, but not more often than weekly and in 
Changed length of Long-Term 
Treatment Period to indicate that 
treatment will end at last dose of 
Part A)
Added dose reduction instructions 
to include CYP2D 
Text added to clarify Part A and 
Part B timing


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
but not more often than weekly and in 
increments of 6 mg per day. Dose 
adjustments should be based on all 
available information, including the 
subject’s and caregiver’s reports of 
adverse events and dyskinesia control, 
information from rating scales, and all 
safety evaluations. If warranted, study 
sites are encouraged to conduct periodic 
phone calls with the subjects to ensure 
adherence to the treatment regimen and 
retention of unused drug containers.
Not applicable
increments of 6 mg per day. In the case of the 
addition of a strong CYP2D6 inhibitor (i.e., 
paroxetine, fluoxetine, and bupropion), a greater 
dose reduction may be required. Dose reductions in 
this context should be reviewed with the Medical 
Monitor. Dose adjustments should be based on all 
available information, including the subject’s and 
caregiver’s reports of adverse events and 
dyskinesia control, information from rating scales, 
and all safety evaluations. If warranted, study sites 
are encouraged to conduct periodic phone calls 
with the subjects to ensure adherence to the 
treatment regimen and retention of unused drug 
containers.
Subjects who have been on a stable dose of 
SD-809 and any concomitant dopamine receptor 
antagonist (DRA) for a minimum of 4 weeks will 
be invited to participate in the Randomized 
Withdrawal Period (Part B) at the next routine visit 
at the site after approvals from IRB/Ethics 
Committee and as required by country regulations.
If the subject chooses to participate in Part B, then 
participation in Part A will end. Subjects who 
decline to participate in Part B will continue in Part 
A until Week 158. Subjects who decline 
participation in Part B will be given an ongoing 
option to participate at subsequent study visits.
Protocol Synopsis, Study 
Design
Section 3.1 Study Design
Not applicable
Part B:
Part B will consist of a double-blind, randomized 
withdrawal period; treatment with SD-809; and the 
post-treatment safety follow-up. The Randomized 
Withdrawal Period will be 1 week (+3 days 
maximum) in duration and will consist of 2 visits, 
the Pre-withdrawal Visit and the Post-withdrawal 
Visit. After the Randomized Withdrawal Period, 
the subjects will resume treatment with SD-809 on 
the prior established dose for an additional 
12 weeks until end of treatment (EOT). 
At the beginning of the Randomized Withdrawal 
Added Randomization 
Withdrawal Period (Part B)


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
Period, subjects will be randomized in a blinded 
fashion to either SD-809 (current dose) or placebo 
in a 1:1 ratio stratified by concomitant DRA usage. 
Up to 194 subjects (active subjects as of the 
approval date of Amendment 06) will be 
randomized (SD-809 or placebo). Subjects will be 
required to sign a written informed consent. 
Subjects will need to be on a stable dose of SD-809 
and any concomitant DRA for a minimum of 
4 weeks before starting the Randomized 
Withdrawal Period.
Subjects will be scheduled to return 1 week 
(+3 days maximum) after the Pre-withdrawal Visit
of the Randomized Withdrawal Period for efficacy 
and safety assessments. 
At the end of this period, subjects will continue 
treatment with SD-809 at the previous dose 
administered before the Randomized Withdrawal 
Period (last dose in Part A). Treatment with 
SD-809 will continue for 12 weeks until the EOT 
visit.
Video ratings of the AIMS will occur at the 
Pre-withdrawal Visit, the Post-withdrawal Visit, 
and the EOT/ET visit.
Protocol Synopsis, Study 
Design
Section 3.1 Study Design
Post-Treatment Safety Follow-up: All 
subjects will discontinue study drug at 
the Week 158 visit and return for their 
final clinic visit at Week 159 for 
evaluation of safety, dyskinesia control, 
and motor function. During this 1-week 
washout, subjects should not take 
prohibited concomitant medications. 
Subjects will also have a follow-up 
telephone contact at Week 162, 4 weeks 
after their last dose of study drug, to 
evaluate adverse events and 
concomitant medication usage. Between 
the Week 159 visit and the Week 162 
telephone contact, concomitant 
Post-Treatment Safety Follow-up:
Part A:
Subjects who do not participate in Part B will 
continue in Part A, discontinue study drug at the 
Week 158 visit, and return for their final clinic 
visit at Week 159 for evaluation of safety, 
dyskinesia control, and motor function. During this 
1-week follow-up period, subjects should continue 
to not take prohibited concomitant medications. 
Subjects will also have a follow-up telephone 
contact at Week 162, 4 weeks after their last dose 
of study drug, to evaluate adverse events and 
concomitant medication usage.
Subjects who discontinue study drug in Part A will 
complete an ET visit; a follow-up clinic visit 
Updated post-treatment safety 
follow-up to include Part B 


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
medication use is per the discretion of 
the Investigator.
1 week later to evaluate safety, dyskinesia, and 
motor function; and a follow-up telephone contact 
4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since ET.
Part B:
Subjects who complete the Randomized 
Withdrawal Period and subsequent 12 weeks of 
treatment will complete an EOT visit and a 
follow-up telephone contact 4 weeks after the last 
dose of study drug to evaluate the adverse events 
and concomitant medication use since EOT.
Subjects who discontinue study drug in Part B will 
complete an ET visit; a follow-up clinic visit 
1 week later to evaluate safety, dyskinesia, and 
motor function; and a follow-up telephone contact 
4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since ET.
Section 3.2 Rationale for 
Study Design
The study is designed to evaluate the 
long-term safety and tolerability of 
SD-809 in subjects with moderate to 
severe dyskinesia associated with TD.
The study is designed to evaluate the long-term 
safety and tolerability of SD-809 in subjects with 
moderate to severe dyskinesia associated with TD 
(Part A) and the persistence or maintenance of the 
therapeutic effect of SD-809 in subjects with TD 
(Part B).
Updated to include Randomized 
Withdrawal Period (Part B) 
Section 3.2 Rationale for 
Study Design
The present investigation is an open-
label safety study of up to 158 weeks of 
treatment with SD-809 at a 
pharmacologically active dose (or until 
SD-809 has a Regulatory approval for 
treatment of TD) and will enroll 
subjects with drug-induced dyskinesia 
associated with TD who were 
previously exposed to either SD-809 or 
placebo in a parent study.
The present investigation is an open-label safety 
study with a nested, randomized, double-blind, 
1-week withdrawal period of SD-809. The study 
will enroll subjects with TD who were previously 
exposed to either SD-809 or placebo in a parent 
study.
Updated to include Randomized 
Withdrawal Period (Part B)


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Amendment 05 (dated 08 Feb 2017)
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Reason for Change
Section 5.1 Study Drug
5.1
Study Drug
During titration/dose adjustment, SD-
809 tablets will be labeled according to 
applicable regulatory guidelines and 
supplied in weekly blister packs as 6, 9, 
12, 15, and/or 18 mg tablets. Each 
blister pack will contain a sufficient 
supply of study drug until the next 
specified visit, plus overage to account 
for potential delays in study visits or 
evaluations or receipt of their supplies. 
During long-term treatment, SD-809 
will be supplied in 30 count bottles 
and labeled according to applicable 
regulatory guidelines.
5.1
Study Drug
5.1.1
SD-809
During titration/dose adjustment, SD-809 tablets 
will be labeled according to applicable regulatory 
guidelines and supplied in weekly blister packs as 
6, 9, 12, 15, and/or 18 mg tablets. Each blister pack 
will contain a sufficient supply of study drug until 
the next specified visit, plus overage to account for 
potential delays in study visits or evaluations or 
receipt of their supplies. During long-term 
treatment, SD-809 will be supplied in 30-count 
bottles and labeled according to applicable 
regulatory guidelines. During the 1-week 
Randomized Withdrawal Period, SD-809 will be 
supplied in 20-count bottles and labeled according 
to the applicable regulatory guidelines.
5.1.2
Placebo (Part B: Double-Blind, 
Randomized Withdrawal Period Only)
Placebo tablets are identical in appearance to the 
SD-809 and contain the same inactive ingredients 
as SD-809.
Updated to include Randomized 
Withdrawal Period
Added Section 5.1.2 to include 
placebo used in the Randomized 
Withdrawal Period
Section 5.2.2 Dosing in 
Long-Term Treatment
(Week 3 Until the Last 
Dose in Part A)
5.2.2 Dosing in Long-Term Treatment 
(Weeks 3 to 158)
5.2.2 Dosing in Long-Term Treatment (Week 3 
Until the Last Dose in Part A)
Updated to extend treatment to 
last dose in Part A
Protocol Synopsis, Dose 
Regimen
Section 5.2.3 Dosing in 
the Double-Blind, 
Randomized Withdrawal 
Period
Not applicable 
5.2.3
Dosing in the Double-Blind, Randomized 
Withdrawal Period
Subjects in the Randomized Withdrawal Period 
will continue to receive their current dose of 
SD-809 or will receive matching placebo. At the 
end of the Randomized Withdrawal Period, 
subjects will continue with, or return to, the same 
dose of SD-809 taken before the Randomized 
Withdrawal Period (last dose in Part A), beginning 
the day after the Post-withdrawal Visit and 
Added section 5.2.3 to include 
dosing information for the 
Randomized Withdrawal Period
Added Table 3: Titration 
Schedule After 1-Week 
Randomized Withdrawal Period 
(if Necessary)


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Reason for Change
continuing for 12 weeks. Subjects who do not 
return for the Post-withdrawal Visit within the 
10 days (1 week [+3 days maximum]) may be 
required to undergo titration, as decided by the 
Investigator in consultation with the Medical 
Monitor (if necessary) per the guidelines in 
Table 3. Titration is not permitted during the 
Randomized Withdrawal Period and will be 
allowed after return to open-label dosing.
Section 5.2.4 Dose 
Reduction, Suspension, or 
Discontinuation
Discontinuation
Discontinue study drug and complete an 
early termination visit if, based on 
readings of 12-lead ECGs interpreted in 
the central ECG laboratory, the subject 
meets either of the following criteria:

a mean QTcF value >500 msec or

a mean change in QTcF of 
>60 msec from Baseline
The reason for a dose reduction, 
suspension, or discontinuation must 
be clearly documented.
Discontinuation
Discontinue study drug and complete an ET visit 
if, based on Investigator evaluation of readings of 
12-lead ECGs, the subject meets either of the 
following criteria:

a mean QTcF value >500 msec or

a mean change in QTcF of >60 msec from 
Baseline
The reason for a dose reduction, suspension, or 
discontinuation must be clearly documented.
Updated Discontinuation to 
indicate that Investigator should 
evaluate ECG readings
Section 5.4 Accountability 
of Study Drug
Not applicable
Prior to the Pre-withdrawal Visit and Post-
withdrawal Visit, the Investigator or designated 
site staff must place a call to the subject as a 
reminder to bring all remaining study drugs to the 
visit. The Investigator or designated site staff must 
collect the study drug(s) from the subject and 
conduct drug accountability.
Added reminder call and 
instruction to collect all study 
drug before subject can start 
blinded treatment in Part B
Section 6.2 Dose 
Adjustment/Titration 
Period
Once adequate control of dyskinesia 
has been achieved or the maximum 
allowable dose has been reached, the 
dose of SD-809 should not be 
increased further.
Once adequate control of dyskinesia has been 
achieved, the dose of SD-809 should not be 
increased further.
Updated to align with Sections 
3.2 and 5.2.1


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Reason for Change
Section 6.3 Long-Term 
Treatment Period (Week 3 
Until the Last Dose in 
Part A)
Long-Term Treatment Period (Up to 
3 Years)
During the remainder of the Long-Term 
Treatment Period, subjects will return to 
the clinic for evaluation of safety and 
dyskinesia once every 13 weeks, 
starting at Week 15 and ending at Week 
158 (i.e., after 3 years of Long-Term 
Treatment Period). Further dose 
adjustments of SD-809 may be made, if 
necessary, but not more often than 
weekly and in increments of 6 mg.
Long-Term Treatment Period (Week 3 Until Last 
Dose in Part A)
During the remainder of the Long-Term Treatment 
Period, subjects will return to the clinic for 
evaluation of safety and dyskinesia once every 
13 weeks, starting at Week 15 and ending at the 
last dose in Part A (completion of Part A=Week 
158 or beginning of Part B after Amendment 06 
implementation). Further dose adjustments of 
SD-809 may be made, if necessary, but not more 
often than weekly and in increments of 6 mg.
Updated to extend treatment to 
last dose in Part A 
Section 6.3.3 Clinic Visits 
(Part A) (Weeks 28, 54, 
106 and 158 [All ± 3 
Days] or Early 
Termination)
Unless a subject discontinues the study 
early, treatment with study drug will 
stop at the Week 158 visit.
Unless a subject discontinues the study early or 
opts to participate in Part B, treatment with study 
drug will stop at the Week 158 visit.
Updated to include the subject 
option to participate in Part B
Section 6.4 Double-Blind, 
Randomized Withdrawal 
Period (Part B)
Not applicable
6.4
Double-Blind, Randomized Withdrawal 
Period (Part B)
See the Schedule of Events for a detailed summary 
of activities.
At the Pre-withdrawal Visit and Post-withdrawal 
Visit (1 week [+3 days maximum] from the Pre-
withdrawal Visit), the following activities should 
be performed:

Obtain or verify informed consent or assent (for 
subjects who do not have a legally authorized 
representative) after Amendment 06 
implementation (Pre-withdrawal Visit only).

Randomize subject via IRT and dispense study 
drug (Pre-withdrawal Visit only)

Assessment of adverse events, dyskinesia 
control (in consultation with the subject and 
caregiver, if applicable), and concomitant 
medication use 

Vital signs (Pre-withdrawal Visit to include 
orthostatic blood pressure and pulse) and weight 
Added Section 6.4 Double-Blind, 
Randomized Withdrawal Period


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Reason for Change

Clinical laboratory tests: serum chemistry, 
hematology, urinalysis, and urine pregnancy 
test (Pre-withdrawal Visit only; women of 
childbearing potential only)

Single pharmacokinetic (PK) blood sample 
(Post-withdrawal Visit only) 

12-lead ECG

AIMS

Video recording of AIMS

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

MoCA©

Assessment of study drug 
accountability/compliance and collection of all 
study drug before randomization into the 
Randomized Withdrawal Period and at the end 
of the Randomization Withdrawal Period

Subjects will be provided with a sufficient 
supply of study drug (blinded at Pre-withdrawal 
Visit).

The next clinic visit will be 
scheduled/reconfirmed. 
6.4.1
Clinic Visits (Part B Open-label 
Treatment) End of Treatment or Early Termination
See the Schedule of Events for a detailed summary 
of activities.
At the Part B EOT or Part B ET visit, subjects will 
undergo a more comprehensive evaluation, 
including:

Assessment of adverse events, dyskinesia 
control (in consultation with the subject and 
caregiver, if applicable), and concomitant 
medication use 


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Reason for Change

Physical examination, vital signs (including 
orthostatic blood pressure and pulse), and 
weight

Complete neurological examination

Clinical laboratory tests: serum chemistry, 
hematology, urinalysis, and urine pregnancy 
test (women of childbearing potential only) 

12-lead ECG

AIMS

Video recording of AIMS

UPDRS Part III (motor examination)

BARS

HADS

C-SSRS: Since Last Visit version

ESS

MoCA©

Assessment of study drug 
accountability/compliance and collection of all 
study drug

The next clinic visit will be 
scheduled/reconfirmed 
Unless a subject discontinues the study early, 
treatment with study drug will stop at the EOT 
visit.
Note: If the subject discontinues from the study 
early, every effort should be made to complete the 
ET procedures as outlined above and in the 
Schedule of Events. In addition, subjects 
discontinuing prematurely from the study should 
have a follow-up visit 1 week after discontinuing 
therapy and a follow-up telephone contact 4 weeks 
after discontinuing therapy, if possible. The 
procedures outlined in Section 6.4 should be 
followed.
Section 6.5 Post-
Treatment Safety Follow-
Up
Following discontinuation of study drug 
at the Week 158 visit, subjects will have 
a clinic visit at Week 159 for evaluation 
of safety, dyskinesia, and motor 
Following discontinuation of study drug at the 
Week 158 visit in Part A, subjects will have a 
clinic visit at Week 159 for evaluation of safety, 
dyskinesia, and motor function and a telephone 
Updated visit designations


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Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
function and a telephone contact at 
Week 162 for review of AEs and 
concomitant medication use since 
Week 159. During the first week after 
stopping study drug (i.e., through the 
Week 159 visit), subjects should not 
take prohibited concomitant 
medications. Between the Week 159 
visit and the Week 162 telephone 
contact, concomitant medication use is 
per the discretion of the Investigator.
contact at Week 162 for review of adverse events 
and concomitant medication use since Week 159. 
Following discontinuation of study drug at the ET 
visit in Part A, subjects will have a clinic visit 1 
week later for evaluation of safety, dyskinesia, and 
motor function and a telephone contact 4 weeks 
after the last dose for review of adverse events and 
concomitant medication use since ET. 
Following discontinuation of study drug at the 
EOT visit in Part B, subjects will have a telephone 
contact 4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since EOT.
Following discontinuation of study drug at the ET 
visit in Part B, subjects will have a clinic visit 
1 week later for evaluation of safety, dyskinesia, 
and motor function and a telephone contact 4 
weeks after the last dose of study drug to evaluate 
the adverse events and concomitant medication use 
since ET.
During the first week after stopping study drug, 
subjects should not take prohibited concomitant 
medications. Between the Week 158, EOT, or ET 
visit and the follow-up telephone contact, 
concomitant medication use is per the discretion of 
the Investigator.
Section 6.5.1 Clinic Visit 
(1 Week after Early 
Termination ±3 Days)
6.4.1
Clinic Visit (Week 159 ± 
3 Days)
All subjects will return 1 week after the 
Week 158 or Early Termination visit for 
evaluation of safety, dyskinesia, and 
motor function. The following activities 
should be performed:
6.5.1
Clinic Visit (Week 159 or 1 Week after 
Early Termination ±3 Days)
All subjects will return 1 week after Week 158 
(Part A) or the ET visit (Part A or Part B) for 
evaluation of safety, dyskinesia, and motor 
function. The following activities should be 
performed:
Updated final clinic visit 
description from to include text 
for subjects who terminated early 
in Part A or Part B


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Amendment 05 (dated 08 Feb 2017)
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Reason for Change
Section 6.5.2 Telephone 
Contact (4 Weeks After 
EOT/ET ± 3 Days)
6.4.2
Telephone Contact (Week 162 
± 3 Days)
All subjects will have a follow-up 
telephone contact at Week 162, 3 weeks 
after the Week 159 visit (4 weeks after 
their last dose of study drug [Week 
158]), or 4 weeks after the Early 
Termination visit. During the telephone 
contact, subjects (and caregivers, if 
appropriate) will be questioned about 
AEs and concomitant medication use 
since the subject’s last evaluation.
6.5.2
Telephone Contact (Week 162 ± 3 Days 
or 4 Weeks After EOT/ET ± 3 Days)
All subjects will have a follow-up telephone 
contact at Week 162 (4 weeks after their last dose 
of study drug [Week 158]) (Part A); or 4 weeks 
after the EOT visit (Part B); or 4 weeks after the 
ET visit (Part A or Part B). During the telephone 
contact, subjects (and caregivers, if appropriate) 
will be questioned about adverse events and 
concomitant medication use since the subject’s last 
evaluation.
Updated time period to 4 weeks 
after EOT/ET visit
Section 6.8.5 Orthostatic 
Blood Pressure and Pulse
Orthostatic blood pressure and pulse 
will be recorded at Weeks 6, 54, 106, 
and 158/ET.
Orthostatic blood pressure and pulse will be 
recorded at Weeks 6, 54, 106, 158/ET, the 
Pre-withdrawal Visit, and EOT.
Added Pre-withdrawal Visit and 
EOT
Section 6.10.1 
Concomitant Medications
Not applicable
Valbenazine
Added valbenazine to the 
Prohibited Concomitant 
Medications list
Section 8.1 Analysis 
Populations
Intent-to-Treat (ITT) Population: The 
ITT Population will include all enrolled 
subjects in the study. All efficacy 
measures will be summarized using the 
ITT Population.
Intent-to-Treat (ITT) Population: The ITT 
Population will include all enrolled subjects in the 
study. All efficacy measures in Part A will be 
summarized using the ITT Population.
Randomized Withdrawal ITT Population: The 
Randomized Withdrawal ITT Population will 
include all subjects enrolled to Part B of the study.
Randomized Withdrawal Modified ITT (mITT) 
Population: The Randomized Withdrawal mITT 
Population will include all subjects enrolled in Part 
B who receive study drug during the Randomized 
Withdrawal Period and have a centrally read AIMS 
score at both the Pre-withdrawal Visit and the 
Post-withdrawal Visit. All efficacy measures in the 
Randomized Withdrawal Period will be analyzed 
using the Randomized Withdrawal mITT 
population.
Updated to include Randomized 
Withdrawal populations
Synopsis, Safety 
Endpoints
Section 8.4 Safety 
The following safety endpoints will be 
assessed:

Incidence of AEs, SAEs, severe 
The following safety endpoints will be assessed:

Incidence of adverse events, serious adverse 
events, severe adverse events, drug-related 
Added Randomized Withdrawal 
Period endpoints
>30 ms added to Part A change 


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Amendment 05 (dated 08 Feb 2017)
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Reason for Change
Endpoints
AEs, drug-related AEs, AEs leading 
to withdrawal during the following 
periods:
o
Overall
o
During titration 
o
During long-term treatment 

Observed values and changes from 
baseline in clinical laboratory 
parameters (hematology, chemistry, 
and urinalysis)

Observed values and changes from 
baseline in vital signs

Observed values in ECG 
parameters and abnormal findings

Number of subjects with on-
treatment QTcF values >450 ms, 
>480 ms, >500 ms

Observed values and changes in 
UPDRS Part III (motor 
examination), BARS, HADS, 
C-SSRS, ESS, and MoCA©

Duration of time to achieve stable 
doing of SD-809
adverse events, adverse events leading to 
withdrawal during the following periods:
o
Overall
o
During titration 
o
During long-term treatment 

Observed values and changes from baseline in 
clinical laboratory parameters (hematology, 
chemistry, and urinalysis)

Observed values and changes from baseline in 
vital signs

Observed values in ECG parameters and 
abnormal findings

Number of subjects with on-treatment QTcF 
values >450 ms, >480 ms, >500 ms, or a 
change from Baseline in QTcF of >30 ms or 
>60 ms

Observed values and changes in UPDRS Part 
III (motor examination), BARS, HADS, 
C-SSRS, ESS, and MoCA©

Duration of time to achieve stable dosing of 
SD-809
The following secondary safety endpoints will be 
assessed in Part B Double-Blind, Randomized 
Withdrawal Period

Incidence of adverse events, serious adverse 
events, severe adverse events, drug-related 
adverse events, and adverse events leading to 
withdrawal

Observed values and changes from start of 
randomized withdrawal in clinical laboratory 
parameters (hematology, chemistry, and 
urinalysis)

Observed values and changes from start of 
randomized withdrawal in vital signs

Observed values in ECG parameters and 
abnormal findings

Number of subjects with on-treatment QTcF 
values >450 ms, >480 ms, >500 ms, or a 
from baseline endpoint as 
standard QTcF safety endpoint


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Section 
Amendment 05 (dated 08 Feb 2017)
Amendment 06, dated 23 Jan 2018
Reason for Change
change from Baseline in QTcF of >30 ms or 
>60 ms

Observed values and changes in UPDRS Part 
III (motor examination), BARS, HADS, 
C-SSRS, ESS, and MoCA©
Protocol Synopsis, 
Efficacy Measures
Section 8.5 Efficacy 
Measures
The following efficacy measures will be 
assessed during Part A:

The change in AIMS score (items 1 
through 7) from Baseline of this 
study at each visit that this is 
measured, as assessed by blinded 
central video rating.

The change in AIMS score (items 1 
through 7) from Baseline of this 
study at each visit that this is 
measured, as assessed by the site 
rating.

The proportion of subjects who are 
a treatment success based on the 
CGIC at each visit that this is 
measured. A treatment success is 
defined as Much or Very Much 
Improved on the CGIC from 
Baseline of this study. 

The proportion of subjects who 
have a 50% or greater reduction in 
AIMS score from Baseline of this 
study at each visit that this is 
measured.

The change in the modified CDQ-
24 score from Baseline of this study 
at each visit that this is measured.

The proportion of subjects who are 
a treatment success based on the 
PGIC at each visit that this is 
measured. A treatment success is 
defined as Much or Very Much 
Improved on the PGIC from 
Baseline of this study.
The following efficacy measures will be assessed 
during Part A:

The change in AIMS score (items 1 through 7) 
from Baseline of this study at each visit that 
this is measured, as assessed by the site rating.

The proportion of subjects who are a treatment 
success based on the CGIC at each visit that 
this is measured. A treatment success is 
defined as Much or Very Much Improved on 
the CGIC from Baseline of this study. 

The proportion of subjects who have a 50% or 
greater reduction in AIMS score from Baseline 
of this study at each visit that this is measured.

The change in the modified CDQ-24 score 
from Baseline of this study at each visit that 
this is measured.

The proportion of subjects who are a treatment 
success based on the PGIC at each visit that 
this is measured. A treatment success is 
defined as Much or Very Much Improved on 
the PGIC from Baseline of this study.

The percent change in AIMS score from 
Baseline of this study at each visit that this is 
measured.
Deleted AIMS video recording 
measure


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Section 
Amendment 05 (dated 08 Feb 2017)
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Reason for Change

The percent change in AIMS score 
from Baseline of this study at each 
visit that this is measured.

Based on the change in AIMS score 
from Baseline of this study at each 
visit that this is measured, as 
assessed by blinded central video 
rating, the cumulative proportion of 
responders ranging from a 10% 
improvement from Baseline to a 
90% improvement from Baseline in 
steps of 10 percentage points.
Protocol Synopsis, 
Efficacy Measures
Section 8.5 Efficacy 
Measures
Not applicable
The following efficacy measures will be assessed 
during Part B (Randomized Withdrawal Period):

Primary efficacy endpoint: change from 
Pre-withdrawal Visit AIMS scores (items 1 
through 7) as assessed by blinded central video 
rating to the Post-withdrawal Visit between 
subjects treated with SD-809 and subjects 
treated with placebo.
Updated to include Randomized 
Withdrawal Period primary and 
secondary endpoints
Protocol, Statistics
Section 8.6 Efficacy 
Analysis (Randomized 
Withdrawal Period; 
Part B)
Not applicable
8.6
Efficacy Analysis (Randomized 
Withdrawal Period; Part B)
Analysis of the change in centrally read AIMS 
score (items 1 through 7) during the Randomized 
Withdrawal Period (from the Pre-withdrawal Visit 
to the Post-withdrawal Visit) will use an analysis 
of covariance (ANCOVA) model with the change 
in AIMS score as the dependent variable. The 
model will include randomized withdrawal 
treatment group, AIMS score at the Pre-withdrawal 
Visit, and DRA status at the Pre-withdrawal Visit 
as fixed effects. The least squares means of the 
change in AIMS score will be compared between 
the SD-809 treatment and placebo groups using a 
2-sided test at the alpha=0.05 level of significance. 
In addition, actual values and changes in AIMS 
score will be summarized using descriptive 
Added Section 8.6 for Efficacy 
Analysis of the Randomized 
Treatment Period


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Section 
Amendment 05 (dated 08 Feb 2017)
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Reason for Change
statistics.
The primary efficacy analysis will be tested at the 
α=0.05 level. If less than 135 subjects are enrolled 
into the randomized withdrawal portion of the 
study, inferential statistics will not be provided as 
the study will be insufficiently powered to detect a 
treatment effect given the sample size assumptions.
Protocol Synopsis, Sample 
Size
Section 8.7 Sample Size
Not applicable
During the Randomized Withdrawal Period, there 
will be up to 194 subjects randomized (SD-809 or 
placebo). It is estimated that approximately 
91 subjects per arm will enable a power of at least 
90% to detect a beneficial effect of 1.4 points or 
more in the change from pre-withdrawal to post-
withdrawal in centrally read AIMS when the 
SD-809 arm is compared to placebo, assuming a 
standard deviation of 2.9 and a 2-sided type I error 
rate of 5%.
Updated to describe the 
Randomized Withdrawal Period 
sample
Section 9.1.2 Written 
Informed Consent
Not applicable
Part B Randomized Withdrawal Period
Part B will begin after Amendment 06 
implementation. Subjects who decline to 
participate in the Randomized Withdrawal Period
(Part B) (i.e., sign written informed consent) will 
continue in Part A until Week 158. 
Updated to include informed 
consent details for the 
Randomized Withdrawal Period
Appendix 22, Protocol 
Summary of Changes, 
Amendment 05 (dated 
08 Feb 2017) to 
Amendment 06 (dated 
23 Jan 2018) 
Not applicable
Appendix added
Summarized protocol changes in 
Amendment 06
Global
Not applicable
Updated amendment number, dates, section 
numbers, and tables of contents. Corrected typos; 
errors in punctuation, grammar, and formatting; 
and inconsistencies in style.


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Appendix 23: Protocol Summary of Changes, Amendment 06 (dated 23 Jan 2018) to Amendment 07 (dated 02 May 2018)
Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
Schedule of Events
First table designated as Part A and 
footnotes updated to reflect optional 
move to Part B; additional table created 
for Part B table. Columns include Part B 
Pre-withdrawal Visit, Part B Post-
withdrawal Visit, EOT/ET visit, Follow-
up visit (ET only), Follow-up Call, and 
Unscheduled.
Additional table created for Part C. Columns 
include Part C, EOT/ET visit, Follow-up clinical
visit (ET only), Follow-up Call, and Unscheduled. 
Updated to designate Part C
Study Schematic Diagram
Study Schematic Diagram (Parts A and 
B)
Study Schematic Diagram (Part C)
Timeframe for Part B
Added study schematic diagram 
for Part C and the timeframe for 
Part B
Section 3 Investigational 
Plan
The study is divided into 2 parts, Part A 
and Part B. These parts include a 
Screening Period (Part A), a Titration 
Period (Part A), a Long-Term Treatment 
Period (Part A), a Double-Blind, 
Randomized Withdrawal Period (Part 
B), treatment after completion of the 
Randomized Withdrawal Period (Part 
B), and a Post-Treatment Safety 
Follow-up Period (Part A and Part B).
The study is divided into different parts: Part A and 
Part B for all countries and an additional Part C for 
the EU countries. These parts include a Screening 
Period (Part A), a Titration Period (Part A), a 
Long-Term Treatment Period (Part A), a Double-
Blind, Randomized Withdrawal Period (Part B), 
treatment after completion of the Randomized 
Withdrawal Period (Part B), a continued treatment 
period (Part C), and a Post-Treatment Safety 
Follow-up Period (Part A, Part B, and Part C).
Updated study parts to include 
Part C
Protocol Synopsis, Section 
3.1 Study Design
Informed consent/assent (Part A) will be 
obtained before any study procedures 
are performed. Subjects may have 
informed consent/assent obtained up to 
30 days in advance of subject’s parent 
study Week 13 Visit/TD-Long Term 
Safety (LTS) Baseline Visit. Subjects 
who meet the selection criteria will be 
eligible to participate. 
Informed consent/assent for Part B will 
be obtained after Amendment 06 
implementation and before any study 
procedures related to Part B are 
performed.
Informed consent/assent for Part C will be obtained 
after Amendment 07 implementation and before 
any study procedures related to Part C are 
performed. Subjects who do not sign the informed 
consent/assent for Part C will complete the study at 
Part B Follow-up Call.
Updated to include informed 
consent for Part C


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Amendment 07, dated 02 May 2018
Reason for Change
Protocol Synopsis, Study 
Design
Not applicable
Part C:
Part C will consist of a 52-week period of reduced 
burden safety assessments, for subjects in the EU 
countries. Subjects can only enter Part C once they 
have entered and completed Part B. The Part B 
EOT will coincide with Part C Visit 1 for those 
subjects who are willing to continue with the 52-
week reduced burden safety assessment period.
Post-Treatment Safety Follow-up:
Subjects in EU countries may choose to enroll in 
Part C, in which case Part B EOT will coincide 
with Part C Visit 1.
Part C:
Subjects who complete the 52 weeks of reduced 
burden safety assessments period will complete a 
Part C EOT Visit and a follow-up telephone 
contact 4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since Part C EOT. Subjects who 
discontinue study drug in Part C will complete an 
ET visit, a follow-up clinic visit 1 week later for 
safety evaluation, and a follow-up telephone 
contact 4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since ET.
Updated to include Part C and 
description of transition from Part 
B to Part C
Section 3.1 Study Design
Not applicable
Part C:
For the EU countries, the study will include a 
reduced burden safety assessments period (Part C) 
of 52 weeks for subjects willing to continue in the 
study and who have completed Part B. Subjects 
will continue treatment with SD-809 at the current 
dose administered during the 12-week open-label 
period of Part B. Subjects will be scheduled to 
return every 13 weeks (±1 week) until EOT. A 
follow-up clinic visit will occur 1 week after ET 
and a follow-up telephone call will occur 4 weeks 
after EOT/ET.
Post-Treatment Safety Follow-up:
Part C:
Updated to include Part C


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Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
Subjects who complete the 52 weeks of reduced 
burden safety assessments period will complete a 
Part C EOT visit and a follow-up telephone contact 
4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since Part C EOT. Subjects who 
discontinue study drug in Part C will complete an 
ET visit, a follow-up clinic visit 1 week later for 
safety evaluation, and a follow-up telephone 
contact 4 weeks after the last dose of study drug to 
evaluate the adverse events and concomitant 
medication use since ET.
Section 3.2 Rationale for 
Study Design
The study is designed to evaluate the 
long-term safety and tolerability of SD-
809 in subjects with moderate to severe 
dyskinesia associated with TD (Part A) 
and the persistence or maintenance of 
the therapeutic effect of SD-809 in 
subjects with TD (Part B).
An extension of the study (Part C) with reduced 
burden safety assessments is added to provide 
continued therapy for subjects in the EU countries. 
Part C will be offered only to subjects who 
completed Part B.
Updated to include Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
Section 5.1 Study Drug
5.1
Study Drug
5.1.1
SD-809
During titration/dose adjustment, SD-
809 tablets will be labeled according to 
applicable regulatory guidelines and 
supplied in weekly blister packs as 6, 9, 
12, 15, and/or 18 mg tablets. Each 
blister pack will contain a sufficient 
supply of study drug until the next 
specified visit, plus overage to account 
for potential delays in study visits or 
evaluations or receipt of their supplies. 
During long-term treatment, SD-809 
will be supplied in 30-count bottles 
and labeled according to applicable 
regulatory guidelines. During the 1-
week Randomized Withdrawal Period, 
SD-809 will be supplied in 20-count 
bottles and labeled according to the 
applicable regulatory guidelines.
The study drug is a matrix formulation in the form 
of a tablet to be administered with food. Study 
drug is coated with a polymer coating to aid in 
swallowing. SD-809 tablets have been 
manufactured according to current Good 
Manufacturing Practices regulations.
During titration/dose adjustment in Part A, SD-809 
tablets will be labeled according to applicable 
regulatory guidelines and supplied in weekly 
blister packs as 6, 9, 12, 15, and/or 18 mg tablets. 
Each blister pack will contain a sufficient supply of 
study drug until the next specified visit, plus 
overage to account for potential delays in study 
visits or evaluations or receipt of their supplies. 
During long-term treatment, SD-809 will be 
supplied in 30-count bottles and labeled 
according to applicable regulatory guidelines.
During the 1-week double blinded Randomized 
Withdrawal Period, SD-809 will be supplied in 20-
count bottles and labeled according to the 
applicable regulatory guidelines.
During Part C, SD-809 will be supplied in 30-
count bottles. 
Complete details regarding SD-809 supply, 
dispensing, and ordering will be provided in the 
study Operations Manual.
SD-809 tablets must be stored in a secure area with 
access limited to authorized staff, protected from 
light at controlled room temperature, 15°C to 25°C 
(59°F to 77°F).
Clarified the drug supply for Part 
A and Part C.
Section 5.2 Treatment 
Regimen
Daily doses up to 36 mg/day will be 
given as 1 tablet BID, whereas daily 
doses of 42, 48, 54, and 60 mg/day will 
be given as 2 tablets BID
Daily doses will be administered according to 
instructions provided in the Pharmacy Manual
Daily dosage was removed; added 
reference to the Pharmacy 
Manual.
Section 5.2.4 Dosing in 
Part C
Not applicable
5.2.4 Dosing in Part C
The drug will be provided to study subjects in 
30-count bottles. Each order will contain a 
sufficient supply of study drug until the next 
specified visit, plus overage to account for 
Updated to include dosing details 
in Part C


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Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
potential delays in study visits or evaluations.
Subjects who do not return for Part C Visit 1 
within 10 days of completing the Part B EOT Visit 
may be required to undergo titration, as decided by 
the Investigator in consultation with the Medical 
Monitor (if necessary) per the guidelines in Table 
4. 
Table 4
Titration Schedule Part C End 
of Treatment Period (if 
Necessary)
Part B 
open-
label 
period 
daily dose
1 week 
SD-809 
titration 
daily 
dose 
(Step 1)
1 week 
SD-809 
titration 
daily 
dose 
(Step 2)
SD-809 
daily dose 
after 
completing 
titration
12 mg or 
placebo
N/A
N/A
12 mg
18 mg or 
placebo
12 mg
N/A
18 mg
24 mg or 
placebo
12 mg
N/A
24 mg
30 mg or 
placebo
18 mg
24 mg
30 mg
36 mg or 
placebo
18 mg
24 mg
36 mg
42 mg or 
placebo
24 mg
30mg
42 mg
48 mg or 
placebo
24 mg
36 mg
48 mg
54 mg or 
placebo
30 mg
42 mg
54 mg


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
60 mg or 
placebo
30 mg
48mg
60 mg
Abbreviation: mg, milligram; N/A, not applicable.
Section 6.5 Reduced 
Burden Safety 
Assessments (Part C)
Not applicable
Section 6.5 Reduced Burden Safety Assessments 
(Part C)
See the Schedule of Events for a detailed summary 
of activities.
At Part C Visit 1, the subjects will undergo the 
activities performed at the Part B EOT visit as 
described above and will sign the informed 
consent/assent for Part C.
At Part C Visit 2, Visit 3, Visit 4, or the EOT/ET 
Visit, subjects will undergo reduced burden safety 
assessments, including:

Physical examination, vital signs (including 
resting blood pressure and pulse), and weight

Complete neurological examination (Part C 
EOT/ET only)

Urine pregnancy test (done locally at the study 
site)

12-lead ECG

C-SSRS: Since Last Visit version

Assessment of study drug 
accountability/compliance and collection of all 
study drug

Assessment of AEs and concomitant meds

Re-order study drug (see Operations Manual 
for further details, Part C Visit 2, Visit 3, and 
Visit 4)

The next clinic visit will be 
scheduled/reconfirmed 
Treatment with study drug will stop at the Part C 
EOT Visit.
Updated to include safety 
assessments in Part C
Section 6.6 Post-
Treatment Safety Follow-
Up
Following discontinuation of study drug 
at the EOT visit in Part B, subjects will 
have a telephone contact 4 weeks after 
Following discontinuation of study drug at the 
EOT visit in Part B, subjects will have a telephone 
contact 4 weeks after the last dose of study drug to 
Updated to clarify the transition 
to Part C and to include the safety 
follow-up in Part C


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Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
the last dose of study drug to evaluate 
the adverse events and concomitant 
medication use since EOT.
Following discontinuation of study drug 
at the ET visit in Part B, subjects will 
have a clinic visit 1 week later for 
evaluation of safety, dyskinesia, and 
motor function and a telephone contact 
4 weeks after the last dose of study drug 
to evaluate the adverse events and 
concomitant medication use since ET.
During the first week after stopping 
study drug, subjects should not take 
prohibited concomitant medications. 
Between the Week 158, EOT, or ET 
visit and the follow-up telephone 
contact, concomitant medication use is 
per the discretion of the Investigator.
evaluate the adverse events and concomitant 
medication use since EOT, unless they will 
continue with Part C.
Following discontinuation of study drug at the ET 
visit in Part B, subjects will have a clinic visit 1 
week later for evaluation of safety, dyskinesia, and 
motor function and a telephone contact 4 weeks 
after the last dose of study drug to evaluate the 
adverse events and concomitant medication use 
since ET.
During the first week after stopping study drug, 
subjects should not take prohibited concomitant 
medications. Between the Week 158, EOT, or ET 
visit and the follow-up telephone contact, 
concomitant medication use is per the discretion of 
the Investigator.
Subjects in Part C who complete the 52 weeks of 
reduced burden safety assessments period will 
complete a Part C EOT Visit and a follow-up 
telephone contact 4 weeks after the last dose of 
study drug, to evaluate the adverse events and 
concomitant medication use since Part C EOT. 
Subjects who discontinue study drug in Part C will 
complete an ET visit, a follow-up clinic visit 1 
week later for safety evaluation, and a follow-up 
telephone contact 4 weeks after the last dose of 
study drug to evaluate the adverse events and 
concomitant medication use since ET.
Section 6.6.1 Clinic Visit 
(Week 159 ±3 Days or 1 
Week after Early 
Termination ±3 Days)
All subjects will return 1 week after 
Week 158 (Part A) or the ET visit (Part 
A or Part B) for evaluation of safety, 
dyskinesia, and motor function. The 
following activities should be 
performed:
•
Assessment of adverse events, 
dyskinesia control (in consultation with 
the caregiver, if appropriate), and 
concomitant medication use 
•
Vital signs
All subjects will return 1 week after the ET visit 
(Part C) for evaluation of safety. The following 
activities should be performed:
•
Assessment of adverse events and 
concomitant medication use 
•
Vital signs
•
Weight
•
C-SSRS: Since Last Visit version
•
Next telephone contact will be 
scheduled/reconfirmed
Updated final clinic visit 
description to include Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
•
Weight
•
AIMS
•
UPDRS Part III (motor 
examination)
•
BARS
•
HADS
•
C-SSRS: Since Last Visit 
version
•
ESS
•
Next telephone contact will be 
scheduled/reconfirmed
Section 6.6.2 Telephone 
Contact (4 Weeks After 
EOT/ET ± 3 Days)
6.5.2
Telephone Contact (Week 162 
± 3 Days or 4 Weeks After EOT/ET ± 3 
Days)
All subjects will have a follow-up 
telephone contact at Week 162 (4 weeks 
after their last dose of study drug [Week 
158]) (Part A);
6.5.2
Telephone Contact (Week 162 ± 3 Days 4 
Weeks After EOT/ET ± 3 Days)
All subjects will have a follow-up telephone 
contact at Week 162 (4 weeks after their last dose 
of study drug [Week 158]) (Part A);
Removed Part A visit designator 
for the telephone contact
Section 6.6.2 Telephone 
Contact (4 Weeks After 
EOT/ET ± 3 Days)
All subjects will have a follow-up 
telephone contact at Week 162 (4 weeks 
after their last dose of study drug [Week 
158]) (Part A); or 4 weeks after the EOT 
visit (Part B); or 4 weeks after the ET 
visit (Part A or Part B). During the 
telephone contact, subjects (and 
caregivers, if appropriate) will be 
questioned about adverse events and 
concomitant medication use since the 
subject’s last evaluation.
In Part C, all subjects will have a follow-up 
telephone contact 4 weeks after EOT/ET Visit (±3 
days). During the telephone contact, subjects (and 
caregivers, if appropriate) will be questioned about 
adverse events and concomitant medication use 
since the subject’s last evaluation.
Updated to include description of 
the telephone contact in Part C.
Section 6.7 Unscheduled 
Visit(s)
For unscheduled clinic visit(s) needed 
during the course of the study, the 
following activities should be 
performed, if indicated:
For unscheduled clinic visit(s) needed during Part 
A and Part B, the following activities should be 
performed, if indicated:
Added study parts designators for 
unscheduled clinic visits
Section 6.7 Unscheduled 
Visit(s)
For unscheduled clinic visit(s) needed 
during the course of the study, the 
following activities should be 
performed, if indicated:
•
Assessment of adverse events, 
For unscheduled clinic visit(s) needed during Part 
C, the following activities should be performed, if 
indicated:
•
Vital signs and weight
•
12-lead ECG at the Investigator’s 
Updated to include the 
description of unscheduled clinic 
visits in Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
dyskinesia control (in consultation with 
the subject and caregiver), and 
concomitant medications
•
Vital signs and weight
•
12-lead ECG at the 
Investigator’s discretion
•
Clinical laboratory tests: serum 
chemistry, hematology, and urinalysis 
(at the Investigator’s discretion)
•
Single pharmacokinetic (PK) 
blood sample (for Unscheduled Visits 
due to serious adverse event, within 48 
hours, if possible)
•
UPDRS Part III (motor 
examination) (at the Investigator’s 
discretion)
•
BARS (at the Investigator’s 
discretion)
•
HADS
•
C-SSRS: Since Last Visit 
version
•
ESS (at the Investigator’s 
discretion)
•
Evaluation of study drug dose 
level and adjustment, if necessary (at 
the Investigator’s discretion)
•
Re-order study drug (at the 
Investigator’s discretion)
discretion
•
C-SSRS: Since Last Visit version
•
Dispense study drug (at the Investigator 
discretion)
•
Assess AEs
Section 6.7.2 Unscheduled 
Telephone Visit(s)
For unscheduled telephone visit(s)
needed during the course of the study, 
the following activities should be 
performed
For unscheduled telephone visit(s) needed during 
the course of the studyPart A and Part B, the 
following activities should be performed
Added study parts designators for 
unscheduled telephone visits
Section 6.7.2 Unscheduled 
Telephone Visit(s)
For unscheduled telephone visit(s)
needed during the course of the study, 
the following activities should be 
performed:
•
Assessment of adverse events, 
dyskinesia control, and concomitant 
medications in consultation with the 
For unscheduled telephone visit(s) needed during 
Part C, the following activities should be 
performed:
•
Assessment of adverse events and 
concomitant medications in consultation with the 
subject and caregiver, if appropriate.
Updated to include the 
description of unscheduled 
telephone visits in Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
subject and caregiver, if appropriate.
•
Evaluation of study drug dose 
level and adjustment, if necessary (at 
the Investigator’s discretion)
•
Re-order study drug (at the 
Investigator’s discretion) (see 
Operations Manual for further details)
Section 8.4 Safety 
Endpoints
The following safety endpoints will be 
assessed:
The following safety endpoints will be assessed in 
Part A:
Added study parts designator for 
safety endpoints
Section 8.4 Safety 
Endpoints
The following safety endpoints will be 
assessed:
•
Incidence of adverse events, 
serious adverse events, severe adverse 
events, drug-related adverse events, 
adverse events leading to withdrawal 
during the following periods:
o
Overall
o
During titration 
o
During long-term treatment 
•
Observed values and changes 
from baseline in clinical laboratory 
parameters (hematology, chemistry, and 
urinalysis)
•
Observed values and changes 
from baseline in vital signs
•
Observed values in ECG 
parameters and abnormal findings
•
Number of subjects with on-
treatment QTcF values >450 ms, >480 
ms, >500 ms, or a change from Baseline 
in QTcF of >30 ms or >60 ms
•
Observed values and changes 
in UPDRS Part III (motor examination), 
BARS, HADS, C SSRS, ESS, and 
MoCA©
•
Duration of time to achieve 
stable dosing of SD-809
The following secondary safety 
The following secondary safety endpoints will be 
assessed in Part C:
•
Secondary safety endpoints:
o
Incidence of adverse events, serious 
adverse events, severe adverse events, drug related 
adverse events, and adverse events leading to 
withdrawal from start of Part C
o
Observed values and changes in vital 
signs from start of Part C
o
Observed values and changes in C-SSRS 
from start of Part C
o
Observed values in ECG parameters and 
abnormal findings from start of Part C
o
Number of subjects with on-treatment 
QTcF values >450 ms, >480 ms, >500 ms, or a 
change from Baseline in QTcF of >30 ms or >60 
ms from start of Part C
Updated to include the safety 
endpoints for Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
endpoints will be assessed in Part B:
•
Incidence of adverse events, 
serious adverse events, severe adverse 
events, drug related adverse events, and 
adverse events leading to withdrawal
•
Observed values and changes 
from start of randomized withdrawal in 
clinical laboratory parameters 
(hematology, chemistry, and urinalysis)
•
Observed values and changes 
from start of randomized withdrawal in 
vital signs
•
Observed values in ECG 
parameters and abnormal findings
•
Number of subjects with on-
treatment QTcF values >450 ms, >480 
ms, >500 ms, or a change from Baseline 
in QTcF of >30 ms or >60 ms
•
Observed values and changes 
in UPDRS Part III (motor examination), 
BARS, HADS, C-SSRS, ESS, and 
MoCA©
Section 8.7 Sample Size
During the Randomized Withdrawal 
Period, there will be up to 194 subjects 
randomized (SD-809 or placebo). It is 
estimated that approximately 91 
subjects per arm will enable a power of 
at least 90% to detect a beneficial effect 
of 1.4 points or more in the change from 
pre-withdrawal to post-withdrawal in 
centrally read AIMS when the SD-809 
arm is compared to placebo, assuming a 
standard deviation of 2.9 and a 2-sided 
type I error rate of 5%. 
During the Randomized Withdrawal Period in Part 
B, there will be up to 194 subjects randomized 
(SD-809 or placebo). It is estimated that 
approximately 91 subjects per arm will enable a 
power of at least 90% to detect a beneficial effect 
of 1.4 points or more in the change from pre-
withdrawal to post-withdrawal in centrally read 
AIMS when the SD-809 arm is compared to 
placebo, assuming a standard deviation of 2.9 and 
a 2-sided type I error rate of 5%. Approximately 
102 subjects may enroll in Part C conducted in the 
EU countries.
Added study part designators for 
the sample size and the estimated 
sample size for Part C
Section 9.1.2 Written 
Informed Consent
Informed consent will be obtained 
before the subject can participate in the 
study. If subject lacks the capacity to 
provide informed consent, a LAR must 
provide written informed consent and 
Part C Reduced Burden Safety Assessments
Part C will begin after Amendment 07 
implementation. Subjects who decline to 
participate in Part C (i.e., do not sign written 
informed consent) will complete the study at the 
Updated to include the informed 
consent procedures in Part C


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
the subject must provide assent. The 
contents and process of obtaining 
informed consent will be in accordance 
with all applicable regulatory 
requirements.
It is the responsibility of the Investigator 
or designee to obtain written informed 
consent, using the most current 
informed consent form approved by the 
IRB/IEC and Sponsor, from each 
individual participating in this study 
after adequate explanation of the aims, 
methods, objectives, and potential 
hazards of the study. The Investigator or 
designee must also explain to the 
subjects that they are completely free to 
refuse to enter the study or to withdraw 
from it at any time. Appropriate forms 
for documenting written consent will be 
provided by the Investigator or 
designee.
For this study, each eligible subject will 
be required to provide written informed 
consent utilizing: Consent to 
participation in the study (Information 
Form/Informed Consent Form).
All eligible subjects and caregivers will 
have the study explained by the 
Investigator or designee. They will 
receive a full explanation, in lay terms, 
of the aims of the study, the discomfort, 
risks, and benefits in taking part as well 
as of insurance and other procedures for 
compensation in case of injury. It will 
be explained that the study is for 
research purposes only and is not 
expected to provide any therapeutic 
benefit to the individual. It will be 
pointed out that they can withdraw from 
Part B Follow up Call.


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Section 
Amendment 06, dated 23 Jan 2018
Amendment 07, dated 02 May 2018
Reason for Change
the study at any time without prejudice. 
Each subject will acknowledge receipt 
of this information by giving written 
informed consent for participation in the 
study. The subject and caregiver will be 
given a copy of the signed Information 
Form/Informed Consent Form to retain.
Part B Double-Blind, Randomized 
Withdrawal Period
Part B will begin after Amendment 06 
implementation. Subjects who decline 
to participate in the Randomized 
Withdrawal Period (Part B) (i.e., sign 
written informed consent) will continue 
in Part A until Week 158.
Global
Not applicable
Updated amendment number, dates, section 
numbers, and tables of contents. Corrected typos; 
errors in punctuation, grammar, and formatting; 
and inconsistencies in style.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
An Open-Label, Long-Term Safety Study of SD-809 (Deutetrabenazine) for the 
Treatment of Moderate to Severe Tardive Dyskinesia 
 
 
Study Number SD-809-C-20 
 
 
NCT02198794 
 
 
SAP Approval Date: 03 December 2019 


Statistical Analysis Plan
Study SD-809-C-20
1
Statistical Analysis Plan
Study Number SD-809-C-20
An Open-Label, Long-Term Safety Study of SD-809 (Deutetrabenazine) for the Treatment 
of Moderate to Severe Tardive Dyskinesia
Phase 3
EudraCT number: 2014-001891-73
Approval Date: 03 December 2019
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
Prepared by:
Global Statistics


Statistical Analysis Plan
Study SD-809-C-20
2
STATISTICAL ANALYSIS PLAN APPROVAL


Statistical Analysis Plan
Study SD-809-C-20
3
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................6
INTRODUCTION ...........................................................................................................................7
1.
STUDY OBJECTIVES ................................................................................................8
2.
STUDY DESIGN .........................................................................................................9
2.1.
General Design .............................................................................................................9
2.2.
Primary and Secondary Measures and Endpoints ......................................................18
2.2.1.
Safety Measures and Endpoints..................................................................................18
2.2.2.
Efficacy Measures and Endpoints ..............................................................................18
2.3.
Sample Size and Power Considerations .....................................................................19
2.4.
Randomization and Blinding......................................................................................19
2.5.
Sequence of Planned Analyses ...................................................................................20
2.5.1.
Interim Analyses 1......................................................................................................20
2.5.2.
Interim Analyses 2......................................................................................................20
2.5.3.
Final Analyses and Reporting – Part A and B............................................................20
3.
POPULATIONS /ANALYSIS SETS.........................................................................21
3.1.
Intent-to-Treat Population ..........................................................................................21
3.2.
Safety Population........................................................................................................21
3.3.
Randomized Withdrawal ITT Population...................................................................21
3.4.
Randomized Withdrawal Modified Intent-to Treat Population..................................21
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................22
4.1.
General........................................................................................................................22
4.2.
Specification of Baseline Values................................................................................22
4.3.
Scoring for Rating Scales ...........................................................................................22
4.4.
Handling Withdrawals and Missing Data...................................................................23
4.5.
Study Days and Visit Windows..................................................................................24
5.
STUDY POPULATION.............................................................................................27
5.1.
Part A..........................................................................................................................27
5.1.1.
General........................................................................................................................27
5.1.2.
Patient Disposition......................................................................................................27
5.1.3.
Demographics and Baseline Characteristics...............................................................27


Statistical Analysis Plan
Study SD-809-C-20
4
5.1.4.
Prior Medications........................................................................................................28
5.1.5.
Protocol Deviations ....................................................................................................28
5.2.
Part B ..........................................................................................................................28
5.2.1.
General........................................................................................................................28
5.2.2.
Patient Disposition......................................................................................................28
5.2.3.
Demographics and Baseline Characteristics...............................................................28
6.
EFFICACY ANALYSIS ............................................................................................29
6.1.
Part A..........................................................................................................................29
6.1.1.
General........................................................................................................................29
6.2.
Part B ..........................................................................................................................29
6.2.1.
General........................................................................................................................29
6.2.2.
Efficacy Variables and Analyses................................................................................29
7.
SAFETY ANALYSIS ................................................................................................31
7.1.
Part A..........................................................................................................................31
7.1.1.
General........................................................................................................................31
7.1.2.
Study Drug Administration.........................................................................................31
7.1.3.
Adverse Events ...........................................................................................................31
7.1.4.
Deaths .........................................................................................................................32
7.1.5.
Clinical Laboratory Tests ...........................................................................................32
7.1.6.
Vital Signs ..................................................................................................................33
7.1.7.
Electrocardiogram.......................................................................................................33
7.1.8.
Physical Examination .................................................................................................33
7.1.9.
Neurological Examination..........................................................................................33
7.1.10.
Concomitant Medications...........................................................................................33
7.1.11.
Other Safety Assessments...........................................................................................33
7.2.
Part B ..........................................................................................................................34
7.2.1.
General........................................................................................................................34
7.2.2.
Study Drug Administration.........................................................................................34
7.2.3.
Adverse Events ...........................................................................................................34
7.2.4.
Clinical Laboratory Tests ...........................................................................................34
7.2.5.
Vital Signs ..................................................................................................................35
7.2.6.
Electrocardiogram.......................................................................................................35
7.2.7.
Other Safety Assessments...........................................................................................35


Statistical Analysis Plan
Study SD-809-C-20
5
8.
STATISTICAL SOFTWARE ....................................................................................36
9.
CHANGES TO PROTOCOL SPECIFIED ANALYSES ..........................................37
APPENDIX A.
SMQ CATEGORIES ADVERSE EVENTS AND ADVERSE 
EVENTS OF INTEREST...........................................................................................38
LIST OF TABLES
Table 1:
Schedule of Events .....................................................................................................12


Statistical Analysis Plan
Study SD-809-C-20
6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ANCOVA
analysis of covariance
BARS
Barnes Akathisia Rating Scale
BMI
Body Mass Index
C-SSRS
Columbia-Suicide Severity Rating Scale
CGIC
Clinical Global Impression of Change
CRF
case report form
CSR
clinical study report
DRA
dopamine receptor antagonist
EAIR
Exposure-Adjusted Incidence Rate
ECG
Electrocardiogram
EOT
end of treatment
ESS
Epworth Sleepiness Scale
ET
early termination
HADS
Hospital Anxiety and Depression Scale
ITT
intent-to-treat 
mCDQ-24
Modified Craniocervical Dystonia Questionnaire
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MoCA©
Montreal Cognitive Assessment
NDA
new drug application
PGIC
Patient Global Impression of Change
QTcF
Fridericia-corrected QT interval
SAE
serious adverse event
SAP
Statistical Analysis Plan
SMQ
Standard MedDRA Queries
TD
tardive dyskinesia
UPDRS
Unified Parkinson’s Disease Rating Scale
WHO drug
World Health Organization Dictionary of Medical Codes


Statistical Analysis Plan
Study SD-809-C-20
7
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study SD-809-C-20 (An Open-Label, Long-Term
Safety Study of SD-809 [Deutetrabenazine] for the Treatment of Moderate to Severe Tardive 
Dyskinesia), and was written in accordance with SOP GBP_RD_702 (Statistical Analysis Plan).
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study. 
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg other 
endpoints).When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report.


Statistical Analysis Plan
Study SD-809-C-20
8
1.
STUDY OBJECTIVES
The objectives of this study are: 

Evaluate the safety and tolerability of long-term maintenance therapy with SD-809

Evaluate the efficacy of long-term maintenance therapy of SD-809 to reduce the severity of
abnormal involuntary movements of tardive dyskinesia (TD)

Evaluate the persistence of the therapeutic effect of SD-809


Statistical Analysis Plan
Study SD-809-C-20
9
2.
STUDY DESIGN
2.1.
General Design
This is an open-label, single-arm study in which patients with moderate to severe drug-induced 
TD who have successfully completed a parent study (Study SD-809-C-18, Study SD-809-C-23, 
or any other controlled study of SD-809 for the treatment of moderate to severe TD) will be 
invited to participate.  
Patients who have successfully completed a parent study may be eligible to rollover directly into 
this study after they complete a 1-week washout period and the Week 13 evaluation of the parent 
study. To reduce patient burden, after obtaining informed consent/assent, some data collected in 
the parent study will be used in the SD-809-C-20 study and will provide some of the baseline 
data for SD-809-C-20 (see Table 1). In addition to assessments completed for the parent study
Week 13 visit, evaluations required as part of the SD-809-C-20 study will be completed on the 
same day as the Week 13 visit.
Part A:
Titration Period (up to 6 weeks): As all patients will have discontinued study drug (SD-809 or 
placebo) for 1 week at completion of the parent study, they will undergo titration on SD-809 in 
this study. During titration, the Investigator, in consultation with the patient (and caregiver, if 
appropriate), will determine when an adequate level of dyskinesia control has been achieved. 
The dose of SD-809 should be adjusted (upward or downward) once per week, in increments of 
6 mg per day, until there is adequate control of dyskinesia, the patient experiences a protocol-
defined clinically significant adverse event (defined as related to study drug and either a) 
moderate or severe in intensity or b) meeting the criteria for an SAE), or the maximal allowable 
dose is reached. If a patient experiences a clinically significant AE attributable to SD-809, the 
Investigator will determine if a dose reduction, dose suspension, or withdrawal from the study is 
necessary. Patients will have a telephone contact at Week 1 and a clinic visit at Week 2, to 
evaluate safety and establish a dose of study drug that adequately controls dyskinesia and is well
tolerated. Although patients will enter the long-term treatment period after Week 2, titration to 
optimize dose should occur through Week 6.
Long-Term Treatment Period (Week 3 until the last dose in Part A): During the Long-Term 
Treatment Period, patients will continue titration through Week 6. During titration, all patients 
will be contacted by telephone at Week 3 (the first week of the Long-Term Treatment Period) 
and Week 5 and will return to the clinic at Week 4 and Week 6 for evaluation of safety and 
dyskinesia control. Patients who have not achieved a stable dose by the Week 6 visit may have 
unscheduled visits or telephone contacts to further adjust their dose upward or downward. Site 
interactions for dose adjustment should alternate between telephone contacts and clinic visits. 
During the remainder of the Long-Term Treatment Period, patients will return to the clinic for 
evaluation of safety and dyskinesia once every 13 weeks, starting at Week 15 and ending at the 
last dose in Part A (completion of Part A=Week 158 or beginning of Part B after Amendment 06 
implementation). During long-term treatment, further dose adjustments of SD-809 may be made, 
if necessary, but not more often than weekly and in increments of 6 mg per day. In the case of 
the addition of a strong CYP2D6 inhibitor (i.e., paroxetine, fluoxetine, and bupropion), a greater 


Statistical Analysis Plan
Study SD-809-C-20
10
dose reduction may be required. Dose reductions in this context should be reviewed with the 
Medical Monitor. Dose adjustments should be based on all available information, including the 
patient’s and caregiver’s reports of adverse events and dyskinesia control, information from 
rating scales, and all safety evaluations. If warranted, study sites are encouraged to conduct 
periodic phone calls with the patients to ensure adherence to the treatment regimen and retention 
of unused drug containers.
Patients who have been on a stable dose of SD-809 and any concomitant dopamine receptor 
antagonists (DRA) for a minimum of 4 weeks will be invited to participate in the Randomized 
Withdrawal Period (Part B) at the next routine visit at the site after approvals from IRB/Ethics 
Committee and as required by country regulations. If the patient chooses to participate in Part B, 
then participation in Part A will end. Patients who decline to participate in Part B will continue in 
Part A until Week 158. Patients who decline participation in Part B will be given an ongoing 
option to participate at subsequent study visits.
Part B:
Part B will consist of a double-blind; Randomized Withdrawal Period; treatment with SD-809; 
and post-treatment safety follow-up. The Randomized Withdrawal Period will be 1 week (+3 
days maximum) in duration and will consist of 2 visits, the Pre-Withdrawal Visit and the Post-
Withdrawal Visit. After the Randomized Withdrawal Period, the patients will resume treatment 
with SD-809 on the prior established dose for an additional 12 weeks until end of treatment 
(EOT). A follow-up telephone call will occur 4 weeks after EOT.
At the beginning of the Randomized Withdrawal Period, patients will be randomized in a blinded 
fashion to either SD-809 (current dose) or placebo in a 1:1 ratio stratified by concomitant DRA 
usage. Up to 194 patients (active patients as of the approval date of Amendment 06) will be 
randomized (SD-809 or placebo). Patients will be required to sign a written informed consent. 
Patients will need to be on a stable dose of SD-809 and any concomitant DRA for a minimum of
4 weeks before starting the Randomized Withdrawal Period.
Patients will be scheduled to return 1 week (+3 days maximum) after the Pre-Withdrawal Visit
of the Randomized Withdrawal Period for efficacy and safety assessments.
At the end of this period, patients will continue treatment with SD-809 at the previous dose 
administered before the Randomized Withdrawal Period (last dose in Part A). Treatment with 
SD-809 will continue for 12 weeks until the EOT visit. 
Video ratings of the AIMS will occur at the Pre-Withdrawal Visit, the Post-Withdrawal Visit, 
and the EOT/early termination (ET) visit.
Post-Treatment Safety Follow-up:
Part A: 
Patients who do not participate in Part B will continue in Part A, discontinue study drug at the 
Week 158 visit, and return for their final clinic visit at Week 159 for evaluation of safety, 
dyskinesia control, and motor function. During this 1-week follow-up period, patients should 
continue to not take prohibited concomitant medications. Patients will also have a follow-up 
telephone contact at Week 162, 4 weeks after their last dose of study drug, to evaluate adverse 
events and concomitant medication usage.


Statistical Analysis Plan
Study SD-809-C-20
11
Patients who discontinue study drug in Part A will complete an ET visit; a follow-up clinic visit 
1 week later to evaluate safety, dyskinesia, and motor function; and a follow-up telephone 
contact 4 weeks after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since ET.
Part B:
Patients who complete the Randomized Withdrawal Period and subsequent 12 weeks of 
treatment will complete an EOT visit and a follow-up telephone contact 4 weeks after the last 
dose of study drug to evaluate the adverse events and concomitant medication use since EOT.
Patients who discontinue study drug in Part B will complete an ET visit; a follow-up clinic visit 
1 week later to evaluate safety, dyskinesia, and motor function; and a follow-up telephone 
contact 4 weeks after the last dose of study drug to evaluate the adverse events and concomitant 
medication use since ET.
Schedule of events are outlined in Table 1.


Statistical Analysis Plan
Study SD-809-C-20
12
Table 1:
Schedule of Events
Part A
Screening
Year 1
Year 2
Year 3
Follow-up 
clinic visit 
Follow-up 
call
Unscheduled
Long-Term Treatment Period
Titration Period
Study Weekǁ →
Prior 
Data 
from 
Parent 
Study†
Base-
line‡
1
2
3
4
5
6
15 28
41
54
67
80
93 106
119
132
145 15810/ET11
159 or 1 
week after 
ET
162 or 4 
weeks 
after ET
Visit Window (days) 
+3
± 1 
± 3
Activity Visit Type 
→
V
TC V TC
V TC V
V
V
V
V
V
V
V
V
V
V
V
V
V
TC
V
TC
Evaluate/Adjust Dose
X
X
X
X
X
X
X3
X3
Informed 
Consent/Assent
X§
Screening/
Demographics
*
Inclusion/
Exclusion Criteria
X
Update Medical 
History
X
Vital Signs/
Weight
**
X
X
X2 X
X
X
X2
X
X
X
X2
X
X
X
X2
X
X
Physical Examination
*
X4
X
X
X
Complete 
Neurological Exam
*
X
X
X
Height
*
12-lead ECG
X
X
X
X
X
X
X
X
X
X3,9
Blood Sampling for 
PK
X7,8
Chemistry/
Hematology/
UA
*
X
X
X
X
X
X3
Blinded CYP2D6 
Genotype1
*
Pregnancy Test
U
U
U
U
U
AIMS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Video Recording of 
AIMS
X
X
X
X
X
X
X
X
UPDRS Part III -
Motor
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3


Statistical Analysis Plan
Study SD-809-C-20
13
Screening
Year 1
Year 2
Year 3
Follow-up 
clinic visit 
Follow-up 
call
Unscheduled
Long-Term Treatment Period
Titration Period
Study Weekǁ →
Prior 
Data 
from 
Parent 
Study†
Base-
line‡
1
2
3
4
5
6
15 28
41
54
67
80
93 106
119
132
145 15810/ET11
159 or 1 
week after 
ET
162 or 4 
weeks 
after ET
Visit Window (days) 
+3
± 1 
± 3
Activity Visit Type 
→
V
TC V TC
V TC V
V
V
V
V
V
V
V
V
V
V
V
V
V
TC
V
TC
BARS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
HADS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS5
**
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESS
**
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
CGIC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGIC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MoCA©
X
X
X
X
X
X
X
X
X
X
X
X
Modified CDQ-24
X
X
X
X
X
X
X
X
Dispense/Order Study 
Drug6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3 
X3
Assess Study Drug 
Accountability/
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess AEs
*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Concomitant 
Meds
*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluate Dyskinesia 
Control (patient/
caregiver)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCHEDULE OF EVENTS (Part A) KEY
[V]
Clinic Visit
[TC]
Telephone Contact
[ET]
Early Termination Visit
[U]
Urine pregnancy test for women of childbearing potential only
Abbreviations: AEs, adverse events; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; CDQ-24, Craniocervical Dystonia 
Questionnaire; CGIC, Clinical Global Impression of Change; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; ESS Epworth 
Sleepiness Scale; HADS, Hospital Anxiety and Depression Scale; MoCA©, Montreal Cognitive Assessment; PGIC, Patient Global Impression of Change; 
PK, pharmacokinetics; SAE, serious adverse event; UA, urinalysis; UPDRS, Unified Parkinson’s Disease Rating Scale. 
ǁ All stable patients will be invited to participate in Part B after Amendment 06 implementation regardless of current study week. Patients will need to be on a 
stable dose of SD-809 and any concomitant dopamine receptor antagonist for a minimum of 4 weeks before starting the Double-Blind, Randomized Withdrawal 
Period.


Statistical Analysis Plan
Study SD-809-C-20
14
† After Informed Consent is obtained, prior data from the parent study will be used in this study as part of screening information as detailed in the informed 
consent/assent.
‡ Data from the Week 13 evaluation of the parent study will provide some of the Baseline data for the present study, although such data will not become 
available for this study until informed consent/assent has been provided.
§ May be performed up to 30 days in advance of Baseline
* Data (Week 12 or earlier) from the parent study will be used in this study as part of screening information. 
**
Data (Week 13) from the parent study will be used as part of Baseline assessment. Additional specific activities required at this visit are denoted by an 
“X”
1   
Assessment transferred from Screening or Baseline evaluation in the parent study.
2   
Perform orthostatic blood pressure and pulse after patient is in standing position for at least 3 minutes.
3   
Assessments to be completed at Investigator’s discretion.
4   
Brief physical examination, which includes evaluation of the cardiovascular, respiratory, and abdominal systems.
5   
The C-SSRS Since Last Visit version is administered at all visits.
6   
Study medication supply will be ordered (see Operations Manual for further details).
7   
Patients who experience an SAE should have a blood sample collected for pharmacokinetic assessment as soon as possible after the SAE and within 
48 hours of last dose of study drug, if possible.
8   
Patients who have not achieved adequate control of dyskinesia during the study may have up to two blood samples collected within 48 hours of the last 
dose of study drug for future pharmacokinetic assessment of α- and β-HTBZ. The pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor.
9   
Patients undergoing an increase in dose of their current antipsychotic treatment, switching to a new antipsychotic agent, or having an additional 
antipsychotic treatment added to their regimen will require additional ECG monitoring (see Section 6.6.1 of the protocol).
10   
Patients who have been on a stable dose of SD-809 and any concomitant dopamine receptor antagonist for 4 weeks will be invited to participate in the 
Randomized Withdrawal Period (Part B). If the patient chooses to participate in Part B, then participation in Part A will end.
11   
Patients will complete a follow-up visit 1 week after ET and a follow-up call 4 weeks after ET.


Statistical Analysis Plan
Study SD-809-C-20
15
Part B
Randomized Withdrawal Period
Open-label 
Treatment
Follow-up
Part B
Pre-Withdrawal Visit
Part B
Post-Withdrawal Visit11
EOT2/ET
Follow-up 
clinic visit 
(ET only)
Follow-up 
Call
Unscheduled
Study Week →
After Amendment 06 
Implementation1,12
+1 Week
12 Weeks after 
Post-Withdrawal 
Visit
1 Week after 
ET
4 Weeks 
after 
EOT/ET
Visit Window (days) 
+3
±3
Activity Visit Type →
V
V
V
V
TC
V
TC
Evaluate/Adjust Dose3
X4
X4
Informed Consent/Assent
X5
Randomization via IRT
X
Screening/
Demographics
Inclusion/
Exclusion Criteria
Update Medical History
Vital Signs/
Weight
X6
X
X6
X
X
Physical Examination
X
Complete Neurological Exam
X
12-lead ECG
X
X
X
X4,11
Blood Sampling for PK
X
X9,10
Chemistry/
Hematology/
UA
X
X 
X
X4
Pregnancy Test
U
U
AIMS
X
X
X
X
Video Recording of AIMS
X
X
X
UPDRS Part III - Motor
X
X
X
X
X4
BARS
X
X
X
X
X4
HADS
X
X
X
X
X
C-SSRS7
X
X
X
X
X
ESS
X
X
X
X
X4
CGIC
PGIC
MoCA©
X
X
X


Statistical Analysis Plan
Study SD-809-C-20
16
Randomized Withdrawal Period
Open-label 
Treatment
Follow-up
Part B
Pre-Withdrawal Visit
Part B
Post-Withdrawal Visit11
EOT2/ET
Follow-up 
clinic visit 
(ET only)
Follow-up 
Call
Unscheduled
Study Week →
After Amendment 06 
Implementation1,12
+1 Week
12 Weeks after 
Post-Withdrawal 
Visit
1 Week after 
ET
4 Weeks 
after 
EOT/ET
Visit Window (days) 
+3
±3
Activity Visit Type →
V
V
V
V
TC
V
TC
Modified CDQ-24
Dispense/Order Study Drug8
X
X
X4 
X3
Assess Study Drug Accountability/
Compliance13,14
X
X
X
Assess AEs
X
X
X
X
X
X
X
Assess Concomitant Meds
X
X
X
X
X
X
X
Evaluate Dyskinesia Control 
(patient/caregiver)
X
X
X
X
X
X
SCHEDULE OF EVENTS (Part B) KEY
[V]
Clinic Visit
[TC]
Telephone Contact
[EOT]
End of Treatment
[ET]
Early Termination Visit
[U]
Urine pregnancy test for women of childbearing potential only
Abbreviations: AEs, adverse events; AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; CDQ-24, Craniocervical Dystonia
Questionnaire; CGIC, Clinical Global Impression of Change; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; ESS Epworth
Sleepiness Scale; HADS, Hospital Anxiety and Depression Scale; IRT, MoCA©, Montreal Cognitive Assessment; PGIC, Patient Global Impression of Change;
PK, pharmacokinetics; SAE, serious adverse event; UA, urinalysis; UPDRS, Unified Parkinson’s Disease Rating Scale.
1   
Assessments required for the Pre-Withdrawal Visit will be those required for the next scheduled visit, or visit as determined by the Investigator, after 
Amendment 06 implementation and patient consent for Part B.
2   
The EOT visit will occur 12 weeks after the Post-Withdrawal Visit.
3   
Titration is not permitted during the Randomized Withdrawal Period and will be allowed after return to open-label dosing.
4   
Assessments to be completed at Investigator’s discretion.
5   
Patients who do not sign the informed consent for Part B will continue participation in Part A. Patients who decline participation in Part B will be given 
an ongoing option to participate at subsequent study visits.
6   
Perform orthostatic blood pressure and pulse. 
7   
The C-SSRS Since Last Visit version is administered at all visits.
8   
Study medication supply will be ordered (see Operations Manual for further details).


Statistical Analysis Plan
Study SD-809-C-20
17
9   
At the discretion of the Principal Investigator and/or Medical Monitor, patients who experience an SAE may have a blood sample collected for 
pharmacokinetic assessment after experiencing the SAE. All such blood samples will be collected within 48 hours of last dose of study drug.
10   
Patients who have not achieved adequate control of dyskinesia during the study may have up to two blood samples collected within 48 hours of the last 
dose of study drug for future pharmacokinetic assessment of α- and β-HTBZ. The pharmacokinetic sampling for inadequate efficacy must be pre-
approved by the Medical Monitor.
11   
Patients undergoing an increase in dose of their current antipsychotic treatment, switching to a new antipsychotic agent, or having an additional 
antipsychotic treatment added to their regimen will require additional ECG monitoring (see Section 6.6.1 of the protocol).
12   
If the patient chooses to participate in Part B, the first visit will be the patient’s next scheduled visit, or as soon as possible, as determined by the 
Investigator, after Amendment 06 implementation. The Post-Withdrawal Visit will occur 1 week (+3 days maximum). If the Post-Withdrawal Visit is >3 
days beyond the 1 week time period, the patient may be required to undergo titration, as decided by the Investigator in consultation with the Medical 
Monitor (if necessary) per the guidelines in Table 3 of the protocol. After the Randomized Withdrawal Period, the patient will continue on or return to 
previous (before placebo) SD-809 dose.
13   
Prior to the Pre-Withdrawal Visit, the Investigator or designated site staff must place a call to remind the patient to bring all remaining study drugs to the 
visit. The Investigator or designated site staff must collect the study drug(s) from the patient and conduct drug accountability.
14   
Prior to the Post-Withdrawal Visit, the Investigator or designated site staff must place a call to remind the patient to bring all remaining study drugs to 
the visit. The Investigator or designated site staff must collect the study drug(s) from the patient and conduct drug accountability.


Statistical Analysis Plan
Study SD-809-C-20
18
2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Safety Measures and Endpoints
The safety measures and endpoints in Part A are as follows:
1. Incidence of AEs, SAEs, severe AEs, drug related AEs, AEs leading to withdrawal, AEs 
leading to dose reduction, AEs leading to dose suspension during the following periods: 
overall, during titration, and during long-term treatment
2. Observed values and changes from baseline in clinical laboratory parameters 
(hematology, chemistry, and urinalysis)
3. Observed values and changes from baseline in vital signs
4. Observed values in electrocardiogram (ECG) parameters and abnormal findings
5. Number of patients with on-treatment QTcF (Fridericia-corrected QT interval) values 
>450 ms, >480 ms, >500 ms, or a change from baseline in QTcF of >30 ms or >60 ms.
6. Observed values and changes in Unified Parkinson’s Disease Rating Scale (UPDRS) Part 
III (motor examination), Barnes Akathisia Rating Scale (BARS), Hospital Anxiety and 
Depression Scale (HADS), Columbia-Suicide Severity Rating Scale (C-SSRS), Epworth 
Sleepiness Scale (ESS), and MoCA© (Montreal Cognitive Assessment)
The safety measures and endpoints in Part B (Randomized Withdrawal Period) are as follows:
1. Incidence of adverse events, serious adverse events, drug-related adverse events, and 
adverse events leading to withdrawal.
2. Observed values and changes from start of randomized withdrawal in clinical laboratory 
parameters (hematology, chemistry, and urinalysis)
3. Observed values and changes from start of randomized withdrawal in vital signs
4. Observed values in electrocardiogram (ECG) parameters and abnormal findings
5. Number of patients with on-treatment QTcF (Fridericia-corrected QT interval) values 
>450 ms, >480 ms, >500 ms, or a change from baseline in QTcF of >30 ms or >60 ms.
6. Observed values and changes in UPDRS Part III (motor examination), BARS, HADS, C-
SSRS, ESS, and MoCA©
2.2.2.
Efficacy Measures and Endpoints
The efficacy measures and endpoints in Part A are as follows:
AIMS:

The change in total motor AIMS score (items 1 through 7) from Baseline of this study 
at each visit that this is measured, as assessed by the site rating.

The percent change in total motor AIMS score from Baseline of this study at each 
visit that this is measured.


Statistical Analysis Plan
Study SD-809-C-20
19

The proportion of patients who have a 50% or greater reduction in total motor AIMS 
score from Baseline of this study at each visit that this is measured. 

The proportion of patients who have a 70% or greater reduction in total motor AIMS 
score from Baseline of this study at each visit that this is measured. 

The change in AIMS items 8, 9, and 10 from Baseline of this study to each visit that 
this is measured.
CGIC:

The proportion of patients who are a treatment success, based on the CGIC at each 
visit that this is measured. A treatment success is defined as Much or Very Much 
Improved on the CGIC from Baseline of this study.
PGIC:

The proportion of patients who are a treatment success, based on the PGIC at each 
visit that this is measured. A treatment success is defined as Much or Very Much 
Improved on the PGIC from Baseline of this study.
mCDQ-24:

The change in mCDQ-24 (Modified Craniocervical Dystonia Questionnaire) from 
Baseline of this study at each visit that this is measured.
The efficacy measure and endpoint in Part B is as follows:

Primary efficacy endpoint: change from Pre-Withdrawal Visit total motor AIMS 
score as assessed by blinded central video rating to the Post-Withdrawal Visit
between patients treated with SD-809 and patients treated with placebo.
2.3.
Sample Size and Power Considerations
Because this is an open-label study, the sample size is not based on statistical considerations. 
It is estimated that approximately 91 patients per arm in the Randomized Withdrawal Period will 
enable a power of at least 90% to detect a beneficial effect of 1.4 points or more in the change 
from pre-withdrawal to post-withdrawal in centrally read AIMS when the SD-809 arm is 
compared to placebo, assuming a standard deviation of 2.9 and a 2-sided type I error rate of 5%.
At the time of finalizing this SAP, all patients have started Part B, or completed part A, or have 
withdrawn from Part A. 143 patients were randomized to Part B, resulting in a power of 
approximately 80%. 
2.4.
Randomization and Blinding
At the beginning of the Randomized Withdrawal Period, patients will be randomized in a blinded 
fashion to either SD-809 (current dose) or placebo in a 1:1 ratio stratified by DRA status.


Statistical Analysis Plan
Study SD-809-C-20
20
2.5.
Sequence of Planned Analyses
2.5.1.
Interim Analyses 1
The first interim analysis was conducted for the purpose of preparing the integrated summary of 
safety for the NDA submission. The interim analysis will be based on patient data accrued as of 
30-Jun-2016. 
2.5.2.
Interim Analyses 2
A second interim analysis was conducted for the purpose of preparing an integrated summary of 
safety. The interim analysis was based on patient data accrued as of 1-Dec-2018. 
2.5.3.
Final Analyses and Reporting – Part A and B
Final analyses for Part A and B of this study will be performed after the last patient that enrolled 
into Part B has completed Part B of the study.


Statistical Analysis Plan
Study SD-809-C-20
21
3.
POPULATIONS /ANALYSIS SETS
3.1.
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will include all patients who were enrolled in the study, 
regardless of whether or not a patient received a dose of study drug.
3.2.
Safety Population
The Safety population will include all patients who were administered any study drug. Patients 
who were enrolled but withdrew prior to dosing will not be included in the safety population.
3.3.
Randomized Withdrawal ITT Population
The randomized withdrawal ITT population will include all patients enrolled in Part B of the 
study.
3.4.
Randomized Withdrawal Modified Intent-to Treat Population
The randomized withdrawal modified intent-to-treat (mITT) population will include all patients 
enrolled in Part B who receive study drug during the Randomized Withdrawal Period and have a 
total motor AIMS score as assessed by blinded central video rating at both the Pre-Withdrawal 
Visit and the Post-Withdrawal Visit.


Statistical Analysis Plan
Study SD-809-C-20
22
4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation, standard 
error, median, minimum, and maximum. Descriptive statistics for categorical variables include 
patient counts and percentages.
4.2.
Specification of Baseline Values
Baseline of this study is the last observed data on or prior to the first dose of drug in the present 
study (SD-809-C-20). Some of the data used for baseline of this study will come from the parent 
study (see Table 1). For baseline data that is coming from the parent study, baseline of this study 
will be the last observed data collected during the follow-up phase of the parent study. If data are
not collected or are missing during the follow-up period in the parent study, then baseline of this 
study will be the last observed data on or prior to the first dose of drug in the parent study.
4.3.
Scoring for Rating Scales
A detailed description for all rating scales below can be found in the protocol.
The AIMS is composed of 12 clinician-administered and scored items. The total motor AIMS 
score is the sum of items 1 through 7.
The mCDQ-24 is composed of 24 self-administered questions and has 5 domains. The mCDQ-24 
questions are rated on a 5-point scale from 0 (never or not at all) to 4 (always or very severely). 
Patients are instructed to indicate how they felt during the past two weeks because of their 
abnormal movements by selecting one of the five statements for each question. Following are the 
domains assessed in the mCDQ-24:

Stigma (questions 7, 8, 9, 10, 18, 22)

Emotional wellbeing (questions 11, 12, 13, 14, 15)

Pain (questions 4, 5, 21)

ADL (questions 1, 2, 3, 6, 19, 20)

Social/family life (questions 16, 17, 23, 24)
Each raw domain score is calculated as the sum of the questions in the particular domain. For 
each domain, raw sub-scores (sum of the individual question scores) will be calculated and then 
linearly transformed to a 0–100 scale, where a score of 0 indicates the best and a score of 100 the 
worst possible score. The total score (sum of the raw sub-scores) is similarly transformed to a 0–
100 scale (best to worst score).
The UPDRS motor (part III) consists of the 27 questions related to motor functions in part III of 
the UPDRS scale. Each of the ratings is assessed on a 5-point scale from 0 to 4, with higher 
values indicating increasing severity/intensity/frequency. The UPDRS motor score is the sum of 
the 27 questions in part III. The UPDRS subscale scores are balance (items 27, 30), bradykinesia 
(items 19, 31), movements (items 23A-B, 24A-B, 25A-B, 26A-B), posture and gait (items 28, 


Statistical Analysis Plan
Study SD-809-C-20
23
29), rigidity (items 22A-E), speech (item 18), and tremor (20A-E, 21A-B). The subscale scores 
are calculated as the sum of the individual items.
The BARS is composed of 4 items: an objective assessment of akathisia, two subjective 
measures (self-awareness of restlessness and distress related to restlessness), and a global clinical 
assessment. The objective assessment of akathisia, and subjective assessments of self-awareness, 
restlessness and distress related to restlessness are assessed on a 4-point scale from 0-3, with 
higher values indicating increasing severity/intensity/frequency. A summary score is calculated 
based on these 3 items resulting in a total score ranging from 0 to 9. The Global Clinical 
Assessment of Akathisia uses a 6-point scale ranging from 0 (absent) – 5 (severe).
The HADS is composed of 14 items, 7 each for anxiety and depression. The anxiety subscale is 
the sum of items 1, 3, 5, 7, 9,11, and 13, and the depression subscale is the sum of items 2, 4, 6, 
8, 10, 12, and 14.  
The ESS is composed of 8 self-administered questions on a 4-point Likert scale (0 to 3). The 
ESS total score is the sum of 8 questions and can range between 0 and 24 with higher scores 
indicating a higher level of daytime sleepiness.
The MoCA© is composed of 11 items. The MoCA© total score is the sum of the 11 items. Item 11 
is used to correct for patients with 12 years of education (or less) and is only included in the sum 
when total score is <30. The maximum total possible score is 30 points, indicating no cognitive 
impairment.
4.4.
Handling Withdrawals and Missing Data
Data summarization for a visit will be based on observed data only.
For AIMS assessed by the site rating, if a response to 1 question is missing, the missing response 
will be replaced with the average of the remaining responses. If responses to 2 or more questions 
are missing, the missing responses will not be replaced and the total score will be set to missing.
For mCDQ-24, if a response to 1 question within a domain is missing, the missing response will 
be replaced with the average of the remaining responses within the domain; if responses to 2 or 
more questions within a domain are missing, the missing responses will not be replaced and the 
domain score will be set to missing; if at least 1 domain score is missing then the total score will 
be set to missing.
For UPDRS motor (part III), if responses to 5 or fewer questions are missing, the missing 
responses will be replaced with the average of the remaining responses. If responses to 6 or more 
questions are missing, the missing responses will not be replaced and the total score will be set to 
missing.
For HADS, if a response to 1 question within a subscale is missing, the missing response will be 
replaced with the average of the remaining responses within the subscale. If a response to 2 or 
more questions within a subscale are missing, the missing responses will not be replaced and the 
subscale score will be set to missing.
For ESS, if responses to 2 or fewer questions are missing, the missing responses will be replaced 
with the average of the remaining responses. If responses to 3 or more questions are missing, the 
missing responses will not be replaced and the total score will be set to missing.


Statistical Analysis Plan
Study SD-809-C-20
24
For all other rating scales, if any response is missing then the total or subscale score will be set to 
missing.
4.5.
Study Days and Visit Windows
Study days will be numbered relative to the 1st day of study drug administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the 1st dose of study drug. Days 
will be numbered relative to study start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the start of study 
drug and day –1 being the day before the start of study drug).
Part A Visits:
For efficacy and safety by-visit analyses, data collected at post baseline scheduled visits will be 
included using their scheduled visit and data collected at early termination and unscheduled 
visits will be included and assigned to a visit window as described below. After the assignments 
are made use the following rules: if there is a scheduled visit with an early termination and/or 
unscheduled visit in the same visit window, the scheduled visit will be used in the analysis; if 
there is no scheduled visit but an early termination and unscheduled visit in the same visit 
window, the early termination visit will be used in the analysis; if there is no scheduled or early 
termination visit but an unscheduled visit in a visit window, the unscheduled visit will be used in 
the analysis.
Efficacy: Visit Windows for Early Termination and Unscheduled Visits
Study Day
Visit
AIMS site
CGIC, PGIC
mCDQ-24
Week 2
2 to 21
Week 4
22 to 35
2 to 35
Week 6
36 to 74
36 to 74
2 to 74
Week 15
75 to 151
75 to 151
75 to 151
Week 28
152 to 242
152 to 242
152 to 242
Week 41
243 to 328
243 to 328
243 to 328
Week 54
329 to 424
329 to 424
329 to 560
Week 67
425 to 515
425 to 515
Week 80
516 to 606
516 to 606
Week 93
607 to 697
607 to 697
Week 106
698 to 788
698 to 788
561 to 924
Week 119
789 to 879
789 to 879
Week 132
880 to 970
880 to 970
Week 145
971 to 1061
971 to 1061
Week 158
1062 to 1110
1062
925
Follow-up
1111


Statistical Analysis Plan
Study SD-809-C-20
25
Safety: Visit Windows for Early Termination and Unscheduled Visits
Study Day
Visit
[1]
[2]
[3]
[4]
[5]
[6]
[7]
Week 2
2 to 21
2 to 21
2 to 21
2 to 21
Week 4
22 to 35
22 to 35
22 to 67
22 to 35
Week 6
36 to 74
36 to 119
2 to 119
2 to 74
2 to 210
36 to 74
Week 15
75 to 151
75 to 151
68 to 151
75 to 151
Week 28
152 to 242
120 to 242
120 to 287
152 to 242
152 to 242
152 to 242
Week 41
243 to 328
243 to 328
243 to 328
243 to 378
243 to 328
Week 54
329 to 424
329 to 560
288 to 560
329 to 424
211 to 560
329 to 424
Week 67
425 to 515
425 to 515
379 to 515
425 to 515
Week 80
516 to 606
516 to 606
516 to 606
516 to 606
Week 93
607 to 697
607 to 697
607 to 742
607 to 697
Week 106
698 to 788
561 to 924
561 to 924
698 to 833
561 to 924
698 to 833
Week 119
789 to 879
743 to 879
Week 132
880 to 970
834 to 1015
880 to 970
834 to 1015
Week 145
971 to 1061
971 to 1110
Week 158
1062 to 1110
925
925
1016
925
1016
Follow-up
1111
1111
[1] Vital signs, weight, UPDRS, BARS, HADS, C-SSRS; [2] ECG; [3] Laboratory tests; [4] MoCA©; [5] Standing,
Supine, and Orthostatic heart rate and blood pressure; [6] Sitting heart rate and blood pressure; [7] ESS.
Part B Visits:
For efficacy and safety by-visit analyses, data collected at the ET visit during open-label 
treatment will be included and assigned to the EOT visit. Data collected at unscheduled visits 
during open-label treatment will not be included in any analyses.
Part A and B Combined:
Some analyses, such as the analyses of adverse events, will be performed by time period. For
these analyses, the following definitions will be used:

Titration Period - from the first dose of treatment until 7 days after the week 6 visit. If
a patient discontinues treatment before 7 days after the week 6 visit, then the Titration
Period is until the last dose of treatment.

Maintenance Period - from 8 days after the week 6 visit until the day of the week 158
visit for patients only in Part A and until the day of the open-label treatment EOT
visit for patients in both Parts A and B. If a patient enters the Maintenance Period but
discontinues treatment early, the Maintenance Period is until the last dose of
treatment.


Statistical Analysis Plan
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26

Overall Treatment Period - includes the Titration and the Maintenance Periods, if
applicable.

Follow-up Period - from the end of the Overall Treatment Period through the end of
the study.


Statistical Analysis Plan
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5.
STUDY POPULATION
5.1.
Part A
5.1.1.
General
The ITT population will be used for all study population summaries. Summaries will be 
presented by parent study treatment group (prior SD-809 and prior placebo) and overall.
5.1.2.
Patient Disposition
Patients in the ITT population, patients in the ITT population but not treated, patients in the 
safety population, patients in the randomized withdrawal ITT and randomized withdrawal mITT 
populations, patients who completed Parts A and B and the study, patients who withdrew from 
Parts A and B and the study, and patients who enrolled in Part C will be summarized using 
descriptive statistics. Patients who withdrew from Parts A and B and the study will also be 
summarized using descriptive statistics by reason for withdrawal.  
The Part A visit when patients enrolled in Part B will be summarized using descriptive statistics.
Patients reaching each Part A visit will be summarized using descriptive statistics.
Reasons for withdrawal by Part A visits using the categories prior to week 54 visit, week 54 visit 
to before week 106 visit, and week 106 visit to before week 145 visit will be summarized using 
descriptive statistics. 
5.1.3.
Demographics and Baseline Characteristics
The continuous variables of patient age, weight, height, and body mass index (BMI), all 
collected at baseline in the parent study, will be summarized using descriptive statistics. The 
categorical variables of patient sex, race, ethnicity, and education (≤12 or >12 years) (collected 
at baseline in the parent study) will be summarized using descriptive statistics for each category. 
Missing categories will be presented if necessary.  
The continuous variables of time since tardive dyskinesia diagnosis in years, baseline total motor 
AIMS score, and baseline mCDQ-24 total score, all determined from baseline in the parent 
study, will be summarized using descriptive statistics. The categorical variables of baseline use 
of DRA (Yes/No), background comorbid illness types, use of a strong CYP2D6 inhibitor 
(Yes/No), poor CYP2D6 metabolizer (Yes/No), and impaired CYP2D6 function (Yes/No), all 
determined from baseline in the parent study, will be summarized using descriptive statistics for 
each category.
Strong CYP2D6 inhibitor status was determined by classifying patients as taking versus not 
taking a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion) at baseline in the parent 
study. Impaired CYP2D6 function was defined as use of a strong CYP2D6 inhibitor at baseline 
in the parent study and/or a poor CYP2D6 metabolizer.


Statistical Analysis Plan
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5.1.4.
Prior Medications
All prior medications will be coded using the World Health Organization dictionary of medical 
codes (WHO Drug). The incidence of prior medications will be summarized using descriptive 
statistics by therapeutic class and preferred term. The therapeutic class will be displayed as the 
ATC3 code if available or the most specific ATC code if ATC3 is not available. The preferred 
term is displayed as the collapsed preferred term (single generic ingredients collapsed to base 
substance preferred term). Patients are counted only once in each therapeutic class category, and 
only once in each preferred term category. Prior medications will include all medications taken 
prior to the first day of study drug treatment.
5.1.5.
Protocol Deviations
Patients with at least 1 protocol deviation as recorded on the CRF, and protocol deviations for 
each category will be summarized using descriptive statistics.
5.2.
Part B
5.2.1.
General
The randomized withdrawal ITT population will be used for all Part B study population 
summaries. Summaries will be presented by randomized withdrawal treatment group (SD-809 
and placebo) and overall.
5.2.2.
Patient Disposition
Patients in the randomized withdrawal ITT and randomized withdrawal mITT populations,
patients who completed Part B, and patients who withdrew during Part B will be summarized 
using descriptive statistics. Patients who withdrew during Part B will also be summarized using 
descriptive statistics by reason for withdrawal.
5.2.3.
Demographics and Baseline Characteristics
The continuous variables of patient age, weight, and body mass index (BMI) (all collected at the 
Pre-Withdrawal Visit, and height (collected at baseline in the parent study) will be summarized 
using descriptive statistics. The categorical variables of patient sex, race, ethnicity, and education 
(≤12 or >12 years) (collected at the Pre-Withdrawal Visit) will be summarized using descriptive 
statistics for each category. Missing categories will be presented if necessary.  
The continuous variables of time since tardive dyskinesia diagnosis (calculated at the Pre-
Withdrawal Visit) and pre-withdrawal total motor AIMS score will be summarized using 
descriptive statistics. The categorical variables of pre-withdrawal use of DRA (Yes/No), 
pre-withdrawal use of CYP2D6 inhibitors, and pre-withdrawal use of a strong CYP2D6 inhibitor 
(Yes/No) will be summarized using descriptive statistics for each category.
Strong CYP2D6 inhibitor status was determined by classifying patients as taking versus not 
taking a strong CYP2D6 inhibitor (paroxetine, fluoxetine, or bupropion) at the Pre-Withdrawal 
Visit.


Statistical Analysis Plan
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29
6.
EFFICACY ANALYSIS
6.1.
Part A
6.1.1.
General
The ITT population will be used for all efficacy summaries. Summaries will be presented by 
parent study treatment group and overall for Part A visits.
All continuous efficacy endpoints will be summarized for actual values and changes (or percent 
changes) from baseline of this study to each visit using descriptive statistics.
All categorical efficacy endpoints will be summarized at each visit using descriptive statistics. In 
addition, the CGIC and PGIC ratings at each visit will be summarized using descriptive statistics.
The mCDQ-24 domain scores will also be summarized for actual values and changes from 
baseline of this study to each visit using descriptive statistics.
No inferential statistics will be presented for efficacy endpoints.
6.2.
Part B
6.2.1.
General
The randomized withdrawal mITT population will be used for the efficacy analysis in Part B. 
The summaries will be presented by randomized withdrawal treatment group and overall, unless 
otherwise noted.
6.2.2.
Efficacy Variables and Analyses
The primary efficacy variable is the change in total motor AIMS score as assessed by blinded 
central video rating from Pre-Withdrawal Visit to Post-Withdrawal Visit
Analysis of the change in total motor AIMS score as assessed by blinded central video rating
during the Randomized Withdrawal Period (from the Pre-Withdrawal Visit to the Post-
Withdrawal Visit) will use an analysis of covariance (ANCOVA) model with the change in total 
motor AIMS score as the dependent variable. The model will include randomized withdrawal 
treatment group and DRA status at the Pre-Withdrawal Visit as fixed effects, and the total motor 
AIMS score at the Pre-Withdrawal Visit value as a covariate. The least squares means of the 
change in total motor AIMS score will be compared between the SD-809 treatment and placebo 
groups using a 2-sided test at the alpha=0.05 level of significance. The SAS code for this test is 
as follows:
 
  
   
   


Statistical Analysis Plan
Study SD-809-C-20
30
The least square (LS) mean and standard error for the treatment groups, and the LS mean 
difference, 95% confidence interval (CI), and p-value for the comparison (SD-809 vs. placebo) 
will be presented at the Post-Withdrawal Visit.
Total motor AIMS score values (central reading) and changes from the Pre-Withdrawal Visit to 
the Post-Withdrawal Visit and EOT visit will be summarized using descriptive statistics for each 
treatment group. The overall summary will not be presented at the Post-Withdrawal Visit.
In addition, total motor AIMS score (site rating) values and changes from the Pre-Withdrawal 
Visit to the Post-Withdrawal Visit and EOT visit will be summarized using descriptive statistics 
for each treatment group. The overall summary will not be presented at the Post-Withdrawal 
Visit.


Statistical Analysis Plan
Study SD-809-C-20
31
7.
SAFETY ANALYSIS
7.1.
Part A
7.1.1.
General
The safety population will be used for all safety summaries. Summaries will be presented by 
parent study treatment group and overall. Summaries will be presented for Parts A and B 
combined unless otherwise noted.    
7.1.2.
Study Drug Administration
Duration of treatment (days treated) is the number of days on treatment based on the first and last 
day of treatment with the study drug (last day of study drug – first day of study drug + 1). Weeks 
on treatment using the categories ≥2 weeks, ≥4 weeks, ≥6 weeks, ≥15 weeks, ≥28 weeks, ≥41 
weeks, ≥54 weeks, ≥67 weeks, ≥80 weeks¸ ≥93 weeks, ≥106 weeks, ≥119 weeks, ≥132 weeks, 
≥145 weeks, ≥158 weeks and ≥171 weeks will be summarized using descriptive statistics. 
Duration of treatment (days) will also be summarized as continuous data using descriptive 
statistics.
Total daily dose (mg) will be summarized as continuous data at each Part A visit using 
descriptive statistics. In addition, total daily dose (mg) will be summarized by individual dose 
and dose categories (<24 mg, ≥24 to ≤36 mg, >36 to ≤48 mg, and >48 mg) as categorical data at 
each Part A visit using descriptive statistics.
Percent treatment compliance is calculated as 100*(number of tablets used / number of tablets 
expected to be used). The number of tables used is the number of tablets dispensed minus the 
number of tablets returned. If a patient does not return the pill bottle, it will be assumed that the 
patient took no study medication from that bottle for the purposes of calculating compliance. The 
number of tablets expected to be used is based on the number of morning and evening dosing 
times during the treatment period (1 tablet is used for each dosing time point). A patient will be 
deemed compliant over the treatment period if the patient has taken 80% to 105% of the 
expected tablets of study drug.
Percent treatment compliance will be summarized as continuous data using descriptive statistics. 
In addition, percent treatment compliance will be summarized as categorical data using 
descriptive statistics for the following categories: <80%, 80% to 105%, >105%.
7.1.3.
Adverse Events
All AEs will be coded using MedDRA. Summaries will be presented in the overall treatment 
period (titration plus maintenance treatment period) for all AEs (overall and by severity), AEs 
determined by the investigator to be treatment-related, serious AEs, AEs causing discontinuation 
from the study, non-serious AEs, AEs leading to dose reduction, and AEs leading to dose 
suspension. In addition, all AEs will be summarized separately for the titration period, 
maintenance treatment period, and follow-up period. 
All AEs in the overall treatment period will be summarized by strong CYP2D6 inhibitor status 
(Yes/No), poor CYP2D6 metabolizer phenotype status (Yes/No), impaired CYP2D6 function 


Statistical Analysis Plan
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32
status (Yes/No), baseline use of DRA status (Yes/No), and background comorbid illness type. In 
addition, serious AEs and AEs by severity will be summarized by impaired CYP2D6 function 
status.  
The incidence of adverse events will be summarized using descriptive statistics by system organ 
class and preferred term. Patients are counted only once in each system organ class category and 
only once in each preferred term category. For all AEs in the overall treatment period, the event 
rate will also be presented. The event rate is defined as 100*(total number of AEs / patient years 
of treatment in Parts A and B combined). Treatment-related adverse event summaries will 
include adverse events with possible, probable, definite, or missing relationship to study drug. 
For the summaries by severity, patients are counted at the greatest severity only once in each 
system organ class category and only once in each preferred term category. 
The Standard MedDRA Queries (SMQs) of depression (excl suicide and self injury), 
suicide/self-injury, akathisia, Parkinson-like events, and Torsade de pointes/QT prolongation 
AEs, and somnolence and sedation AEs of interest as specified in Appendix A will be 
summarized using descriptive statistics. In addition, time to first SMQ AE or AE of interest will 
be presented using Kaplan-Meier curves for each SMQ AE or AE of interest. For this analysis, 
patients who do not experience the event will be censored at the end of treatment in Parts A and 
B combined.
In addition, the exposure-adjusted incidence rate (EAIR) of AEs in the overall treatment period 
will be presented for the overview of AEs, AEs by SOC and preferred terms, and the SMQ 
summaries. EAIR is calculated as the number of patients with an AE divided by patient-years of 
treatment. For calculating patient years, patients with an AE contribute with treatment exposure 
up to the day of their first AE, patients without an AE contribute their entire treatment duration 
in Parts A and B combined as described above for the censoring if patients do not experience an 
event.
The EAIR for all AEs in the overall treatment period and for SMQ categories will be 
summarized by the time periods of <15 weeks, ≥15 to <54 weeks, ≥54 to <106 weeks, ≥106 to 
<158 weeks, and ≥158 weeks using descriptive statistics.  
All AEs in the overall treatment period that occurred in ≥4% of patients will be summarized by 
preferred term using descriptive statistics.
Listings for AEs leading to death, serious AEs, AEs causing discontinuation, AEs leading to 
dose reduction, and AEs leading to dose suspension will be presented.
7.1.4.
Deaths
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR. 
7.1.5.
Clinical Laboratory Tests
Summary statistics for serum, chemistry, hematology, and urinalysis laboratory tests will be 
presented at baseline of this study and each Part A visit that this is measured using standard 
international units. Serum chemistry laboratory tests will also be presented using conventional 
units. Laboratory tests values and changes from baseline of this study to each visit will be 


Statistical Analysis Plan
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33
summarized using descriptive statistics. Shifts (below, within, and above the normal range) from 
baseline of the parent study to each Part A visit will be summarized using patient counts.
7.1.6.
Vital Signs
Summary statistics for resting heart rate and blood pressure, respiration rate, temperature, and 
weight will be presented at baseline of this study and at each Part A visit that these are measured. 
Summary statistics for orthostatic heart rate and blood pressure will be presented at baseline of 
this study and each Part A visit that this is measured. Vital signs values and changes from 
baseline to each visit the vital sign is measured will be summarized using descriptive statistics.
Orthostatic changes in heart rate and orthostatic changes in blood pressure vital signs values are 
calculated as the standing minus supine value at the same visit.
7.1.7.
Electrocardiogram
Shifts (normal, abnormal not clinically significant, and abnormal clinically significant) from 
baseline of this study to each Part A visit that this is measured will be summarized using patient 
counts.  
The number of patients with postbaseline QTcF values >450 ms, >480 ms, >500 ms, or a change 
from baseline in QTcF of >30 ms or >60 ms, PR interval values >200 ms, QRS duration values 
>100 ms, and QT interval values >500 ms will be summarized using descriptive statistics. This 
summary will be repeated for patients who have a normal QTcF at baseline according to the 
protocol definition.
7.1.8.
Physical Examination
A listing will be presented for all physical examination data.
7.1.9.
Neurological Examination
A listing will be presented for all neurological examination data.
7.1.10.
Concomitant Medications
All concomitant medications will be coded using the WHO Drug. The incidence of concomitant 
medications will be summarized using descriptive statistics by therapeutic class and preferred 
term. Patients are counted only once in each therapeutic class category, and only once in each 
preferred term category. Concomitant medications will include all medications taken while the 
patient takes study drug.
In addition, separate summaries will be presented including only concomitant medications prior 
to baseline and concomitant medications that started post baseline.
7.1.11.
Other Safety Assessments
Summary statistics for the UPDRS motor score and subscale scores will be presented at baseline
of this study and each Part A visit that this is measured. UPDRS motor score and subscale scores 
values and changes from baseline of this study to each visit will be summarized using descriptive 
statistics.


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34
Summary statistics for the BARS summary score will be presented at baseline of this study and
each Part A visit that this is measured. BARS summary score values and changes from baseline
of this study to each visit will be summarized using descriptive statistics.
Summary statistics for the HADS depression and anxiety subscales scores will be presented at 
baseline of this study and each Part A visit that this is measured. HADS subscale values and 
changes from baseline of this study to each visit will be summarized using descriptive statistics.
Summary statistics for the C-SSRS baseline version will be presented at screening and for the C-
SSRS last visit version will be presented at baseline of this study and each Part A visit that this is 
measured. Patients with suicidal ideation and behavior items as well as self-injurious behavior 
without suicidal intent will be summarized at each visit as categorical data using descriptive 
statistics.
Also for C-SSRS, patients with suicidal ideation and behavior items as well as self-injurious 
behavior without suicidal intent will be summarized at anytime postbaseline as categorical data 
using descriptive statistics. Shifts (yes, no) from baseline of this study to anytime postbaseline
will be summarized using patient counts for the suicidal ideation and behavior categories as well 
self-injurious behavior without suicide intent. 
Summary statistics for the ESS total score will be presented at baseline of this study and each 
Part A visit that this is measured. ESS total score values and changes from baseline of this study 
to each visit will be summarized using descriptive statistics.
Summary statistics for the MoCA© total score will be presented at baseline of this study and each 
Part A visit that this is measured. MoCA© total score values and changes from baseline of this 
study to each visit will be summarized using descriptive statistics.
7.2.
Part B
7.2.1.
General
The randomized withdrawal ITT population will be used for all Part B safety summaries. 
Summaries will be presented by randomized withdrawal treatment group (SD-809 and placebo) 
and overall for Part B visits.
7.2.2.
Study Drug Administration
Total daily dose (mg) will be summarized as continuous data at each Part B visit using 
descriptive statistics.
7.2.3.
Adverse Events
All AEs in the Part B Randomized Withdrawal Period will be summarized using descriptive 
statistics by system organ class and preferred term.
7.2.4.
Clinical Laboratory Tests
Summary statistics for serum, chemistry, hematology, and urinalysis laboratory tests will be 
presented at the Pre-Withdrawal Visit and each Part B visit that this is measured using standard 
international units. Serum chemistry laboratory tests will also be presented using conventional 
units. Laboratory tests values and changes from the Pre-Withdrawal Visit to each visit will be 


Statistical Analysis Plan
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35
summarized using descriptive statistics. Shifts (below, within, and above the normal range) from 
the Pre-Withdrawal Visit to each Part B visit will be summarized using patient counts.
7.2.5.
Vital Signs
Summary statistics for resting heart rate and blood pressure, respiration rate, temperature, and 
weight will be presented at the Pre-Withdrawal Visit and at each Part B visit that these are
measured. Summary statistics for orthostatic heart rate and blood pressure will be presented at 
the Pre-Withdrawal Visit and each Part B visit that this is measured. Vital signs values and 
changes from the Pre-Withdrawal Visit to each visit the vital sign is measured will be 
summarized using descriptive statistics.
Orthostatic changes in heart rate and orthostatic changes in blood pressure vital signs values are 
calculated as the standing minus supine value at the same visit.
7.2.6.
Electrocardiogram
Shifts (normal, abnormal not clinically significant, and abnormal clinically significant) from the 
Pre-Withdrawal Visit to each Part B visit that this is measured will be summarized using patient 
counts.
7.2.7.
Other Safety Assessments
Summary statistics for the UPDRS motor score and subscale scores will be presented at the Pre-
Withdrawal Visit and each Part B visit that this is measured. UPDRS motor score and subscale 
scores values and changes from the Pre-Withdrawal Visit to each visit will be summarized using 
descriptive statistics.
Summary statistics for the BARS summary score will be presented at the Pre-Withdrawal Visit
and each Part B visit that this is measured. BARS summary score values and changes from the 
Pre-Withdrawal Visit to each visit will be summarized using descriptive statistics.
Summary statistics for the HADS depression and anxiety subscales scores will be presented at 
the Pre-Withdrawal Visit and each Part B visit that this is measured. HADS subscale values and 
changes from the Pre-Withdrawal Visit to each visit will be summarized using descriptive 
statistics.
Summary statistics for the C-SSRS last visit version will be presented at the Pre-Withdrawal 
Visit and each Part B visit that this is measured. Patients with suicidal ideation and behavior 
items as well as self-injurious behavior without suicidal intent will be summarized at each visit 
as categorical data using descriptive statistics.
Summary statistics for the ESS total score will be presented at the Pre-Withdrawal Visit and each 
Part B visit that this is measured. ESS total score values and changes from the Pre-Withdrawal 
Visit to each visit will be summarized using descriptive statistics.
Summary statistics for the MoCA© total score will be presented at the Pre-Withdrawal Visit and 
each Part B visit that this is measured. MoCA© total score values and changes from the Pre-
Withdrawal Visit to each visit will be summarized using descriptive statistics.


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Study SD-809-C-20
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8.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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9.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
ECG variables at each visit will not be analyzed in this study.


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APPENDIX A. SMQ CATEGORIES ADVERSE EVENTS AND ADVERSE 
EVENTS OF INTEREST
Depression (excl suicide and self injury) (SMQ) – narrow search
Activation syndrome
Adjustment disorder with depressed mood
Adjustment disorder with mixed anxiety and depressed mood
Agitated depression
Anhedonia
Antidepressant therapy
Childhood depression
Decreased interest
Depressed mood
Depression
Depression postoperative
Depressive symptom
Dysphoria
Electroconvulsive therapy
Feeling guilty
Feeling of despair
Feelings of worthlessness
Helplessness
Major depression
Menopausal depression
Post stroke depression
Postictal depression
Postpartum depression
Suicide/self-injury (SMQ) – narrow search
Completed suicide
Depression suicidal
Intentional overdose
Intentional self-injury
Poisoning deliberate
Self-injurious behaviour
Self-injurious ideation
Suicidal behaviour
Suicidal ideation
Suicide attempt
Akathisia (SMQ) – narrow and broad search
Akathisia
Extrapyramidal disorder
Hyperkinesia
Hyperkinesia neonatal
Motor dysfunction


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Movement disorder
Psychomotor hyperactivity
Restlessness
Parkinson-like events (SMQ) – narrow and broad search
Action tremor
Akinesia
Bradykinesia
Bradyphrenia
Cogwheel rigidity
Drooling
Dysphonia
Extrapyramidal disorder
Freezing phenomenon
Gait disturbance
Hypertonia
Hypertonia neonatal
Hypokinesia
Hypokinesia neonatal
Masked facies
Micrographia
Mobility decreased
Motor dysfunction
Movement disorder
Muscle rigidity
Muscle tone disorder
Musculoskeletal stiffness
On and off phenomenon
Parkinson’s disease
Parkinson’s disease psychosis
Parkinsonian crisis
Parkinsonian gait
Parkinsonism rest tremor
Parkinsonism
Parkinsonism hyperpyrexia syndrome
Postural reflex impairment
Postural tremor
Resting tremor
Tremor
Tremor neonatal
Walking disability
Somnolence and sedation – preferred terms
Sedation
Somnolence 
Sopor
Stupor 


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Lethargy 
Torsade de pointes/QT prolongation (SMQ) – narrow and broad search
Cardiac arrest
Cardiac death
Cardiac fibrillation
Cardio-respiratory arrest
Electrocardiogram QT interval abnormal
Electrocardiogram QT prolonged
Electrocardiogram U-wave abnormality
Electrocardiogram repolarization abnormality
Long QT syndrome
Long QT syndrome congenital
Loss of consciousness
Sudden cardiac death
Sudden death
Syncope
Torsade de pointes
Ventricular arrhythmia
Ventricular fibrillation
Ventricular flutter
Ventricular tachyarrhythmia
Ventricular tachycardia