Clinical trial NCT01897896
Conditions: Chorea Associated With Huntington Disease
Keywords: Chorea Huntington Disease
Sponsor: Auspex Pharmaceuticals, Inc.
Start date: 2013-11-12; Completion date: 2017-08-21
Enrollment: 119 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of SD-809 extended release (ER) in participants switching from tetrabenazine to SD-809 ER. In addition, the safety and tolerability of long-term treatment with SD-809 ER will be assessed in "Switch" participants as well as "Rollover" participants completing a randomized, double blind, placebo-controlled study of SD-809 ER.

Detailed description:

Arms: arm 1: Participants who completed study SD-809-C-15 (NCT01795859, including 1-week washout period and Week 13 evaluation), will receive 6 milligrams (mg) SD-809 ER tablet once daily as a starting dose in this study. Dose titration will be continued through Week 8 to optimize dose. Dose of SD-809 ER can be adjusted weekly in increments of 6 milligrams per day (mg/day) (6 or 12 mg/day after a total daily dose of 48 mg is reached) based on chorea control and adverse events. Daily doses of SD-809 ER 12 mg and higher will be administered twice daily. Maximum total daily dose of SD-809 ER will be 72 mg/day (36 mg twice daily), unless participant is receiving a strong CYP2D6 inhibitor(such as, paroxetine, buproprion, fluoxetine), in which case maximum total daily dose will be 42 mg (21 mg twice daily). Long-term treatment with SD-809 ER at a stable dose (further dose adjustments are permitted, if clinically indicated) will be continued until SD-809 ER become commercially available in United States. arm 2: Participants who were receiving an approved dosing regimen of tetrabenazine for at least 8 weeks prior to screening, will be converted overnight from their existing tetrabenazine regimen to SD-809 ER regimen to achieve targeted steady-state area under the curve (AUC) of total (alpha+beta)- Dihydrotetrabenazine (HTBZ) metabolites that is predicted to be comparable to that of participant's prior tetrabenazine regimen. Participants will remain on initial dose of SD-809 ER through Week 1. Dose adjustment will be continued through Week 4 to optimize the dose. Dose of SD-809 ER can be adjusted weekly (upward or downward) in increments of 6 mg per day (6 mg/day or 12 mg/day after a total daily dose of 48 mg is reached), based on chorea control and treatment regimen tolerability. Long-term treatment with SD-809 ER at a stable dose (although further dose adjustments are permitted, if clinically indicated) will be continued until SD-809 ER become commercially available in United States.
Interventions: intervention 1: SD-809
Intervention descriptions: intervention 1: SD-809 tablets will be provided in dose strengths of 6, 9 and 12 mg.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 3
An Open-Label, Long Term Safety Study of SD-809 ER in Subjects with Chorea
Associated with Huntington Disease
Study SD-809-C-16
NCT01897896
Protocol with Amendment 3 Approval Date: 2 March 2015


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Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
2 
STUDY CONTACTS 
SPONSOR: 
Auspex Pharmaceuticals, Inc. 
3333 N. Torrey Pines Court, Suite 400 
La Jolla, CA  92037 
USA 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
Co-Principal Investigator 
 
 
 
CLINICAL MONITOR 
 
 
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
3 
PROTOCOL SYNOPSIS 
PROTOCOL 
SD-809-C-16 
TITLE 
An Open-Label, Long Term Safety Study of SD-809 ER in Subjects With Chorea 
Associated With Huntington Disease  
Running Title 
Alternatives for Reducing Chorea in HD (ARC-HD) 
PHASE 
3 (Safety) 
INDICATION 
Treatment of chorea associated with Huntington disease 
NO. SITES 
Approximately 40 
OBJECTIVES 
1)
Evaluate the safety and tolerability of titration and maintenance therapy with
SD-809 ER
2)
Evaluate the safety and tolerability of switching subjects from tetrabenazine to
SD-809 ER
3)
Evaluate the pharmacokinetics of tetrabenazine, SD-809 and their respective α- and
β-HTBZ metabolites in subjects switching from tetrabenazine to SD-809 ER
STUDY 
POPULATION 
Approximately 116 male and female adult subjects with manifest Huntington disease 
(HD) who are receiving approved doses of tetrabenazine for treatment of chorea (approx. 
36) or have successfully completed the SD-809-C-15 efficacy study (approx. 80) will be
enrolled. 
STUDY DESIGN 
STUDY DESIGN 
This is an open-label, single-arm study in which subjects with manifest HD who are 
receiving FDA-approved doses of tetrabenazine1 (TBZ) for the treatment of chorea 
associated with HD or have successfully completed the SD-809-C-15 efficacy study will 
be invited to participate.  Two groups of subjects will be enrolled into this trial:  
Switch subjects are those who are currently receiving stable doses of tetrabenazine for 
treatment of chorea associated with HD and convert to SD-809 ER based on an algorithm 
designed to achieve comparable exposure to total (α+β)-HTBZ metabolites. 
Rollover subjects are those who have successfully completed Study SD-809-C-15 and 
are continuing on long-term SD-809 ER after a 1-week wash out period. 
Subjects who do not already have a legally authorized representative will undergo an 
independent evaluation by a qualified healthcare provider to determine their capacity to 
provide informed consent.  Informed consent/assent will be obtained before any study 
procedures are performed. A Research Advance Directive (See Section 6.12) will be 
obtained from subjects with the ability to self consent. Subjects rolling over from the 
SD-809-C-15 study may have capacity assessment/informed consent/assent/research 
advance directive obtained up to 30 days in advance of subject’s First-HD Week 13 
Visit/ARC-HD Baseline Visit.   
Subjects Switching from Tetrabenazine (Switch):  Subjects who are currently receiving 
an FDA-approved dose of tetrabenazine that is providing a therapeutic benefit for chorea 
control may be eligible to participate in the study.  Subjects in this cohort will undergo a 
full screening evaluation within 30 days of the Baseline assessment prior to switching to 
SD-809 ER (Schedule of Events A).  These subjects will be converted from their TBZ 
regimen to an SD-809 ER regimen that is predicted to provide comparable exposure to 
total (α+β)-dihydrotetrabenazine (α- and β-HTBZ).  Subjects will continue taking their 
TBZ regimen through midnight of Day 0 and then directly switch to their assigned 
1 The maximum dose of tetrabenazine is 100 mg/day (with a maximum single dose of 37.5 mg), unless the subject has known 
impaired CYP2D6 function, in which case the maximum dose is 50 mg/day with a maximum single dose of 25 mg. 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
4 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DESIGN 
(continued) 
SD-809 ER regimen the next morning.  The dose of SD-809 ER may be adjusted (upward 
or downward) in increments of 6 mg per day (each week) (6 mg/day or 12 mg/day after a 
total daily dose of 48 mg is reached) until a dose level that adequately controls chorea is 
identified, the subject experiences a protocol defined “clinically significant” adverse event 
(defined as related to study medication and either a) moderate or severe in intensity or b) 
meets the criteria for a Serious Adverse Event [SAE])1, or the maximal allowable dose is 
reached.  If a subject experiences a “clinically significant” AE attributable to SD-809 ER, 
the investigator will determine if a dose reduction or suspension is necessary.  The 
investigator, in consultation with the subject and caregiver, will determine when an 
adequate level of chorea control has been achieved.  Subjects will have a clinic visit at 
Week 1 and a telephone contact at Week 2, in order to evaluate safety and establish an 
optimal dose.  Although subjects will enter the Long term treatment period after Week 2, 
dose adjustment (upward or downward) may continue through Week 4 to optimize dose 
level.  Additional dose adjustments may be made after Week 4 if clinically indicated. 
Subjects Enrolled from the SD-809-C-15 Study (Rollover):  Subjects who have 
successfully completed Study SD-809-C-15 may be eligible to rollover directly into this 
study after they complete a one week washout and the Week 13 evaluation of Study 
SD-809-C-15.  To reduce subject burden, after obtaining capacity assessment (if 
necessary)/informed consent/assent and Research Advance Directive (if applicable), some 
data collected in the SD-809-C-15 study will be utilized in the SD-809-C-16 study and 
will provide some of the baseline data for SD-809-C-16 (See Schedule of Events B).  In 
addition to assessments completed for the SD-809-C-15 Week 13 visit, evaluations 
required as part of the SD-809-C-16 study will be completed on the same day as the Week 
13 visit. All subjects are expected to rollover to SD-809-C-16 at the Week 13 visit of SD-
809-C-15.   
As Rollover subjects will have discontinued study drug (SD-809 ER or placebo) for 1 
week at completion of the SD-809-C-15 study they will undergo titration on SD-809 ER.  
During titration, the investigator, in consultation with the subject and caregiver, will 
determine when an adequate level of chorea control has been achieved.  The dose of 
SD-809 ER may be adjusted (upward or downward), in increments of 6 mg per day (each 
week) (6 mg/day or 12 mg/day after a total daily dose of 48 mg is reached), until there is 
adequate control of chorea, the subject experiences a protocol defined “clinically 
significant” adverse event (defined as related to study medication and either a) moderate 
or severe in intensity or b) meets the criteria for a Serious Adverse Event [SAE])1, or the 
maximal allowable dose is reached.   If a subject experiences a “clinically significant” AE 
attributable to SD-809 ER, 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, in order to evaluate safety and establish a dose of study drug that 
adequately controls chorea and is well-tolerated.  Although subjects will enter the long 
term treatment period after Week 2, titration may continue through Week 8 to optimize 
dose level.  Additional dose adjustments may be made after week 8 if clinically indicated. 
 
Long-Term Treatment Period: During long term treatment, all subjects will be 
contacted by telephone at Week 3 (the first week of Long-Term Treatment Period) and 
will return to the clinic at Weeks 4, 8, 15, 28 and every 13 weeks thereafter for evaluation 
of safety and chorea control.  Rollover subjects will have an additional telephone contact 
at Week 5. Switch subjects will have an additional telephone contact at Week 7, to remind 
subjects to complete diary card before the Week 8 visit.  Subjects who have not achieved 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
5 
a dose level that adequately controls chorea and is well tolerated by the Week 4 visit 
(Switch subjects) or Week 5 telephone contact (Rollover subjects) should have 
unscheduled visits or telephone contacts in order to further adjust their dose upward or 
downward.  Site interactions for dose adjustment should alternate between telephone 
contacts and clinic visits.  During long-term treatment, further dose adjustments of 
SD-809 ER may be made, if necessary, but not more often than weekly.  Dose 
adjustments should be based on all available information including the subject’s and 
caregiver’s reports of adverse events and chorea control, as well as information from 
rating scales and safety evaluations, when available. Long term treatment will continue 
until SD-809 ER becomes commercially available in the U.S. 
Post-Treatment Safety Follow Up:  All subjects will discontinue study drug at the End 
of Treatment visit and return for their final clinic visit one week later for evaluation of 
safety, chorea and motor function.  During this one week washout, subjects should not 
take prohibited concomitant medications.  Subjects will also have a follow up telephone 
contact four weeks after their last dose of study drug, to evaluate adverse events and 
concomitant medication usage. 
PK Sub-Study (Switch subjects only):  A sub-study will be conducted to evaluate the 
pharmacokinetics (PK) of tetrabenazine and SD-809 ER in Switch subjects.  
Approximately 12 subjects will have rich PK sampling and approximately 24 subjects will 
have sparse PK sampling (See PK section of synopsis).  The PK of tetrabenazine and 
metabolites will be assessed at the Baseline visit and the PK of SD-809 and metabolites 
will be assessed at the Week 8 visit.  If a subject requires a dose change at Week 8, the 
Week 8 visit assessments should be conducted except for PK sampling which should be 
postponed until Week 15. 
FORMULATION 
SD-809 extended release (ER) tablets will be provided in dose strengths of 6, 9 and 
12 mg.  Each dose strength will have a marking of SD 6, SD 9 and SD 12, corresponding 
to the dose strength and a distinct color:  6 mg - purple; 9 mg - blue; 12 mg - beige. 
 
During dose adjustment/titration, SD-809 ER will be supplied in weekly blister cards.   
 
Once the investigator determines that a stable dose has been reached, SD-809 ER will 
be supplied in 30 count containers. 
DOSE 
REGIMEN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General guidance: 
 
All treatment regimens will be administered with meals  
 
A daily dose of 6 mg will be given once a day in the morning and daily doses of 
12 mg and higher will be administered twice daily, approximately 10 hours apart 
during the day. 
 
The maximum total daily dose of SD-809 ER is 72 mg (36 mg BID), unless the 
subject is receiving a strong CYP2D6 inhibitor (See Appendix 11), in which case the 
maximum total daily dose is 42 mg 
o Individual doses up to and including 12 mg are given as a single tablet 
o Individual doses of 15 to 24 mg will be given as two tablets 
o Individual doses of 27 to 36 mg will be given as three tablets 
 
Dose increases or decreases may occur no more frequently than once per week 
 
Dose adjustments are limited to 6 mg/day (each week) (6 mg/day or 12 mg/day after a 
total daily dose of 48 mg is reached).  Dose reductions in increments greater than 6 
mg should be reviewed with the Clinical Monitor. (See Section 5.2.5)   
 
If a strong CYP2D6 inhibitor is started (i.e., paroxetine, fluoxetine, bupropion), the 
Clinical Monitor should be notified as a dose reduction of more than 6 mg may be 
required.  
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
6 
 
 
DOSE 
REGIMEN 
(continued) 
Switch Subjects: 
 
Initial dosing regimen: Based on the subject’s tetrabenazine total daily dose, an initial 
dosing regimen of SD-809 ER will be assigned which targets a steady state AUC of 
total (α+β)-HTBZ that is comparable to that of the subject’s tetrabenazine regimen:  
If a Switch Subject’s 
Incoming Total Daily 
TBZ Dose is: 
Then, the Initial Total 
Daily SD-809 ER Dose 
Should Be: 
Taken As: 
Morning 
Dose 
Evening 
Dose 
12.5 mg 
→ 
6 mg 
6 mg 
̶ 
25 mg 
→ 
12 mg 
6 mg 
6 mg 
37.5 mg 
→ 
18 mg 
9 mg 
9 mg 
50 mg 
→ 
24 mg 
12 mg 
12 mg 
62.5 mg 
→ 
30 mg 
15 mg 
15 mg 
75 mg 
→ 
36 mg 
18 mg 
18 mg 
87.5 mg 
→ 
42 mg 
21 mg 
21 mg 
100 mg 
→ 
48 mg 
24 mg 
24 mg 
 
 
The dose of SD-809 ER may be adjusted (upward or downward) in increments of 
6 mg per day (each week) (6 mg/day or 12 mg/day after a total daily dose of 48 mg is 
reached) until a dose level that adequately controls chorea is identified, the subject 
experiences a protocol defined “clinically significant” adverse event (defined as 
related to study medication and either a) moderate or severe in intensity or b) meets 
the criteria for a Serious Adverse Event [SAE])1; or the maximal allowable dose is 
reached.  If a subject experiences a “clinically significant” AE attributable to SD-809 
ER, the investigator will determine if a dose reduction or suspension is necessary.  
Rollover Subjects: 
 
The starting dose will be SD-809 ER 6 mg in the AM, regardless of previous 
treatment in the SD-809-C-15 trial.  Prior treatment assignment from Study SD-809-
C-15 will remain blinded. 
 
During the titration period, the dose of SD-809 ER may be increased or decreased on 
a weekly basis in increments of 6 mg per day (6 mg/day or 12 mg/day after a total 
daily dose of 48 mg is reached) until there is adequate control of chorea; the subject 
experiences a protocol defined “clinically significant” adverse event (defined as 
related to study medication and either a) moderate or severe in intensity or b) meets 
the criteria for a Serious Adverse Event [SAE])1; or the maximal allowable dose is 
reached.   If a subject experiences a “clinically significant” AE attributable to SD-809 
ER, the investigator will determine if a dose reduction or suspension is necessary.    
Long term Treatment: 
For all subjects during the long-term treatment period, the dose of SD-809 ER may be 
adjusted (upward or downward) in increments of 6 mg per day (6 mg/day or 12 mg/day 
after a total daily dose of 48 mg is reached), if necessary, to optimize chorea control while 
minimizing adverse events.  However, such changes in dose may not occur more 
frequently than once per week. 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
7 
SAMPLE SIZE 
Approximately 116 subjects: 
 
Approximately 80 Rollover subjects (any eligible SD-809-C-15 subject may 
enroll) 
 
Approximately 36 Switch subjects 
INCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INCLUSION 
CRITERIA 
(continued) 
1. Subject is at least 18 years of age or the age of majority (whichever is older) at 
Screening. 
2. Subject has been diagnosed with manifest HD, as indicated by characteristic motor 
exam features, and has a documented expanded CAG repeat (≥ 37) at or before 
Screening1. 
3. Subject meets either of the following:  
 
Has successfully completed2 participation in Study SD-809-C-15  OR        
 
Has been receiving an FDA-approved dose of tetrabenazine3 that has been 
stable for ≥ 8 weeks before Screening and is providing a therapeutic benefit 
for control of chorea. 
4. Subject has a Total Functional Capacity (TFC) score ≥ 5 at Screening. 
5. Subject is able to swallow study medication whole. 
6. Subject has provided written, informed consent or, if subject lacks the capacity to 
provide informed consent (as determined by an independent assessment by a qualified 
healthcare provider not directly involved in other study activities), a legally 
authorized representative (LAR) has provided written informed consent and the 
subject has provided assent. 
7. Subject has provided a Research Advance Directive, if subject has the capacity to 
provide informed consent (See Section 6.12). 
8. Female subjects of childbearing potential4 agree to use an acceptable method of 
contraception from screening through study completion.  Female subjects of 
                                                 
1 A CAG repeat number obtained prior to the Screening Visit may be used to document subject eligibility if either of the 
following conditions are met:  
 At Screening, there is documentation available in the subject’s records that shows the subject has an expanded CAG repeat    
(≥ 37) from a prior laboratory assessment.  
 At Screening, there is documentation available of a subject’s prior laboratory assessment of an allele length that states a subject 
has a genotype consistent with a diagnosis of HD (i.e., laboratory analysis confirming the CAG repeat number was at least 40). 
Note: If neither condition above is met, results from the CAG repeat sample collected at the Screening Visit must be used to 
determine study eligibility.  A CAG Repeat Number of ≥ 37 must be documented prior to enrolling a subject into the study. 
Note: Regardless of whether a prior CAG result is available, all Switch subjects will undergo CAG repeat testing at the Screening 
Visit, and any enrolled subject whose CAG repeat is found not to be ≥ 37 will be withdrawn from the study. 
2 Successful completion of Study SD-809-C-15 is defined as (1) study participation through Week 13 (2) the subject has 
generally been compliant with study medication and procedures, in the opinion of the investigator and (3) the subject has no 
ongoing adverse events that are serious (SAE) or severe in intensity or are expected to interfere with safety evaluations in this 
study. 
3 The maximum dose of tetrabenazine is 100 mg/day (with a maximum single dose of 37.5 mg), unless the subject has known 
impaired CYP2D6 function, in which case the maximum dose is 50 mg/day with a maximum single dose of 25 mg. 
4 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 Screening.   


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
8 
childbearing potential must be using one of the following acceptable birth control 
methods 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 Baseline. 
 
Stable hormonal contraception (with approved oral, transdermal, or depot 
regimen) for at least 3 months prior to screening. 
 
9. The subject has a reliable caregiver who interacts with the patient on a daily basis, 
oversees study drug administration, assures attendance at study visits and participates 
in evaluations, as required.   
 
Note:  Subjects with a TFC score of 5-7 at Screening must have a live-in 
caregiver. 
 
Note:  Subjects with a TFC score of 5-7 at Screening or those who enrolled with 
the consent of an LAR, must have caregivers present at all study visits. 
 
Note:  For subjects with a TFC score of 8-13 at Screening who did not require an 
LAR to provide informed consent, the caregiver must attend the following visits: 
Screening, Baseline, Weeks 4, 8, 15, 28 and visits every 13 weeks thereafter 
through the End of Treatment visit. Caregivers will be encouraged to attend other 
visits. 
10. Subject is able to ambulate without assistance for at least 20 yards (Note: The use of 
assistive devices (i.e., walker, cane) are permitted during ambulation). 
11. Has sufficient reading skills to comprehend the subject completed rating scales. 
EXCLUSION 
CRITERIA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Subject has a serious untreated or undertreated psychiatric illness, such as depression, 
at Screening or Baseline.  
 
Note:  Subjects receiving antidepressant therapy may be enrolled if on a stable 
dose for at least 8 weeks before Screening (See Appendix 12) for prohibited 
antidepressants). 
2. Subject has active suicidal ideation at Screening or Baseline. 
3. Subject has history of any of the following suicidal thoughts or behavior at Screening 
or 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 or behavior 
 
A previous actual, interrupted or aborted suicide attempt 
4. Subject has a score ≥11 on the depression subscale of the Hospital Anxiety and 
Depression Scale (HADS) at Baseline. 
5. Subject has an unstable or serious medical or psychiatric illness at Screening or 
Baseline. 
6. Subject has received tetrabenazine within 7 days of Baseline (Rollover subjects). 
7. Subject has received any of the following concomitant medications within 30 days of 
Screening or Baseline: 
 
Antipsychotics (See Appendix 13) 
 
Metoclopromide  


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
9 
 
 
 
 
 
 
 
 
 
 
 
 
EXCLUSION 
CRITERIA 
(continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monoamine oxidase inhibitors (MAOI) 
 
Levodopa or dopamine agonists 
 
Reserpine 
 
Amantadine 
 
Memantine (Rollover subjects only) 
o Switch subjects may receive Memantine if on a stable, approved dose for 
at least 30 days. 
8. Subject has a score of ≥11 on the Swallowing Disturbance Questionnaire (SDQ) at 
Screening or Baseline. 
9. Subject has a Unified Parkinson’s Disease Rating Scale (UPDRS) dysarthria score of 
≥3 at Screening or Baseline. 
10. Subject requires treatment with drugs known to prolong the QT interval.  Note: 
 
Quetiapine (Seroquel) is not allowed. 
 
Escitalopram (Lexapro or Cipralex)1 is allowed when administered according to 
approved labeling. 
 
Citalopram (Celexa)2 is allowed when administered according to approved 
labeling. 
 
See Appendix 16 for Celexa and Lexapro (Cipralex) dosing information 
 
See Appendix 12 for a complete list of prohibited or restricted QT prolonging 
drugs. 
11. Subject has a QTcF value >450 ms (males) or >460 ms (females), or >480 ms (with 
right bundle branch block) on 12-lead ECG at Screening.   
 
 Note: Subjects with left bundle branch block are not eligible. 
12. Subject has evidence of hepatic impairment at Screening, as indicated by:  
 
AST or ALT >2.5 times the upper limit of normal. 
 
Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the upper limit of 
normal (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 Clinical Monitor in order to be 
enrolled.  
 
Prothrombin time > 4 sec prolonged. 
 
Positive Hepatitis B surface antigen (HBsAg). 
13. Subject has evidence of significant renal impairment at Screening, indicated by a 
creatinine clearance <50 mL/min, as estimated by the Cockroft-Gault formula. 
                                                 
1  Escitalopram (Lexapro or Cipralex): The maximum allowed dose is 20 mg/day.  The maximum dose for subjects 
≥ 65 years old is 10 mg/day. 
2  Citalopram (Celexa) is allowed with the following restrictions (See Appendix 16): 
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. 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
10 
14. Subject has known allergy to any of the components of study medication. 
15. Subject has participated in an investigational drug or device trial other than SD-809-
C-15 within 30 days (or 5 drug half-lives) of Screening, whichever is longer. 
16. Subject is pregnant or breast-feeding at Screening or Baseline. 
17. Subject acknowledges present use of illicit drugs at Screening or Baseline. 
18. Subject has a history of alcohol or substance abuse in the previous 12 months, as 
defined in the DSM-IV, or subject is unable to refrain from substance abuse 
throughout the study. 
SAFETY 
PARAMETERS  
 
 
 
 
 
 
 Adverse events (AEs)  
 Clinical laboratory tests  
 Physical examination 
(PE) 
 Vital signs 
 12-lead ECGs  
 Epworth Sleepiness 
Scale (ESS) 
 Columbia Suicide Severity Rating Scale (C-SSRS)  
 Unified Huntington’s Disease Rating Scale 
(UHDRS)  
 Swallowing Disturbance Questionnaire (SDQ) 
 Unified Parkinson’s Disease Rating Scale 
(UPDRS) dysarthria item  
 Barnes Akathisia Rating Scale (BARS)  
 Hospital Anxiety and Depression Scale (HADS)  
 Montreal Cognitive Assessment (MoCA) 
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
11 
ENDPOINTS 
 
Incidence of adverse events (AEs), serious AEs, severe AEs, drug related AEs, AEs 
leading to withdrawal during the following periods: 
 
Overall 
 
During titration in Rollover subjects (up to 8 weeks) 
 
During dose adjustment in Switch subjects (up to 4 weeks) 
 
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  > 450ms, > 480ms, > 500ms 
 
Observed values and changes in UHDRS, UPDRS (dysarthria), BARS, HADS, ESS, 
C-SSRS, and MoCA© 
 
Duration of time to achieve stable dosing of SD-809 ER 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
12 
PHARMACO-
KINETICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACO-
KINETICS 
(Continued) 
 
 
A pharmacokinetic (PK) sub-study will be conducted in subjects switching from TBZ to 
SD-809 ER.  Blood samples will be obtained for measurement of plasma concentrations 
of SD-809, tetrabenazine and their respective α-HTBZ, β-HTBZ, total (α+β)-HTBZ and 
other metabolites, as required.  Approximately one third of the PK sub-study population 
will have rich samples drawn and the remaining two thirds will have sparse sampling.  
The rich sampling cohort should be enrolled first.  Subjects who are unable or unwilling 
to participate in the rich sampling cohort may be assigned to the sparse sampling cohort. 
Blood samples will be collected at Baseline (on tetrabenazine) and at Week 8 (on SD-809 
ER) as follows: 
Cohort 
Visit 
Day 0 (TBZ) 
Week 8* (SD-809 ER) 
Rich Sampling 
(N=12) 
Morning 
only 
Pre-dose, 0.5, 1, 2 and 
6 hours post-dose 
Pre-dose, 1.5, 2.5, 4 
and 6 hours post-dose 
Sparse 
Sampling 
(N=24) 
Morning 
Pre-dose and 1-2 
hours post-dose 
Pre-dose and 2-4 hours 
post-dose  
Afternoon 
1st sample during the 
visit and 2nd at least 1 
hr† afterward 
1st sample during the 
visit and 2nd at least 2 
hrs† afterward 
* If a subject requires a dose change at Week 8, the Week 8 visit assessments should be conducted except for 
PK sampling which should be postponed until Week 15. 
† The second PK sample for sparse sampling (afternoon) should be taken as late as possible 
Subjects in the rich sampling cohort must have a morning visit in which the AM dose of 
tetrabenazine or SD-809 ER is administered in clinic.  Subjects in the sparse sampling 
cohort may have a morning or an afternoon visit.  If sparse sample subjects have a 
morning visit, the AM dose of tetrabenazine or SD-809 ER should be administered in 
clinic as with the rich sampling cohort.  If the subject is assigned to the rich group at the 
Screening Visit but forgets to hold tetrabenazine dose the morning of the Baseline visit, 
the subject must be re-consented to undergo sparse sampling.  If sparse sampling subjects 
have an afternoon visit, tetrabenazine or SD-809 ER should be taken per their usual 
schedule.  At each time point, four (4) mL of blood will be collected into lithium heparin 
tubes and processed to plasma.  After centrifugation, the plasma will be split into 2 
aliquots and stored frozen in polypropylene plasma storage tubes at -70°C or below. 
Switch Subjects will be provided with a diary at Screening and at Week 4 to record meal 
and dosing times before PK sampling visits at Baseline and Week 8.  Prior to clinic visits 
subjects will be reminded to record the start time of their last meal and the time of their 
last dose in their diary and to bring the diary with them to the clinic visit.    
Subjects in the rich sampling cohort and those in the sparse sampling cohort who 
have a morning visit should be reminded not to take their morning dose at home 
prior to their Baseline visit (tetrabenazine), and prior to their Week 8 visit (SD-809 
ER) as it will be administered in clinic. Morning clinic visits should be scheduled 
early in the day to allow sufficient time for PK blood sampling. 
Subjects who withdraw early from the study should have a single blood sample collected 
for PK at the Early Termination Visit if the last dose was within the prior 48 hours, if 
possible.  
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 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
13 
possible. The date and time of the last dose of study medication should be recorded along 
with the date and time of the sample collection. 
STATISTICS 
 
 
 
 
 
 
 
 
Safety: 
Safety data will be summarized descriptively for the overall population and based on prior 
treatment [SD-809 ER or placebo (Rollover subjects) or tetrabenazine (Switch subjects)].  
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 for Rollover subjects will utilize the 
Baseline from Study SD-809-C-15 (C-15 Baseline) and the Baseline from the present 
study (C-16 Baseline), as appropriate, and will be specified in the Statistical Analysis 
Plan.    
Pharmacokinetics: 
A population pharmacokinetic analysis will be performed using data from all subjects 
switching from TBZ to SD-809 ER in this study together with data obtained from subjects 
in Study SD-809-C-15 to examine the pharmacokinetics of SD-809 and TBZ and to 
explore the potential effect of various covariates on the pharmacokinetics of SD-809 and 
TBZ.  The population pharmacokinetic analysis will be discussed in detail in a 
prospective Statistical Analysis Plan. 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 2 
CONFIDENTIAL 
14 
SCHEDULE OF EVENTS A – SUBJECTS SWITCHING FROM TETRABENAZINE 
 
Screening 
 
Long Term Treatment 
Follow up 
Unscheduled 
Dose Adjustment 
 
 
Study Week→ 
Up to -4 
-1 
Baseline
1 
1 
2 
3 
4 
7 
8 
15 
28 
28 + q13 
wks 
End of 
Treatment 
1 wk FU 4 wk FU 
 
 
Visit Window (days)  → 
 
± 3 
0 
± 1 
 
± 3 
n/a 
Visit →   Screening 
T1 
V1 
V2 
T2 
T3 
V3 
T4 
V4 
V5 
V6 
Vx17 
End Tx/ET 
FU 
FFU 
UV18 
UT
C 
Activity Visit type → 
V 
TC 
V 
V 
TC 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
Evaluate/Adjust Dose  
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X3 
Evaluate Capacity for consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Subject ID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Unique ID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Advance Directive** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selection Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight 
X 
 
X2 
X 
 
 
X 
 
X2 
X 
X 
X 
X2 
X 
 
X 
 
Physical Examination 
X4 
 
X 
 
 
 
 
 
 
 
X4 
 
X 
 
 
 
 
Complete Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X16 
 
 
X16 
 
X 
 
 
 
X 
 
 
 
 
Blood sampling for PK 
 
 
X12 
 
 
 
 
 
X13 
 
 
 
X5 
 
 
X5 
 
Provide/Remind/Review 
diary Card for meal/dosing 
times 
X9 
X9 
X11 
 
 
 
X10 
X10 
X11 
 
 
 
 
 
 
 
 
Chemistry/Hematology/UA 
X* 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
CAG Repeat 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded CYP2D6 Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Screen (HBsAg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/FSH6 
S 
 
U 
 
 
 
 
 
 
 
U 
U 
U 
 
 
 
 
HADS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
C-SSRS7 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
MoCA© 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Motor 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
UHDRS - Cognitive 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Behavior 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Functional 
Assessment 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS - Independence 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS - TFC 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
UHDRS - Summary 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UPDRS -  Dysarthria 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
SDQ 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
BARS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
ESS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/Order Study Drug8 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X3 
Drug Acct/Compliance 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Assess Adverse Events 
 
 
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 
Administer TBZ or SD-809 ER 
 
 
X14 
 
 
 
 
 
X15 
 
 
 
 
 
 
 
 
Evaluate Chorea Control 
(subject/caregiver) 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 2 
CONFIDENTIAL 
15 
 
Screening 
 
Long Term Treatment 
Follow up 
Unscheduled 
Dose Adjustment 
 
 
Study Week→ 
Up to -4 
-1 
Baseline
1 
1 
2 
3 
4 
7 
8 
15 
28 
28 + q13 
wks 
End of 
Treatment 
1 wk FU 4 wk FU 
 
 
Visit Window (days)  → 
 
± 3 
0 
± 1 
 
± 3 
n/a 
Visit →   Screening 
T1 
V1 
V2 
T2 
T3 
V3 
T4 
V4 
V5 
V6 
Vx17 
End Tx/ET 
FU 
FFU 
UV18 
UT
C 
Activity Visit type → 
V 
TC 
V 
V 
TC 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
Return Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 2 
CONFIDENTIAL 
16 
SCHEDULE OF EVENTS KEY SUBJECTS SWITCHING FROM TETRABENAZINE 
[V]  
Clinic Visit 
[TC]  
Telephone Contact 
[ET]   
Early Termination Visit 
 
[FU]  
Follow Up Visit one week after end of treatment 
[FFU] 
Final Follow Up Visit four weeks after end of treatment 
[S]  
Serum pregnancy test for women of childbearing potential only 
[U]  
Urine pregnancy test for women of childbearing potential only 
 
*     Screening labs to include Prothrombin Time (PT) with INR 
**   Subjects who have the capacity to provide informed consent only (See Section 6.12) 
1    Baseline visit (Day 0) will occur on the day before the scheduled first dose of SD-809 ER (Day 1) 
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    Subjects who withdraw early from the study should have a single blood sample collected for PK at the Early Termination Visit if the last dose was within the prior 48 hours, if 
possible. Subjects who experience an SAE should have a single blood sample collected for metabolites of SD-809 within 48 hours of SAE, if possible 
6    Serum follicle stimulating hormone (FSH) level to be assessed in post-menopausal females only (at Screening only). 
7    At Screening, administer the C-SSRS Baseline version.  At Baseline and every visit thereafter, administer the C-SSRS Since Last Visit version. 
8    Study medication supply will be ordered. (See Operations Manual for further details).  
9    Provide Diary Card to record meals and tetrabenazine dosing times for upcoming PK sampling day.  Subjects should be reminded approx. 7 days before next scheduled visit to 
complete diary card. Subjects in the “Rich” cohort and “Sparse” cohort, scheduled for a morning visit, will be reminded to hold dose of tetrabenazine on the day of their 
Baseline visit. Subjects in the “Sparse” cohort, scheduled for an afternoon visit, will be reminded to take their usual dose(s) of tetrabenazine at home per their usual schedule 
on the day of their Baseline visit. 
10    Provide diary card to record the start time of the subject’s last meal and the time of their last dose of SD-809 ER prior to the Week 8 visit and ask the subject to bring the diary 
card with them to the next clinic visit. Subjects should be reminded approx. 7 days before next scheduled visit to complete diary card.  Subjects in the “Rich” cohort and 
“Sparse” cohort, scheduled for a morning visit, will be reminded to hold dose of SD-809 ER on the day of their Week 8 visit. Subjects in the “Sparse” cohort, scheduled for 
an afternoon visit, will be reminded to take their usual dose(s) of SD-809 ER at home per their usual schedule on the day of their Week 8 visit. 
11    Collect and review diary card 
12    PK blood sample for tetrabenazine and metabolites 
13    PK blood sample for SD-809 and metabolites.  If subject requires a dose change at Week 8, PK sampling should be postponed until Week 15. 
14    Administer tetrabenazine in clinic if subject scheduled for morning visit. If subject is scheduled for afternoon visit, they will take their usual dose of tetrabenazine at home.  
15    Administer SD-809 ER in clinic if subject scheduled for morning visit. If subject is scheduled for afternoon visit, they will take their usual dose of SD-809 ER at home. 
16    For subjects on allowed doses of Celexa or Lexapro (Cipralex): 
 
Week 1: A 12-lead ECG is required at this visit. 
 
Week 4: If the dose of study drug has been increased since the last ECG, a 12-lead ECG is required at this visit. 
17 After Week 28, perform clinic visits every 13 weeks until the End of Treatment Visit.  Obtain safety labs and urine pregnancy test every 26 weeks after Week 28, and perform 
UHDRS-TFC every 52 weeks after Week 28. 
18 For subjects requiring an Unscheduled Clinic Visit for any reason, assessments denoted with X should be performed; all other assessments are as indicated at Investigator’s 
discretion (see Section xxx). 
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 2 
CONFIDENTIAL 
17 
SCHEDULE OF EVENTS B – SUBJECTS ROLLING OVER FROM SD-809-C-15 
 
 
Screening 
                  
Long Term Treatment 
Follow up 
Unscheduled 
Titration Period 
 
Study Week →   
 
Baseline‡ 
1 
2 
3 
4 
5 
8 
15 
28 
28 + q13 
wks 
End of 
Treatment 
1 wk FU 4 wk FU
 
 
Visit Window (days)  → 
 
 +3 
± 1  
 
± 3 
n/a 
                                            
Visit  → 
Prior Data from  
Study C-15† 
V1 
T1 
V2 
T2 
V3 
T3 
V4 
V5 
V6 
Vx9 
End Tx/ET 
FU 
FFU 
UV10 
UTC 
Activity Visit type  → 
 
V 
TC 
V 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
Evaluate/Adjust Dose   
 
 
X 
X 
X 
X 
X 
X  
 
 
 
 
 
 
X 
X3 
Evaluate Capacity for consent 
 
 X§# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
 
X§ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Advance Directive†† 
 
X§ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selection Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Update Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight 
 
** 
 
X 
 
X 
 
X2 
X 
X 
X 
X2 
X 
 
X 
 
Physical Examination 
* 
 
 
 
 
 
 
 
 
X4 
 
X 
 
 
 
 
Complete Neurological Exam 
* 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
* 
 
 
X8 
 
X8 
 
X 
 
 
 
X 
 
 
 
 
Blood sampling for PK 
 
 
 
 
 
 
 
  
 
 
 
X7 
 
 
X7 
 
Chemistry/Hematology/UA 
* 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
CAG Repeat1 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded CYP2D6 Genotype1 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
U 
 
 
 
 
 
 
 
U 
U 
U 
 
 
 
 
HADS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
C-SSRS5 
 
** 
 
X  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
MoCA© 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Motor 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
UHDRS – Cognitive 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS – Behavior 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Functional 
Assessment 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS – Independence 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS – TFC 
* 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
UHDRS - Summary 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UPDRS - Dysarthria 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
SDQ 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
BARS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
ESS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/Order Study Drug6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X3 
Drug 
Accountability/Compliance 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Assess Adverse Events 
* 
 
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 
Evaluate Chorea Control 
(subject/caregiver) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Return Study Drug 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 2 
CONFIDENTIAL 
18 
SCHEDULE OF EVENTS KEY – SUBJECTS ROLLING OVER FROM SD-809-C-15 
 
[V]  
Clinic Visit 
[TC]  
Telephone Contact 
[ET]   
Early Termination Visit 
 
[FU]  
Follow Up Visit one week after end of treatment 
[FFU] 
Final Follow Up Visit four weeks after end of treatment 
 [U]  
Urine pregnancy test for women of childbearing potential only 
 
† 
After Informed Consent is obtained, data from Study SD-809-C-15 will be utilized in this study as part of screening information as detailed in the informed 
consent/assent. 
††  
Subjects who have the capacity to provide informed consent only (See Section 6.12)  
‡ 
Data from the Week 13 evaluation of Study SD-809-C-15 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 
# 
For subjects who were determined to have the capacity to provide informed consent in Study SD-809-C-15. 
* 
Data (Week 12 or earlier) from Study SD-809-C-15 will be utilized in this study as part of screening information.  
** 
Data (Week 13) from Study SD-809-C-15 will be utilized 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 Study SD-809-C-15 
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 for Rollover subjects 
6    
Study medication supply will be ordered (See Operations Manual for further details). 
7    
Subjects who withdraw early from the study should have a single blood sample collected for PK at the Early Termination Visit if the last dose was within the prior 48 
hours, if possible. Subjects who experience an SAE should have a single blood sample collected for metabolites of SD-809 within 48 hours of SAE, if possible. 
8    
For subjects on allowed doses of Celexa or Lexapro (Cipralex): 
 
Week 2: A 12-lead ECG is required at this visit. 
 
Week 4: If the dose of study drug has been increased since the last ECG, a 12-lead ECG is required at this visit. 
9 
After Week 28, perform clinic visits every 13 weeks until the End of Treatment Visit.  Obtain safety labs and urine pregnancy test every 26 weeks after Week 28, and 
perform UHDRS-TFC every 52 weeks after Week 28. 
10 
For subjects requiring an Unscheduled Clinic Visit for any reason, assessments denoted with X should be performed; all other assessments are as indicated at 
Investigator’s discretion. 
 




Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
20 
TABLE OF CONTENTS 
STUDY CONTACTS ..................................................................................................................... 2 
PROTOCOL SYNOPSIS ............................................................................................................... 3 
SCHEDULE OF EVENTS A – SUBJECTS SWITCHING FROM TETRABENAZINE ............ 14 
SCHEDULE OF EVENTS B – SUBJECTS ROLLING OVER FROM SD-809-C-15 ................ 17 
PROTOCOL SIGNATURE PAGE .............................................................................................. 19 
TABLE OF CONTENTS .............................................................................................................. 20 
LIST OF APPENDICES ............................................................................................................... 24 
LIST OF ABBREVIATIONS ....................................................................................................... 25 
1 
INTRODUCTION ................................................................................................................. 28 
1.1 
Disease Background ....................................................................................................... 28 
1.2 
Tetrabenazine ................................................................................................................. 28 
1.3 
Deuterium ....................................................................................................................... 29 
1.3.1 
Clinical Experience with Deuterium ....................................................................... 29 
1.4 
SD-809 (d6-Tetrabenazine) ............................................................................................ 30 
2 
STUDY OBJECTIVES ......................................................................................................... 31 
3 
INVESTIGATIONAL PLAN................................................................................................ 31 
3.1 
Study Design .................................................................................................................. 31 
3.2 
Rationale for Study Design ............................................................................................ 34 
3.3 
Rationale for Dose Selection .......................................................................................... 35 
4 
STUDY POPULATION ........................................................................................................ 35 
4.1 
Population Characteristics .............................................................................................. 35 
4.2 
Inclusion Criteria ............................................................................................................ 35 
4.3 
Exclusion Criteria ........................................................................................................... 37 
5 
STUDY TREATMENT ......................................................................................................... 39 
5.1 
Investigational Product ................................................................................................... 39 
5.2 
Treatment Regimen ........................................................................................................ 39 
5.2.1 
General Guidelines.................................................................................................. 39 
5.2.2 
Dosing in Switch Subjects ...................................................................................... 40 
5.2.3 
Dosing in Rollover subjects .................................................................................... 41 
5.2.4 
Dosing in Long Term Treatment (Weeks 3-54) ..................................................... 41 
5.2.5 
Dose Reduction or Suspension ............................................................................... 42 
5.3 
Treatment Administration .............................................................................................. 42 


Auspex Pharmaceuticals, Inc. 
Protocol SD-809-C-16 
Huntington Study Group 
ARC-HD 
Amendment 3 
CONFIDENTIAL 
21 
5.4 
Accountability of Study Drug ........................................................................................ 42 
5.5 
Study Drug Compliance ................................................................................................. 43 
6 
STUDY METHODS AND PROCEDURES ......................................................................... 43 
6.1 
Screening Period ............................................................................................................ 43 
6.1.1 
Screening Visit (up to Week -4) (Switch Subjects) ................................................ 43 
6.1.2 
Prior Data from Study SD-809-C-15 (Rollover Subjects) ...................................... 46 
6.1.3 
Baseline Visit (Day 0) ............................................................................................. 46 
6.2 
Dose Adjustment/Titration Period ................................................................................. 48 
6.2.1 
Switch Subjects - Weeks 1 and 2 ............................................................................ 49 
6.2.2 
Rollover Subjects - Weeks 1 and 2 ......................................................................... 50 
6.3 
Long Term Treatment Period (up to 52 weeks) ............................................................. 51 
6.3.1 
Telephone Contacts (One week prior to Baseline visit [Switch only]; Week 3 ± 3 
days [All Subjects]; Week 5 ± 3 days [Rollover only]; Week 7±3 days [Switch only]) ...... 52 
6.3.2 
Clinic Visits (Weeks 4, 8, 15, 28, and 41 [all ± 3 days]) ........................................ 52 
6.3.3 
Clinic Visit (Week 54 ± 3 days or Early Termination) ........................................... 53 
6.4 
Post-Treatment Safety Follow Up .................................................................................. 54 
6.4.1 
Clinic Visit (Week 55 ± 3 days) ............................................................................. 55 
6.4.2 
Telephone Contact (Week 58 ± 3 days) .................................................................. 55 
6.5 
Unscheduled Visit(s) ...................................................................................................... 55 
6.6 
Safety Evaluations .......................................................................................................... 57 
6.6.1 
Demographics and Medical History ....................................................................... 57 
6.6.2 
Physical Examination.............................................................................................. 57 
6.6.3 
Complete Neurological Examination ...................................................................... 57 
6.6.4 
Vital Signs ............................................................................................................... 57 
6.6.5 
Orthostatic Blood Pressure and Pulse ..................................................................... 57 
6.6.6 
Laboratory Tests ..................................................................................................... 58 
6.6.7 
12-lead Electrocardiogram (ECG) .......................................................................... 58 
6.6.8 
Detecting Adverse Events ....................................................................................... 59 
6.7 
Rating Scales .................................................................................................................. 59 
6.7.1 
Hospital Anxiety and Depression Scale (HADS) ................................................... 59 
6.7.2 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................... 59 
6.7.3 
Unified Huntington’s Disease Rating Scale (UHDRS) .......................................... 59 
6.7.4 
Montreal Cognitive Assessment (MoCA©) ............................................................ 60 
6.7.5 
Unified Parkinson’s Disease Rating Scale (UPDRS) ............................................. 60 


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6.7.6 
Barnes Akathisia Rating Scale (BARS) .................................................................. 60 
6.7.7 
Epworth Sleepiness Scale (ESS) ............................................................................. 60 
6.7.8 
Swallowing Disturbance Questionnaire (SDQ) ...................................................... 60 
6.8 
Pharmacokinetic Evaluations ......................................................................................... 61 
6.9 
Subject Restrictions ........................................................................................................ 62 
6.9.1 
Concomitant Medications ....................................................................................... 62 
6.9.2 
Use of Alcohol or Sedating drugs ........................................................................... 63 
6.9.3 
Other Restrictions ................................................................................................... 63 
6.10 
Caregiver Responsibilities.............................................................................................. 63 
6.11 
Capacity Assessment ...................................................................................................... 63 
6.12 
Research Advance Directive .......................................................................................... 64 
6.13 
Withdrawal Criteria ........................................................................................................ 64 
6.14 
Discontinued Subjects .................................................................................................... 64 
6.15 
Study Termination .......................................................................................................... 64 
7 
ADVERSE EVENTS ............................................................................................................ 64 
7.1 
Definitions ...................................................................................................................... 65 
7.1.1 
Adverse Event ......................................................................................................... 65 
7.1.2 
Suspected Adverse Reaction ................................................................................... 66 
7.1.3 
Adverse Reaction .................................................................................................... 66 
7.1.4 
Unexpected Adverse Event ..................................................................................... 66 
7.1.5 
Serious Adverse Event (SAE) ................................................................................. 66 
7.2 
Recording of Adverse Events ......................................................................................... 67 
7.2.1 
Recording of Non-Serious Adverse Events (AEs).................................................. 67 
7.2.2 
Recording of Serious Adverse Events (SAEs)........................................................ 68 
7.3 
Evaluation of Adverse Events (Serious and Non-Serious) ............................................ 68 
7.3.1 
Severity ................................................................................................................... 68 
7.3.2 
Relationship to Study Drug ..................................................................................... 69 
7.3.3 
Action Taken with Study Treatment ....................................................................... 69 
7.3.4 
Treatment Required ................................................................................................ 69 
7.3.5 
Outcome .................................................................................................................. 70 
7.4 
Procedures for Reporting Serious Adverse Events ........................................................ 70 
7.4.1 
Completion and Transmission of the SAE Report .................................................. 70 
7.4.2 
Regulatory Reporting Requirements for SAEs ....................................................... 70 


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7.5 
Procedures for Reporting Pregnancy Exposure and Birth Events.................................. 71 
8 
STATISTICAL PROCEDURES AND DATA ANALYSIS ................................................ 71 
8.1 
Analysis Populations ...................................................................................................... 71 
8.2 
Demographics and Baseline Data .................................................................................. 71 
8.3 
Safety Analyses .............................................................................................................. 71 
8.4 
Safety Endpoints ............................................................................................................ 72 
8.5 
Sample Size .................................................................................................................... 72 
8.6 
Pharmacokinetics ........................................................................................................... 73 
8.7 
Protocol Deviations and Violations ............................................................................... 73 
8.8 
Data Recording ............................................................................................................... 73 
8.9 
Data Quality Assurance .................................................................................................. 73 
8.10 
Data Management .......................................................................................................... 73 
9 
ADMINISTRATIVE ISSUES ............................................................................................... 74 
9.1 
Investigator Obligations ................................................................................................. 74 
9.1.1 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) Approval
 
74 
9.1.2 
Written Informed Consent ...................................................................................... 74 
9.1.3 
Emergency Contact with Investigator ..................................................................... 75 
9.1.4 
Ethical Considerations ............................................................................................ 75 
9.1.5 
Privacy Rule ............................................................................................................ 75 
9.2 
Protocol Amendments .................................................................................................... 75 
9.3 
Records Retention .......................................................................................................... 75 
9.4 
Study Monitoring ........................................................................................................... 76 
9.4.1 
Steering Committee ................................................................................................ 76 
9.4.2 
Clinical Monitoring ................................................................................................. 76 
9.5 
Quality Assurance .......................................................................................................... 76 
10 INFORMATION DISCLOSURE AND INVENTIONS ....................................................... 77 
10.1 
Ownership ...................................................................................................................... 77 
10.2 
Confidentiality ................................................................................................................ 77 
10.3 
Publication ...................................................................................................................... 77 
11 REFERENCES ...................................................................................................................... 78 
12 APPENDICES ....................................................................................................................... 80 
 


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LIST OF APPENDICES 
Appendix 1: Site Investigator Signature Page .............................................................................. 81 
Appendix 2: Unified Huntington’s Disease Rating Scale (UHDRS) ........................................... 82 
Appendix 3: Hospital Anxiety and Depression Scale (HADS) .................................................... 98 
Appendix 4: Columbia Suicidality Severity Rating Scale (C-SSRS) – Baseline ......................... 100 
Appendix 5: Columbia Suicidality Severity Rating Scale (C-SSRS) – Since Last Visit .............104 
Appendix 6: Unified Parkinson’s Disease Rating Scale (UPDRS): Speech............................... 108 
Appendix 7: Montreal Cognitive Assessment (MoCA©)............................................................ 109 
Appendix 8: Epworth Sleepiness Scale (ESS) ............................................................................ 113 
Appendix 9: Barnes Akathisia Rating Scale (BARS) ................................................................. 115 
Appendix 10: Swallowing Disturbance Questionnaire (SDQ) ................................................... 118 
Appendix 11: Strong CYP2D6 Inhibitors ................................................................................... 120 
Appendix 12: Prohibited or restricted QT Prolonging Drugs ..................................................... 121 
Appendix 13: Prohibited Antipsychotic Drugs ........................................................................... 122 
Appendix 14:  Simulated Exposures of Total (α+β)-HTBZ for Tetrabenazine and SD-809 ...... 123 
Appendix 15:  Simulated Exposures (AUC24) of Total (α+β)-HTBZ for Initial SD-809 Regimens 
at Steady State in CYP2D6 Poor Metabolizers........................................................................... 124 
Appendix 16: Celexa and Lexapro (Cipralex) Dosing Information ........................................... 125 


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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 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AST 
Aspartate transaminase 
AUC 
Area Under Curve 
BARS 
Barnes Akathisia Rating Scale 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
C 
Carbon 
CAG 
Cytosine Adenine Guanine 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practice 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCC 
Clinical Trials Coordination Center 
CYP2D6 
Cytochrome P450 2D6 
CYP450 
Cytochrome P450 
D, d 
Deuterium 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
ECG 
Electrocardiogram 
ER 
Extended Release 
ESS 
Epworth Sleepiness Scale 
EU 
European Union 


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Abbreviation 
Definition 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
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 disease 
HIV 
Human immunodeficiency virus 
HTBZ 
Dihydrotetrabenazine 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
MAO 
Monoamine oxidase 
MCV 
Mean cell volume 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MoCA© 
Montreal Cognitive Assessment 
ms 
Millisecond 
NINDS 
National Institute of Neurological Disorders & Stroke 
O 
Oxygen 
PK 
Pharmacokinetic 
PR 
PR interval - measured from the beginning of the P wave to the beginning of 
the QRS complex 
QRS 
QRS duration (complex) - a structure on the ECG that corresponds to the 
depolarization of the ventricles 


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Abbreviation 
Definition 
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  
RBC 
Red blood cell 
SAE 
Serious Adverse Event  
SDQ 
Swallowing Disturbance Questionnaire 
SF-36 
Short Form 36 Health Survey 
SOP 
Standard Operating Procedure 
SSRI 
Selective serotonin reuptake inhibitor 
TBZ 
tetrabenazine 
TMC 
Total maximal chorea score 
TFC 
Total functional capacity 
tmax 
Time of maximum drug concentration 
UHDRS 
Unified Huntington’s Disease Rating Scale 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
US 
United States 
VMAT 
Vesicular monoamine transporter  


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1 INTRODUCTION 
1.1 
Disease Background 
Huntington disease (HD) is a fatal neurodegenerative autosomal dominant disorder characterized 
by progressive motor, cognitive, and behavioral symptoms that cause profound disability.  The 
adult onset form of HD typically manifests between 35 and 40 years of age.  Progression of the 
disease is slow and inexorable, with death ensuing approximately 10 to 20 years after onset of 
the first motor symptoms.  The worldwide prevalence of HD is estimated to be 5-10 cases per 
100,000 persons.  
Histopathologically, HD is characterized by progressive loss of medium spiny neurons in the 
striatum and to a lesser extent of pyramidal neurons in the cortex.  The disease is due to a 
mutation in the polyglutamine repeat sequence in the huntingtin gene located on Chromosome 4.   
The most commonly recognized motor sign of HD is the involuntary movement chorea, which 
can affect all muscle groups.  Chorea has the potential to interfere with daily functioning.  In its 
early stages, chorea can contribute to impaired speaking, writing, and Activities of Daily Living 
(ADLs) such as feeding, dressing and bathing.  In its later stages, chorea can cause gait 
instability and poor postural control, with an increased risk of injury from falling or flailing into 
objects. 
Both preclinical studies in transgenic mice and clinical experience in patients with a genetic 
predisposition to HD implicate a relative excess of dopamine in the pathogenesis of these 
involuntary movements.  These observations led to the development of tetrabenazine, which 
depletes presynaptic dopamine, as a treatment for chorea associated with Huntington disease. 
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 disease (HD).  
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 in patients with Huntington disease can be 
found in the SD-809 ER Investigator’s Brochure (IB), which includes the tetrabenazine 
prescribing information. 
Limitations of the Current Commercial Product 
The commercial form of tetrabenazine (Xenazine®, Nitoman®) is an immediate release 
formulation.  While generally effective in the treatment of chorea, tetrabenazine has limitations 
for use in Huntington disease patients, 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.   


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 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 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 commercial tetrabenazine, Auspex has developed a deuterated 
analogue of tetrabenazine (referred to as SD-809) which, due to the deuteration, is eliminated 
more slowly than tetrabenazine (See below). It is also administered in an extended release 
formulation.  As outlined in Section 1.4 and the Investigator’s Brochure, SD-809 extended 
release (ER) has been shown to reduce plasma fluctuation and dosing frequency and thus, has the 
potential to improve overall tolerability as compared to 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 (1).  The adult male body contains approximately 57% 
water (2), the major source of H in the body (3).  A 70 kilogram (Kg) male contains 
approximately 39,900g of water of which 0.0156% or 6.22g is D2O, yielding a naturally-
occurring body content of 1.24g of deuterium.  
Small molecule drugs have been developed in which carbon (C)-H bonds have been replaced 
with C-D bonds (4).  The increased mass of deuterium in the 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 (1).  
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 (4).  
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 H20 or in other organic materials (4). 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 (5, 6).  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 


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long term use of deuterated water (D2O).  Acute exposures of to up to 23% D replacement in 
plasma were tolerated without reported adverse events (7).  In several metabolic labeling studies 
healthy subjects consumed daily doses of up to 9.8g D in the form of D2O for up to 4-9 weeks, 
treatments sufficient to maintain 1.0–2.0% D enrichment in body water.  No adverse events were 
reported in these studies (8-12).  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 (13).  
1.4 
SD-809 (d6-Tetrabenazine) 
SD-809 is a deuterated analog 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 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. 
The safety and pharmacokinetics of oral SD-809 have been evaluated in five Phase 1 studies in 
healthy adult volunteers.  Single doses of SD-809 (either as an immediate-release or as an 
extended-release [ER] formulation) have been administered to 130 subjects at doses ranging 
from 7.5 to 24 mg, either alone or in conjunction with CYP2D6 inhibition.  Multiple dose 
regimens of the ER 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 1 to 1½ hours post-dosing following administration of an immediate release 
formulation.  Peak plasma concentrations were significantly later (median tmax 3 to 4 hours) and 
lower for the ER 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 7.5-22.5 mg SD-809 ER, 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, 
comparatively less than has been reported with in a similar drug interaction study with 
tetrabenazine. 
To date, five Phase 1 studies in healthy volunteers have been conducted with SD-809, including 
two with an immediate release formulation (powder in capsule) (AUS-SD-809-CTP-06, SD-809-
C-12) and three with extended release formulations (AUS-SD-809-CTP-07 Part 1 and Part 2 and 


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SD-809-C-08, SD-809-C-11).  In total, 100 subjects have received single doses of SD-809 or 
SD-809 ER, ranging from 7.5 to 22.5 mg and 24 subjects have received repeated doses of 
SD-809 ER for up to 5 days at 22.5 mg BID.  In these studies, no SAEs were reported and all 
AEs were mild to moderate in intensity.  Commonly reported AEs included headache, 
somnolence, nausea, dizziness and vessel puncture reaction.  When tetrabenazine was used as a 
comparator, the adverse events of SD-809 were qualitatively similar to tetrabenazine.  The 
adverse events reported with SD-809 were also consistent with prior clinical experience with 
tetrabenazine. 
Additional information on the study results may be found in the SD-809 ER Investigator’s 
Brochure.  
A well controlled study of SD-809 ER is presently being conducted in subjects with chorea 
associated with HD (Study SD-809-C-15:  A Randomized, Double Blind, Placebo Controlled 
Study of SD-809 Extended Release for the Treatment of Chorea associated with Huntington 
Disease).  Subjects who successfully complete Study SD-809-C-15 are candidates to participate 
in this open label safety study.  In addition, subjects on stable, FDA-approved doses of TBZ will 
also be considered for this study.  
2 STUDY OBJECTIVES 
The objectives of this study are:  
1. Evaluate the safety and tolerability of titration and maintenance therapy with SD-809 ER 
2. Evaluate the safety and tolerability of switching subjects from tetrabenazine to 
SD-809 ER 
3. Evaluate the pharmacokinetics of tetrabenazine, SD-809 and their respective α- and 
β-HTBZ metabolites in subjects switching from tetrabenazine to SD-809 ER 
3 INVESTIGATIONAL PLAN 
This is an open-label, single-arm study designed to evaluate the long term safety and tolerability 
of SD-809 ER dose adjustments/titrations for the treatment of chorea associated with HD over 
long term treatment.  Approximately 116 subjects who are receiving FDA-approved doses of 
tetrabenazine for treatment of chorea (approx. 36) or have successfully completed the SD-809-C-
15 efficacy study (approx. 80) will be enrolled.  The study will be conducted at approximately 40 
centers in the U.S., Canada, and Australia.  The study is divided into a screening period, a dose 
adjustment/titration period, a long term treatment period and a post-treatment safety follow up 
period.  Overall study participation will continue until SD-809 ER becomes commercially 
available in the U.S. 
3.1 
Study Design 
This is an open-label, single-arm study in which subjects with manifest HD who are receiving 
FDA-approved doses of tetrabenazine1 for treatment of chorea associated with HD or have 
successfully completed the SD-809-C-15 efficacy study will be invited to participate.  Successful 
completion of Study SD-809-C-15 is defined as (1) study participation through Week 13 (2) the 
                                                 
1 The maximum dose of tetrabenazine is 100 mg/day (with a maximum single dose of 37.5 mg), unless the subject has known 
impaired CYP2D6 function, in which case the maximum dose is 50 mg/day with a maximum single dose of 25 mg. 


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subject has generally been compliant with study medication and procedures, in the opinion of the 
investigator and (3) the subject has no ongoing adverse events that that are serious (SAE)1, 
severe in intensity or are expected to interfere with safety evaluations in this study. Two groups 
of subjects will be enrolled into this trial: 
Switch subjects are those who are currently receiving stable doses of tetrabenazine for treatment 
of chorea associated with HD and convert to SD-809 ER based on an algorithm designed to 
achieve comparable exposure to total (α+β)-HTBZ metabolites. 
Rollover subjects are those who have successfully completed Study SD-809-C-15 and may be 
eligible to continue on long-term SD-809 ER after a 1-week wash out period.  
Subjects who do not already have a legally authorized representative will undergo an 
independent evaluation by a qualified healthcare provider to determine their capacity to provide 
informed consent prior to consent/assent process.  Informed consent/assent will be obtained 
before any study procedures are performed.  A Research Advance Directive (See Section 6.12) 
will be obtained from subjects with the ability to self consent.  Subjects rolling over from the 
SD-809-C-15 study may have capacity assessment (if necessary)/informed consent/assent and 
Research Advance Directive (if applicable) (See Section 6.12) obtained up to 30 days in advance 
of subject’s First-HD Week 13 Visit/ARC-HD Baseline Visit. Subjects who meet the selection 
criteria will be eligible to participate.  
Subjects Switching from Tetrabenazine (Switch):  Subjects who are currently receiving an 
FDA approved dose of tetrabenazine (TBZ) that is providing a therapeutic benefit for chorea 
control associated with HD will be eligible to participate in the study.  Subjects in this cohort 
will undergo a full screening evaluation within 30 days of the Baseline assessment prior to 
switching to SD-809 ER.  See Schedule of Events A.  These subjects will be converted from 
their TBZ regimen to an SD-809 ER regimen that is predicted to provide comparable exposure to 
total (α+β)-dihydrotetrabenazine (α- and β-HTBZ).  Subjects will continue taking their TBZ 
regimen through midnight of Day 0 and then directly switch to their assigned SD-809 ER 
regimen the next morning.  The dose of SD-809 ER may be adjusted weekly (upward or 
downward) in increments of 6 mg per day (6 mg/day or 12 mg/day after a total daily dose of 48 
mg is reached) to identify a dose level that adequately controls chorea, the subject experiences a 
protocol defined “clinically significant” adverse event (defined as related to study medication 
and either a) moderate or severe in intensity or b) meets the criteria for a Serious Adverse Event 
[SAE])1; or the maximal allowable dose is reached.  If a subject experiences a “clinically 
significant” AE attributable to SD-809 ER, the investigator will determine if a dose reduction or 
suspension is necessary.  The investigator, in consultation with the subject and caregiver, will 
determine when an adequate level of chorea control has been achieved.  Subjects will have a 
clinic visit at Week 1 and a telephone contact at Week 2, in order to evaluate safety and establish 
an optimal dose.  Although subjects will enter the Long term treatment period after Week 2, dose 
adjustment (upward or downward) may continue through Week 4 to optimize dose level.  
Additional dose adjustments may be made after Week 4 if clinically indicated. 
Subjects Enrolled from the SD-809-C-15 Study (Rollover):  Subjects who have successfully 
completed Study SD-809-C-15 may be eligible to rollover directly into this study after they 
complete a one week washout and the Week 13 evaluation of Study SD-809-C-15.  To reduce 
subject burden, after obtaining capacity assessment (if applicable)/informed consent/assent and 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


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Research Advance Directive (if applicable), some data collected in the SD-809-C-15 study will 
be utilized in the SD-809-C-16 study and will provide some of the baseline data for SD-809-C-
16 (See Schedule of Events B).  In addition to assessments completed for the SD-809-C-15 
Week 13 visit, evaluations required as part of the SD-809-C-16 study will be completed on the 
same day as the Week 13 visit. All subjects are expected to rollover to SD-809-C-16 at the Week 
13 visit of SD-809-C-15. 
As Rollover subjects will have discontinued study drug (SD-809 ER or placebo) for 1 week at 
completion of the SD-809-C-15 study, they will undergo titration on SD-809 ER.  During 
titration, the investigator, in consultation with the subject and caregiver, will determine when an 
adequate level of chorea control has been achieved.  The dose of SD-809 ER may be adjusted 
(upward or downward), in increments of 6 mg per day (each week) (6 mg/day or 12 mg/day after 
a total daily dose of 48 mg is reached), until there is adequate control of chorea; the subject 
experiences a protocol defined “clinically significant” adverse event (defined as related to study 
medication and either a) moderate or severe in intensity or b) meets the criteria for a Serious 
Adverse Event [SAE])1, or the maximal allowable dose is reached.  If a subject experiences a 
“clinically significant” AE attributable to SD-809 ER, 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, in order to evaluate safety and establish a dose of study drug that 
adequately controls chorea and is well-tolerated.  Although subjects will enter the Long term 
treatment period after Week 2, titration may continue through Week 8 to optimize dose level.  
Additional dose adjustments may be made after Week 8 if clinically indicated. 
Long-Term Treatment Period: During long term treatment, all subjects will be contacted by 
telephone at Week 3 (the first week of Long-term treatment period) and will return to the clinic 
on Weeks 4, 8, 15, 28 and every 13 weeks thereafter for evaluation of safety and chorea control.  
Switch subjects will have an additional telephone contact at Week 7.  Rollover subjects will have 
an additional telephone contact at Week 5.  Subjects who have not achieved a stable dose by the 
Week 4 visit (Switch subjects) or Week 5 telephone contact (Rollover subjects) may have 
unscheduled visits or telephone contacts in order to further adjust their dose upward or 
downward.  Site interactions for dose adjustment should alternate between telephone contacts 
and clinic visits.  During long-term treatment, further dose adjustments of SD-809 ER may be 
made, if necessary, but not more often than weekly.  Dose adjustments should be based on all 
available information including the subject’s and caregiver’s reports of adverse events and 
chorea control, information from rating scales and all safety evaluations. Long term treatment 
will continue until SD-809 ER becomes commercially available in the U.S. 
Post-Treatment Safety Follow Up: All subjects will discontinue study drug at the End of 
Treatment visit and return for their final clinic visit one week later for evaluation of safety, 
cognition, behavior, chorea and motor function.  During this one week washout, subjects should 
not take prohibited concomitant medications.  After the one week washout is complete, 
concomitant medication use is per the discretion of the investigator.  Subjects will also have a 
follow up telephone contact four weeks after their last dose of study drug, to evaluate adverse 
events and concomitant medication usage. 
PK Sub-Study:  A sub-study will be conducted to evaluate the pharmacokinetics (PK) of 
tetrabenazine and SD-809 ER in Switch subjects.  Approximately 12 subjects will have rich PK 
sampling and approximately 24 subjects will have sparse PK sampling (See Section 6.8).  The 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


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PK of tetrabenazine and metabolites will be assessed at the Baseline visit and the PK of SD-809 
ER and metabolites will be assessed at the Week 8 visit.   If a subject requires a dose change at 
Week 8, the Week 8 visit assessments should be conducted except for PK sampling which should 
be postponed until Week 15. 
3.2 
Rationale for Study Design 
The study is designed to evaluate the long term safety and tolerability of SD-809 ER in subjects 
with chorea associated with HD.  Two cohorts of subjects may enter the study: 1) Rollover 
subjects, who successfully complete the well-controlled efficacy study (SD-809-C-15) and 
2) Switch subjects, who are receiving FDA-approved doses of tetrabenazine for treatment of 
chorea.   
Given the two groups of subjects entering this trial have different background therapy at entry; 
identification of their optimal dose will be approached differently.  Rollover subjects from Study 
SD-809-C-15 will have discontinued study medication (SD-809 ER or placebo) for at least one 
week and consequently they will begin dosing at 6 mg/day and titrate to their optimal dose level 
for up to 8 weeks.  In contrast, Switch subjects will be on a stable dose of TBZ at entry and will 
make a direct conversion to SD-809 ER overnight based on their incoming TBZ regimen.  As 
such, Switch subjects should reach their target dose more rapidly and they are allowed up to 4 
weeks to adjust their SD-809 ER regimen after conversion.  Although the time to reach an 
optimal dose may differ between these cohorts, both groups are expected to reach a 
pharmacologically active dose by two weeks:  Rollover subjects would be at 12 mg/day, unless 
they experienced adverse events or adequate chorea control; and Switch subjects would have 
converted to a dose level that provides comparable exposure to their incoming tetrabenazine 
dose, with one intervening visit to evaluate/adjust dose level.  Accordingly, the long term period 
of the study will be deemed to have started after two weeks of treatment even though dose 
adjustment may continue after this point. 
For both Rollover and Switch subjects, the SD-809 ER dose level should be adjusted in order to 
identify a dose that reduces chorea and is well-tolerated.  In addition to the assessments of chorea 
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 chorea is 
determined individually for each subject.  Once adequate control of chorea 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. 
To convert Switch subjects from stable doses of tetrabenazine to an effective dose of SD-
809 ER, extensive Phase 1 work has been conducted to characterize the pharmacokinetics of 
both drugs and their active metabolites [total (α+β)-HTBZ].  These data allowed construction of 
a pharmacokinetic model that permitted calculation of the plasma exposure associated with 
various tetrabenazine and SD-809 ER regimens.  Based on a subject’s incoming tetrabenazine 
regimen, an initial SD-809 ER regimen will be identified that provides comparable exposure 
(AUC) to total (α+β)-HTBZ with reduced peak concentrations.  Following conversion, subjects 
will have clinic visits at Weeks 1 and 4 and telephone contacts at Weeks 2 and 3 to optimize 
dose level. 
Rollover subjects will begin treatment at the lowest SD-809 ER dose of 6 mg/day and undergo 


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Protocol SD-809-C-16 
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35 
titration/evaluation on a weekly basis for chorea control, adverse events, and possible dose 
adjustment.  Subjects will have clinic visits at Weeks 2 and 4 and telephone contacts at Weeks 1, 
3, and 5 to optimize dose level. 
The present investigation is an open label safety study of long term treatment with SD-809 ER at 
a pharmacologically active dose and will enroll subjects with chorea associated with HD who 
were either previously exposed to SD-809 ER or placebo (from Study SD-809-C-15, First-HD); 
or who are switching directly from TBZ to SD-809 ER.  It is, therefore, adequate to characterize 
the safety and tolerability of titration and maintenance therapy with SD-809 ER in the target 
population.   
The U.S. prescribing information for tetrabenazine indicates that CYP2D6 genotyping should be 
performed at dose levels 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 be 
performed in a blinded manner 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 ER treatment will be individualized, and, therefore fixed doses 
will not be evaluated in the study.  The starting dose of 6 mg of SD-809 ER provides an AUC of 
total (α+β)-HTBZ that is comparable to the 12.5 mg starting dose of tetrabenazine, but with a 
lower peak concentration and higher trough concentration.  The dose level of SD-809 ER 
treatment will be evaluated on a weekly basis during the titration/dose adjustment period, based 
on assessments of chorea control and adverse events, in order to determine if dose adjustment is 
needed.  This approach is consistent with the tetrabenazine prescribing information.   
Dose adjustments should occur in increments of 6 mg/day (each week) (6 mg/day or 12 mg/day 
after a total daily dose of 48 mg is reached).  Dose reductions in increments greater than 6 mg 
should be reviewed with the Clinical Monitor (See Section 5.2.5).   
The maximum total daily dose of SD-809 ER is 72 mg per day, unless the subject is receiving a 
strong CYP2D6 inhibitor (e.g., paroxetine, See Appendix 11), in which case the maximum total 
daily dose is 42 mg. 
4 STUDY POPULATION 
4.1 
Population Characteristics 
Male and female adult subjects with HD who are receiving approved doses of tetrabenazine1 for 
treatment of chorea or have successfully completed the SD-809-C-15 efficacy study and meet 
eligibility criteria will be enrolled. 
4.2 
Inclusion Criteria 
1. Subject is at least 18 years of age or the age of majority (whichever is older) at Screening. 
                                                 
1 The maximum dose of tetrabenazine is 100 mg/day (with a maximum single dose of 37.5 mg), unless the subject has known 
impaired CYP2D6 function, in which case the maximum dose is 50 mg/day with a maximum single dose of 25 mg.  


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2. Subject has been diagnosed with manifest HD, as indicated by characteristic motor exam features, 
and has a documented expanded CAG repeat (≥ 37) at or before Screening1. 
3. Subject meets either of the following:  
 Has successfully completed2 participation in Study SD-809-C-15  OR        
 Has been receiving an FDA approved dose of tetrabenazine3 that has been stable for ≥ 
8 weeks before Screening and is providing a therapeutic benefit for control of chorea 
4. Subject has a Total Functional Capacity (TFC) score ≥ 5 at Screening. 
5. Subject is able to swallow study medication whole. 
6. Subject has provided written, informed consent or, if subject lacks the capacity to provide 
informed consent (as determined by an independent assessment by a qualified healthcare 
provider not directly involved in other study activities), a legally authorized 
representative (LAR) has provided written informed consent and the subject has provided 
assent. 
7. Subject has provided a Research Advance Directive if subject has the capacity to provide 
informed consent (See Section 6.12). 
8. Female subjects of childbearing potential4 agree to use an acceptable method of 
contraception from screening through study completion.  Female subjects of childbearing 
potential must be using one of the following acceptable birth control methods 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 Baseline. 
                                                 
1 A CAG repeat number obtained prior to the Screening Visit may be used to document subject eligibility if either of the 
following conditions are met:  
 At Screening, there is documentation available in the subject’s records that shows the subject has an expanded CAG repeat    
(≥ 37) from a prior laboratory assessment.  
 At Screening, there is documentation available of a subject’s prior laboratory assessment of an allele length that states a subject 
has a genotype consistent with a diagnosis of HD (i.e., laboratory analysis confirming the CAG repeat number was at least 40). 
Note: If neither condition above is met, results from the CAG repeat sample collected at the Screening Visit must be used to 
determine study eligibility.  A CAG Repeat Number of ≥ 37 must be documented prior to enrolling a subject into the study. 
Note: Regardless of whether a prior CAG result is available, all Switch subjects will undergo CAG repeat testing at the Screening 
Visit, and any enrolled subject whose CAG repeat is found not to be ≥ 37 will be withdrawn from the study. 
2 Successful completion of Study SD-809-C-15 is defined as (1) study participation through Week 13 (2) the subject has 
generally been compliant with study medication and procedures, in the opinion of the investigator and (3) the subject has no 
ongoing adverse events that that are serious (SAE) or severe in intensity or are expected to interfere with safety evaluations in this 
study. 
3 The maximum dose of tetrabenazine is 100 mg/day (with a maximum single dose of 37.5 mg), unless the subject has known 
impaired CYP2D6 function, in which case the maximum dose is 50 mg/day with a maximum single dose of 25 mg.  
4 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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 Stable hormonal contraception (with approved oral, transdermal, or depot regimen) 
for at least 3 months prior to screening. 
9. The subject has a reliable caregiver who interacts with the patient on a daily basis, 
oversees study drug administration, assures attendance at study visits and participates in 
evaluations, as required.  
 Note:  Subjects with a TFC score of 5-7 at Screening must have a live-in caregiver 
 Note:  Subjects with a TFC score of 5-7 at Screening or those who enrolled with the 
consent of an LAR, must have caregivers present at all study visits. 
 Note:  For subjects with a TFC score of 8-13 at Screening who did not require an 
LAR to provide informed consent, the caregiver must attend the following visits: 
Screening, Baseline, Weeks 4, 8, 15, 28 and visits every 13 weeks thereafter through 
the End of Treatment visit. Caregivers will be encouraged to attend other visits. 
10. Subject is able to ambulate without assistance for at least 20 yards (Note: The use of 
assistive devices (i.e., walker, cane) are permitted during ambulation). 
11. Has sufficient reading skills to comprehend the subject completed rating scales. 
4.3 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded: 
1. Subject has a serious untreated or undertreated psychiatric illness, such as depression, at 
Screening or Baseline.  
 Note:  Subjects receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 8 weeks before Screening (See Appendix 12) for prohibited 
antidepressants). 
2. Subject has active suicidal ideation at Screening or Baseline. 
3. Subject has history of any of the following suicidal thoughts or behavior at Screening or 
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 or behavior 
 A previous actual, interrupted or aborted suicide attempt 
4. Subject has a score ≥11 on the depression subscale of the Hospital Anxiety and 
Depression Scale (HADS) at Baseline. 
5. Subject has an unstable or serious medical or psychiatric illness at Screening or Baseline. 
6. Subject has received tetrabenazine within 7 days of Baseline (Rollover subjects). 
7. Subject has received any of the following concomitant medications within 30 days of 
Screening or Baseline: 
 Antipsychotics (See Appendix 13) 
 Metoclopromide  
 Monoamine oxidase inhibitors (MAOI) 
 Levodopa or dopamine agonists 


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 Reserpine 
 Amantadine 
 
Memantine (Rollover subjects only) 
o Switch subjects may receive Memantine if on a stable, approved dose for at least 30 days.  
8. Subject has a score of ≥11 on the Swallowing Disturbance Questionnaire (SDQ) at 
Screening or Baseline. 
9. Subject has a Unified Parkinson’s Disease Rating Scale (UPDRS) dysarthria score of ≥3 
at Screening or Baseline. 
10. Subject requires treatment with drugs known to prolong the QT interval.  Note: 
 Quetiapine (Seroquel) is not allowed. 
 Escitalopram (Lexapro or Cipralex)1 is allowed when administered according to 
approved labeling. 
 Citalopram (Celexa)2 is allowed when administered according to approved labeling. 
 See Appendix 16 for Celexa and Lexapro (Cipralex) dosing information 
 See Appendix 12 for a complete list of prohibited or restricted QT prolonging drugs. 
11. Subject has a QTcF value >450 ms (males) or >460 ms (females), or >480 ms (with right 
bundle branch block) on 12-lead ECG at Screening.   
  Note: Subjects with left bundle branch block are not eligible. 
12. Subject has evidence of hepatic impairment at Screening, as indicated by:  
 AST or ALT >2.5 times the upper limit of normal. 
 Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the upper limit of 
normal (ULN) 
o Note: Subjects with Gilbert’s Syndrome are eligible to participate if approved by 
the Clinical Monitor.  
o Note: Subjects with abnormalities in two or more of these analytes (AST, ALT, 
ALP, TBil) must be approved by the Clinical Monitor in order to be enrolled.  
 Prothrombin time > 4 sec prolonged. 
 Positive Hepatitis B surface antigen (HBsAg). 
13. Subject has evidence of significant renal impairment at Screening, indicated by a 
creatinine clearance <50 mL/min, as estimated by the Cockroft-Gault formula. 
14. Subject has known allergy to any of the components of study medication. 
15. Subject has participated in an investigational drug or device trial other than SD-809-C-15 
within 30 days (or 5 drug half-lives) of Screening, whichever is longer. 
                                                 
1  Escitalopram (Lexapro or Cipralex): The maximum allowed dose is 20 mg/day.  The maximum dose for subjects 
≥ 65 years old is 10 mg/day. 
2  Citalopram (Celexa) is allowed with the following restrictions (See Appendix 16): 
d) 
If the subject is a known CYP2C19 poor metabolizer, Celexa is not allowed. 
e) 
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. 
f) 
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. 


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16. Subject is pregnant or breast-feeding at Screening or Baseline. 
17. Subject acknowledges present use of illicit drugs at Screening or Baseline. 
18. Subject has a history of alcohol or substance abuse in the previous 12 months, as defined 
in the DSM-IV (See Operations Manual), or subject is unable to refrain from substance 
abuse throughout the study. 
5 STUDY TREATMENT 
The study medication to be used in this trial is an extended release (ER) formulation of SD-
809.  Three dose strengths of SD-809 ER will be available for use: 6, 9, and 12 mg tablets.  Each 
dose strength will have a black marking of SD 6, SD 9 or SD 12, corresponding to the dose 
strength and a distinct tablet color:  6 mg - purple; 9 mg - blue; 12 mg - beige.     
5.1 
Investigational Product 
The investigational product is a matrix formulation and is designed as a gastro-erosional, 
extended release tablet to be administered with food.  Study drug is coated with a colored 
polymer coating to aid in swallowing.  The colored polymer coating is applied to the tablets 
according to dose strength; 6 mg - purple; 9 mg - blue; 12 mg - beige.  Each dose strength will 
have a black marking of SD 6, SD 9 or SD 12, corresponding to the dose strength.  SD-809 ER 
tablets have been manufactured according to current Good Manufacturing Practices regulations.  
During titration/dose adjustment, SD-809 ER tablets will be supplied in weekly blister packs as 
6, 9, and/or 12 mg tablets and will be labeled according to applicable regulatory guidelines.  
Each blister pack will contain a sufficient supply of drug until the next specified visit, plus 
overage to account for potential delays in study visits or evaluations or receipt of their supplies. 
Once the investigator determines that a stable dose has been reached, SD-809 ER will be 
supplied in 30 count containers and labeled according to applicable regulatory guidelines. 
Complete details regarding SD-809 ER supply, dispensing and ordering will be provided in the 
study Operations Manual. 
SD-809 ER 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). 
5.2 
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 with meals  
 A daily dose of 6 mg will be given once a day in the morning and daily doses of 12 mg and 
higher will be administered twice daily, approximately 10 hours apart during the day. 
 The maximum total daily dose of SD-809 ER is 72 mg (36 mg BID), unless the subject is 
receiving a strong CYP2D6 inhibitor (See Appendix 11), in which case the maximum total 
daily dose is 42 mg 
o Individual doses up to and including 12 mg are given as a single tablet 
o Individual doses of 15 to 24 mg will be given as two tablets 
o Individual doses of 27 to 36 mg will be given as three tablets 


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 Dose adjustments are limited to 6 mg/day (each week) (6 mg/day or 12 mg/day after a total 
daily dose of 48 mg is reached).  Dose reductions in increments greater than 6 mg should be 
reviewed with the Clinical Monitor. (See Section 5.2.5)   
 If a strong CYP2D6 inhibitor is started (i.e., paroxetine, fluoxetine, bupropion), the Clinical 
Monitor should be notified as a dose reduction of more than 6 mg may be required.  
5.2.2 Dosing in Switch Subjects 
For Switch subjects, the initial SD-809 ER dosing regimen will be based on the subject’s 
incoming total daily dose of tetrabenazine.  As outlined in Table 1 and Appendix 14, an initial 
dosing regimen of SD-809 ER will be assigned which targets a steady state AUC of total (α+β)-
HTBZ that is comparable to that of the subject’s tetrabenazine regimen (Table 1). 
After initial dose conversion, the investigator may adjust the dose of SD-809 ER upward or 
downward over the following 4 weeks, if necessary, to a level in which adequate chorea control 
has been achieved and the subject is tolerating the treatment regimen.  Changes in dose should 
not be made more often than once per week unless the subject is experiencing an intolerable 
adverse event. 
Once adequate control of chorea has been achieved, the dose of study drug should not be 
increased further. 
Pharmacokinetic modeling and simulation of Phase 1 data were performed to estimate the overall 
systemic exposure (AUC) for various tetrabenazine and SD-809 ER regimens.  Appendix 14 
depicts the values for AUC0-24 for extensive and intermediate metabolizers of CYP2D6.   
Based on the data in Appendix 14, an initial SD-809 ER regimen has been identified which 
approximates the AUC0-24 for total (α+β)-HTBZ of the corresponding tetrabenazine total daily 
dose in CYP2D6 extensive and intermediate metabolizers (Table 1).  Although the median AUCs 
for SD-809 ER are slightly lower than those for the corresponding tetrabenazine regimen, there 
is considerable overlap in the distributions of this parameter.  Subjects with diminished CYP2D6 
function (e.g., poor metabolizers or receiving potent CYP2D6 inhibitors) who undergo dose 
conversion according to Table 1 may have an initial AUC on SD-809 ER that is up to 30-40% 
below that of their tetrabenazine regimen (See Appendix 15).  As with intermediate and 
extensive metabolizers, there is considerable overlap in the distribution of AUCs between 
SD-809 and tetrabenazine in poor metabolizers.  Furthermore, subjects with inadequate control 
of chorea may undergo dose adjustment for the four weeks following initial dose conversion.  
Additional dose adjustments may be made after Week 4 if clinically indicated. 


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Table 1:  Initial SD-809 Dose Regimen based on Incoming Tetrabenazine Regimen 
If a Switch Subject’s 
Incoming Total Daily 
TBZ Dose is: 
Then, the Initial Total 
Daily SD-809 ER Dose 
Should Be: 
Taken As: 
Morning 
Dose 
Evening 
Dose 
12.5 mg 
→ 
6 mg 
6 mg 
̶ 
25 mg 
→ 
12 mg 
6 mg 
6 mg 
37.5 mg 
→ 
18 mg 
9 mg 
9 mg 
50 mg 
→ 
24 mg 
12 mg 
12 mg 
62.5 mg 
→ 
30 mg 
15 mg 
15 mg 
75 mg 
→ 
36 mg 
18 mg 
18 mg 
87.5 mg 
→ 
42 mg 
21 mg 
21 mg 
100 mg 
→ 
48 mg 
24 mg 
24 mg 
5.2.3 Dosing in Rollover subjects  
The starting dose of SD-809 ER is 6 mg in the morning, regardless of previous treatment in the 
SD-809-C-15 trial.  Treatment assignment (SD-809 ER or placebo) from SD-809-C-15 will 
remain blinded.  Study drug will be titrated over the initial 8 weeks of therapy, if necessary, to 
identify a dose that provides adequate chorea 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.  Additional dose adjustments may be made after week 8 if clinically 
indicated. 
During the titration period, the dose of SD-809 ER may be increased on a weekly basis in 
increments of 6 mg per day (6 mg/day or 12 mg/day after a total daily dose of 48 mg is reached) 
until there is adequate control of chorea; the subject experiences a protocol defined “clinically 
significant” adverse event (defined as related to study medication and either a) moderate or 
severe in intensity or b) meets the criteria for a Serious Adverse Event [SAE])1; 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.  
Once adequate control of chorea has been achieved, the dose of study drug should not be 
increased further. 
5.2.4 Dosing in Long Term Treatment 
Initially during the long-term treatment period, a well-tolerated dose of SD-809 that provides 
adequate chorea control may not yet be established.  Dose adjustments may continue during long 
term treatment as specified in Sections 5.2.2 and 5.2.3.  Once a stable dose is achieved, SD-809 
ER should be dosed at the same level throughout the remaining long term period.  If necessary, 
however, the dose may be adjusted further during long term treatment (upward or downward) to 
optimize chorea control or minimize adverse events.  In general, dose changes are limited to 
6 mg per day (6 mg/day or 12 mg/day after a total daily dose of 48 mg is reached; See Section 
5.2.5).  However, such changes in dose should not occur more frequently than once per week. 
Once subjects are on a stable dose of SD-809 ER, drug will be provided to study subjects in 30-
count containers until the next specified visit.  Each order will contain a sufficient supply of drug 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


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until the next specified visit, plus overage to account for potential delays in study visits or 
evaluations or receipt of their supplies. 
5.2.5 Dose Reduction or Suspension 
If a subject experiences a “clinically significant” adverse event (defined below)1 that is attributed 
to SD-809 ER, 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 reports of adverse events and chorea control, the clinical 
assessment of safety and efficacy by the investigator and information from rating scales. 
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) or if the most recent dose 
increase was 12 mg/day, in which a greater dose reduction may be required.  Dose reductions in 
this context should be reviewed with the Clinical 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.  Dose 
reductions greater than 6 mg/day should be reviewed with the Clinical Monitor.  If a subject 
requires a dose reduction based on a telephone contact during the maintenance period, an 
unscheduled clinic visit should be conducted in a timely manner thereafter. 
Suspension of study medication for up to one week, if warranted, is allowed.   
Suspensions of study medication for adverse events must be reviewed with the Clinical 
Monitor before therapy is restarted.  If study medication is restarted after a suspension for 
an adverse event, a dose reduction of 6 mg or more is permitted. 
Suspensions for more than 7 days must be reviewed by the Clinical Monitor.  If the subject 
restarts study medication within 7 days of suspension, the full dose of SD-809 ER may be 
resumed without titration.  If subject restarts study medication greater than 7 days following a 
suspension, re-titration will be required.    
The reason for a dose reduction or suspension must be clearly documented. 
5.3 
Treatment Administration 
Each tablet should be swallowed whole with water and not broken, crushed or chewed.  Tablets 
should not be taken on an empty stomach. 
Subjects should be instructed to take the investigational product with meals: tablets will be 
administered twice daily 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 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


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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/Accountability 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. 
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 by 
the study monitor at each visit.  When requested in writing by the Sponsor or if a site does not 
have available storage space to hold drug, returned and unused drug supplies will be destroyed 
on site according to the site’s standard operating procedure or returned to the Sponsor (or 
designee) after study drug accountability has been completed by and with approval of the study 
monitor.  Records shall be maintained by the Investigator of any such alternate disposition of the 
study drug.  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.   
5.5 
Study Drug Compliance 
The investigator or designated study staff is responsible for monitoring the subject’s compliance 
with study medication during the trial. Compliance will be assessed by tablet count, i.e., 
evaluation of returned study medication blister cards/containers (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 medication 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 if the subject has taken 80-100% of the expected tablets of study drug. 
6 STUDY METHODS AND PROCEDURES 
6.1 
Screening Period 
6.1.1 Screening Visit (up to Week -4) (Switch Subjects) 
See the Schedule of Events A for a detailed summary of activities. 
Prior to conduct of any study-specific screening procedures, the Investigator, or designee, will 
explain to the subject and caregiver the study procedures, including the risks involved and the 
fact that their participation is voluntary.  If the subject lacks the capacity to provide informed 
consent (as determined by an independent assessment by a qualified healthcare provider not 
directly involved in other study activities), a legally authorized representative must provide 
written informed consent and the subject must provide assent.  Each subject and caregiver will 
acknowledge receipt of this information by signing and dating a current, IRB/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. A Research Advance Directive (See Section 6.12) will be obtained from 


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subjects with the ability to self consent. Subjects rolling over from the SD-809-C-15 study may 
have capacity assessment/informed consent/assent/research advance directive obtained up to 30 
days in advance of subject’s First-HD Week 13 Visit/ARC-HD Baseline Visit.   
Each potentially eligible subject who has signed an informed consent or assent and is screened 
will be assigned a Subject Identification (ID) Number in consecutive order by the site from the 
site-specific Subject Identification list provided to the site by the Clinical Trials Coordination 
Center (CTCC); this four-digit number will identify subjects on all study forms and lab 
specimens.  Should the subject proceed to enrollment, the Subject ID Number will continue to be 
used for the subject through the duration of the study.  For subjects who have signed the 
informed consent form and subsequently do not meet eligibility criteria or withdraw consent, the 
source record should contain at least minimum information as documentation of screen failure 
(i.e., demographics, eligibility criteria reviewed, procedures performed, etc.).   
In addition, subjects will be assigned a 9-digit Unique ID Number at the Screening Visit.  This 
ID system has the ability to track individual subjects across multiple HSG CTCC studies without 
storing any personally identifiable information.  The protected system uses an algorithm of nine 
data element inputs (last name at birth, first name at birth, gender at birth, day, month and year of 
birth, city and country of birth, and mother’s maiden name), and produces an electronic 
“fingerprint” output.  The system stores only the “fingerprint” and clears the individual’s 
inputted data elements from memory.  The subject is then assigned a 9-digit CTCC Unique ID 
Number that is associated with their electronic “fingerprint.”   
Once the informed consent/assent, is signed to obtain the CTCC unique ID, the subject (or 
designee) will be directed to a secure website where he/she or the site Study Coordinator (if the 
patient requests/prefers) will enter the subject’s nine data elements. The CTCC Unique ID 
Number will be printed and provided to the patient.  The Study Coordinator will record this 
number on the eCRF and Confidential Subject ID Log.   
If a patient has participated in previous CTCC studies and already has an existing CTCC Unique 
ID Number, this number will be used for this study.  When the same nine data elements are 
entered in the exact same way they were entered the first time, the same CTCC Unique ID 
Number will be generated.  
The caregiver will also be asked to review and sign the consent form. Caregivers will not be 
assigned Subject Identification or Unique ID numbers. 
After informed consent/assent has been obtained, and any washout of prohibited medications 
completed, screening activities will be performed on all suitable subjects within the 4 weeks 
prior to first dose to determine if subjects meet the inclusion/exclusion criteria.  
Subjects switching from tetrabenazine (Switch subjects) will undergo a full screening 
evaluation within 30 days of the Baseline assessment prior to switching to SD-809 ER.  See 
Schedule of Events A.   
The Switch Screening clinic visit will consist of the following: 
 Evaluate capacity for consent and obtain informed consent/assent 
 Assign Subject ID 
 Assign Unique ID 
 Complete Research Advance Directive, if subject has the capacity to provide informed 


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consent (See Section 6.12) 
 Complete medical history including demographics, concomitant medications (including 
over the counter, vitamins, and herbal supplements) and alcohol use 
 Assessment of chorea control (in consultation with the subject and caregiver) 
 Brief physical examination, vital signs, height and weight 
 Complete neurological examination 
 Clinical laboratory tests:  
o 
Safety labs: serum chemistry, hematology, prothrombin time and urinalysis  
o 
Screening labs: virology screen (HBsAg), serum human chorionic gonadotropin 
(hCG) pregnancy test (women of child-bearing potential only), serum FSH (in order 
to confirm post-menopausal status). 
 Other tests: Blinded CAG repeat 
 Blinded CYP2D6 genotype blood sampling 
 12-lead ECG 
 Columbia Suicide Severity Rating Scale (C-SSRS): Baseline version 
 Unified Huntington’s Disease Rating Scale (UHDRS):  
o 
Motor 
o 
TFC 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Swallowing Disturbance Questionnaire (SDQ) 
 Provide Switch subjects with a diary card to record the start time of their last meal and 
time of their last tetrabenazine dose prior to the Baseline visit and ask them to bring the 
diary card with them to the next clinic visit. 
o Schedule a telecon one week before the Baseline visit to remind Switch subjects 
to complete the diary card, and hold dose of tetrabenazine on the day of their 
Baseline visit if their visit is scheduled in the morning. If the subject is scheduled 
in the afternoon, subjects will be reminded to take their dose(s) of tetrabenazine as 
per their usual schedule. Subjects will be reminded to bring their tetrabenazine 
with them to their Baseline visit.  
 Evaluate selection criteria and, if eligible to enroll, schedule Baseline clinic visit 
 Order study medication 
Abnormal screening labs may be repeated once, without medical monitor approval,  to 
determine the subject’s eligibility.   
Subjects may be rescreened, with approval of the medical monitor, if they have an abnormal 
laboratory value or an acute condition preventing them from qualifying for the study if the 
condition: 
 Has resolved or is resolving 


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 Does not meet the criteria for a Serious Adverse Event 
 Is not expected to interfere with the subject’s ability to complete the study as designed, in 
the opinion of the investigator. 
Screening results will be assessed by the Investigator or Sub-Investigator and subjects who meet 
selection criteria will be considered for enrollment into the study. 
6.1.2 Prior Data from Study SD-809-C-15 (Rollover Subjects) 
See Schedule of Events B for data to be imported from SD-809-C-15 after Informed Consent. 
Subjects who have successfully completed Study SD-809-C-15 may be eligible to rollover 
directly into this study after they complete a one week washout and the Week 13 (visit window 
up to 10 days) evaluation of Study SD-809-C-15.  To reduce subject burden, after obtaining 
capacity assessment (if applicable)/informed consent/assent and Research Advance Directive (if 
applicable), some data collected in the SD-809-C-15 study will be utilized in the SD-809-C-16 
study and provide some of the baseline data for SD-809-C-16 (See Schedule of Events B).  In 
addition to assessments completed for the SD-809-C-15 Week 13 visit, evaluations required as 
part of the SD-809-C-16 study will be completed on the same day as the Week 13 visit. All 
subjects are expected to rollover to SD-809-C-16 at the Week 13 visit of SD-809-C-15.   
Baseline visit study drug will be shipped after site’s approval to receive study drug. See 
Operations Manual for further details. 
6.1.3 Baseline Visit (Day 0) 
See the Schedule of Events A and B 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.   
Subjects switching from tetrabenazine (Switch subjects)  
Subjects will be converted from their TBZ regimen to an SD-809 ER regimen that is predicted to 
provide comparable exposure to total (α+β)-dihydrotetrabenazine (α- and β-HTBZ).  Subjects 
will continue taking their TBZ regimen through midnight of Day 0 and then directly switch to 
their assigned SD-809 ER regimen the next morning.   
The Switch Baseline clinic visit will consist of the following: 
Note: The italicized procedures listed immediately below should be done before PK blood 
sampling to assure the subject still qualifies for study participation: 
 Adverse events and concomitant medication use  
 Collect and review diary card 
 Urine pregnancy test (women of child-bearing potential only) 
 Hospital Anxiety and Depression Scale (HADS) 
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Swallowing Disturbance Questionnaire (SDQ) 


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 Physical examination, vital signs (including orthostatic blood pressure and pulse) and 
weight 
 Baseline results will be assessed by the Investigator or Sub-Investigator and subjects who 
meet eligibility criteria will be enrolled into the study. 
 Clinical laboratory tests: serum chemistry, hematology, and urinalysis 
 PK blood sampling for tetrabenazine (See Section 6.8) 
 Administer tetrabenazine post pre-dose sampling (Switch subjects scheduled for morning 
visits only) 
 Montreal Cognitive Assessment (MoCA©) 
 Complete Unified Huntington’s Disease Rating Scale (UHDRS): 
o 
Motor 
o 
Cognitive 
o 
Behavior 
o 
Functional assessment 
o 
Independence 
o 
TFC 
o 
Summary 
 Barnes Akathisia Rating Scale (BARS) 
 Epworth Sleepiness Scale (ESS) 
 Subjects will be provided with one week of study medication. 
 Week 1 clinic visit will be scheduled. 
Subjects from the SD-809-C-15 Study (Rollover subjects)  
Subjects who have successfully completed Study SD-809-C-15 may be eligible to rollover 
directly into this study after they complete the Week 13 evaluation of Study SD-809-C-15.  To 
reduce subject burden, after obtaining capacity assessment (if necessary)/informed 
consent/assent and Research Advance Directive (if applicable), some data collected in the SD-
809-C-15 study will be utilized in the SD-809-C-16 study and will provide some of the baseline 
data for SD-809-C-16 (See Schedule of Events B).Additional evaluations required as part of the 
SD-809-C-16 study will be completed on the same day as the Week 13 visit of the SD-809-C-15 
study after SD-809-C-16 informed consent/assent is provided. All subjects are expected to 
rollover to SD-809-C-16 at the Week 13 visit of SD-809-C-15.  See Schedule of Events B.  
Prior to conduct of any study-specific screening procedures, the Investigator, or designee, will 
explain to the subject and caregiver the study procedures, including the risks involved and the 
fact that their participation is voluntary.  If subject lacks the capacity to provide informed 
consent (as determined by an independent assessment by a qualified healthcare provider not 
directly involved in other study activities), a legally authorized representative must provide 
written informed consent and the subject must provide assent.  Each subject and caregiver will 
acknowledge receipt of this information by signing and dating a current, IRB/IEC-approved 


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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 Rollover Baseline clinic visit will consist of the following: 
 Evaluate capacity for consent and obtain informed consent/assent (for subjects who do 
not already have a legally authorized representative) 
 Complete Research Advance Directive, if subject has the capacity to provide informed 
consent (See Section 6.12) 
 Update medical history  
 Urine pregnancy test (women of child-bearing potential only) 
 Montreal Cognitive Assessment (MoCA©) 
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o Cognitive 
o Behavior 
 Baseline results will be assessed by the Investigator or Sub-Investigator and subjects who 
meet eligibility criteria will be enrolled into the study. 
 Subjects will be provided with one week of study medication 
 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, in order to evaluate safety and establish a dose of 
study drug that adequately controls chorea and is well-tolerated.  Safety evaluations include 
UHDRS motor examination, laboratory testing, ECGs, monitoring for adverse events and rating 
scales for depression, cognitive function, akathisia, swallowing disturbance and somnolence.  
Subjects on allowed doses of citalopram (Celexa) or escitalopram (Lexapro, Cipralex) will have 
additional ECGs during the titration period as specified in the Schedule of Events. 
For subjects switching from tetrabenazine (Switch subjects) the dose of SD-809 ER may be 
adjusted weekly (upward or downward) in increments of 6 mg per day (6 mg/day or 12 mg/day 
after a total daily dose of 48 mg is reached) until a dose level that adequately controls chorea is 
identified, the subject experiences a protocol defined “clinically significant” adverse event 
(defined as related to study medication and either a) moderate or severe in intensity or b) meets 
the criteria for a Serious Adverse Event [SAE])1; or the maximal allowable dose is reached.  If a 
subject experiences a “clinically significant” AE attributable to SD-809 ER, the investigator will 
determine if a dose reduction or suspension is necessary. The investigator, in consultation with 
the subject and caregiver, will determine when an adequate level of chorea control has been 
achieved.  Subjects will have a clinic visit at Week 1 and a telephone contact at Week 2, in order 
to evaluate safety and establish an optimal dose.  Although subjects will enter the long term 
                                                 
1 See Section 7 for evaluation of AEs regarding severity, relationship to study drug and definition of SAE. 


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treatment period after Week 2, dose adjustment (upward or downward) may continue through 
Week 4 to optimize dose level.  Additional dose adjustments may be made after Week 4 if 
clinically indicated. 
As all subjects from the SD-809-C-15 Study (Rollover subjects) will have discontinued study 
drug (SD-809 ER or placebo) for 1 week after completion of the SD-809-C-15 study, they will 
undergo titration on SD-809 ER.  During titration, the investigator, in consultation with the 
subject and caregiver, will determine when an adequate level of chorea control has been 
achieved.  The dose of SD-809 ER may be adjusted on a weekly basis (upward or downward), in 
increments of 6 mg per day (6 mg/day or 12 mg/day after a total daily dose of 48 mg is reached), 
until there is adequate control of chorea; the subject experiences a protocol defined “clinically 
significant” adverse event (defined as related to study medication 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 ER, 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, in order to evaluate 
safety and establish a dose of study drug that adequately controls chorea and is well-tolerated.  
Although subjects will enter the Long term treatment period after Week 2, titration may continue 
through Week 8 to optimize dose level.  Additional dose adjustments may be made after Week 8 
if clinically indicated. 
Once adequate control of chorea has been achieved or the maximum allowable dose has 
been reached, the dose of SD-809 ER should not be increased further. 
If a subject experiences an AE 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 reports of 
adverse events and chorea control, the clinical assessment of safety and efficacy by the 
investigator, and information from rating scales such as the UHDRS, the HADS, the UPDRS 
(dysarthria item), the Barnes Akathisia Rating Scale, the Epworth sleepiness scale, and the C-
SSRS.  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 Switch Subjects - Weeks 1 and 2 
See the Schedule of Events A for a detailed summary of activities. 
Switch subjects will have a clinic visit at Week 1 and a telephone contact at Week 2 for 
evaluation of safety and SD-809 ER dose level. 
The Switch Week 1 clinic visit will include the following activities: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver), and concomitant medication use 
 Vital signs 
 Weight 
 For subjects on allowed doses of citalopram (Celexa) or escitalopram (Lexapro, 
Cipralex): Perform a 12-lead ECG 
 Hospital Anxiety and Depression Scale (HADS)  


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 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version  
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o Motor 
o Behavior 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Swallowing Disturbance Questionnaire (SDQ) 
 Barnes Akathisia Rating Scale (BARS)  
 Epworth Sleepiness Scale (ESS) 
 Evaluation of SD-809 ER dose level and adjustment, if necessary, based on subject’s 
reports of adverse events and chorea control (in consultation with the subject and 
caregiver), clinical assessment of safety and efficacy, and information from the above 
rating scales. 
 Assessment of medication accountability/compliance 
 Re-order study medication  
 The Week 2 telephone contact will be scheduled/reconfirmed  
The Switch Week 2 telephone contact assessments will include: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver) and concomitant medication use 
 Evaluation of study drug dose level and adjustment, if necessary 
 Re-order study medication (See Operations Manual for further details) 
 Next telephone contact will be scheduled/reconfirmed 
6.2.2 Rollover Subjects - Weeks 1 and 2 
See the Schedule of Events B for a detailed summary of activities. 
Rollover subjects will have a telephone contact at Week 1 and clinic visit at Week 2 of the study 
for evaluation of safety and SD-809 ER dose level. 
The Rollover Week 1 telephone contact will include the following activities: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver) and concomitant medication use 
 Evaluation of study drug dose level and adjustment, if necessary 
 Re-order study medication 
 Next clinic visit will be scheduled/reconfirmed 
The Rollover Week 2 clinic visit will include the following activities: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver), and concomitant medication use 


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 Vital signs 
 Weight 
 For subjects on allowed doses of citalopram (Celexa) or escitalopram (Lexapro, 
Cipralex): Perform a 12-lead ECG 
 Hospital Anxiety and Depression Scale (HADS)  
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o 
Motor  
o 
Behavior 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Barnes Akathisia Rating Scale (BARS)  
 Epworth Sleepiness Scale (ESS) 
 Swallowing Disturbance Questionnaire (SDQ) 
 Assessment of medication accountability/compliance 
 Evaluation of SD-809 ER dose level and adjustment, if necessary, based on subject’s 
reports of adverse events and chorea control (in consultation with the subject and 
caregiver), clinical assessment of safety and efficacy, and information from the above 
rating scales. 
 Re-order study medication (See Operations Manual for further details) 
 The next telephone contact will be scheduled/reconfirmed. 
6.3 
Long Term Treatment Period  
All subjects will enter the long term treatment period after Week 2, although dose adjustment 
may continue in Switch subjects and titration may continue in Rollover subjects.   
During long term treatment, all subjects will be contacted by telephone at Week 3 and will return 
to the clinic on Weeks 4, 8, 15, 28 and every 13 weeks thereafter for evaluation of safety and 
chorea control.  In addition, Rollover subjects will have an additional telephone contact at Week 
5.  Switch subjects will have an additional telephone contact at Week 7, to remind subjects to 
complete diary card before the Week 8 visit.  Subjects who have not achieved a dose level that 
adequately controls chorea and is well tolerated by the Week 4 visit (Switch subjects) or 
Week 5 telecon (Rollover subjects) should have unscheduled visits or telephone contacts in 
order to further adjust their dose upward or downward.  Site interactions for dose 
adjustment should alternate between telephone contacts and clinic visits.  During long-term 
treatment, further dose adjustments of SD-809 ER may made, if necessary, but not more often 
than weekly and in increments of 6 mg (6 mg/day or 12 mg/day after a total daily dose of 48 mg 
is reached).  Dose adjustments should be based on all available information including the 
subject’s and caregiver’s reports of adverse events and chorea control, information from rating 
scales and all safety evaluations.  If subjects become non-ambulatory or require more aid than an 
assistive device during long term treatment, they will be permitted to remain in the study. 


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At the end of the long term treatment period, subjects will undergo a comprehensive evaluation, 
including physical and complete neurological exam, safety labs and 12- lead ECG and 
performance of all rating scales.   
6.3.1 Telephone Contacts (One week prior to Baseline visit [Switch only]; Week 3 ± 3 days 
[All Subjects]; Week 5 ± 3 days [Rollover only]; Week 7±3 days [Switch only]) 
See the Schedule of Events A and B for a detailed summary of activities. 
All subjects will be contacted by telephone during Week 3 to assess adverse events, chorea 
control (in consultation with the subject and caregiver), 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 medication will be re-ordered according to specified 
procedures. 
Rollover subjects will have an additional telephone contact at Week 5 with the same activities. 
Switch subjects will have additional telephone contacts one week prior to their Baseline visit and 
at Week 7 to remind them to complete the diary card and to take or hold the morning dose on the 
day of their Baseline and Week 8 visits as per their assigned cohort (Rich or Sparse) dosing 
requirements. In addition, subjects will be reminded to return diary cards at the Baseline and 
Week 8 visits. 
6.3.2 Clinic Visits (Weeks 4, 8, 15, 28 and every 13 weeks thereafter [all ± 3 days]) 
See the Schedule of Events A and B for a detailed summary of activities. 
Long term treatment period clinic visits includes the following activities: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver) and concomitant medication use  
 Brief physical examination (Week 28) 
 Weight 
 Vital signs (at Week 8, include orthostatic blood pressure and pulse) 
 At Week 4, provide Switch subjects with a diary card to record the start time of their last 
meal and the time of their last dose prior to the Week 8 visit and ask them to bring the 
diary with them to the next clinic visit. 
 
 Collect and review diary card (Week 8 Switch subjects only)  
 For subjects on allowed doses of citalopram (Celexa) or escitalopram (Lexapro, 
Cipralex):  Perform a 12-lead ECG if the dose of study drug has been increased since the 
last ECG was collected (Week 4) 
 12-lead ECG (Week 8) 
 Clinical laboratory tests: serum chemistry, hematology, and urinalysis (Weeks 8 and 28, 
and every 26 weeks after Week 28) 
 Urine pregnancy test (women of child-bearing potential only)(Week 28 and every 26 
weeks thereafter) 


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 Blood sampling for PK (Week 8, Switch subjects only) for SD-809 ER 
 Administer SD-809 post PK sample (Switch subjects scheduled for morning visits only) 
 Hospital Anxiety and Depression Scale (HADS) 
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Montreal Cognitive Assessment (MoCA©) 
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o 
Motor  
o 
Cognitive 
o 
Behavior 
o 
Functional assessment (Week 28) 
o 
Independence (Week 28) 
o 
TFC (Week 28 and every 52 weeks thereafter) 
o 
Summary (Week 28) 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Barnes Akathisia Rating Scale (BARS) 
 Epworth Sleepiness Scale (ESS) 
 Swallowing Disturbance Questionnaire (SDQ) 
 Assessment of medication accountability/compliance  
 Evaluation of study drug dose level and adjustment, if necessary (through Week 4 for 
Switch subjects; through Week 8 for Rollover subjects) 
 Re-order study medication (See Operations Manual for further details)  
 Next clinic visit and telephone contact (Week 4 Rollover subjects only) will be 
scheduled/reconfirmed  
Subjects switching from tetrabenazine (Switch subjects) should continue to receive their long 
term treatment dose after the Week 4 clinic visit, although further dose adjustments are permitted 
if clinically indicated.  
Subjects from the SD-809-C-15 Study (Rollover subjects) should continue to receive their 
long term treatment dose after the Week 8 clinic visit, although further dose adjustments are 
permitted if clinically indicated. 
Note (Switch subjects only):  If a subject requires a dose change at Week 8, the Week 8 
assessments should be conducted except for PK sampling which should be postponed until Week 
15. 
6.3.3 Clinic Visit (End of Treatment ± 3 days or Early Termination) 
See the Schedule of Events A and B for a detailed summary of activities. 
All subjects will stop study drug at the End of Treatment visit.  Subjects will return to the clinic 


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for the following End of Treatment/ET end-of-long term treatment period assessments: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver) 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 child-bearing potential only)   
 12- lead ECG 
 Single PK Blood Sample (for Early Termination Visits, if within 48 hours of last dose, if 
possible) 
 Hospital Anxiety and Depression Scale (HADS) 
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Montreal Cognitive Assessment (MoCA©) 
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o 
Motor  
o 
Cognitive 
o 
Behavior 
o 
Functional assessment 
o 
Independence 
o 
TFC 
o 
Summary 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Barnes Akathisia Rating Scale (BARS) 
 Epworth Sleepiness Scale (ESS) 
 Swallowing Disturbance Questionnaire (SDQ) 
 Assessment of medication accountability/compliance and collection of all study 
medication 
 The next clinic visit will be scheduled/reconfirmed  
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 Schedule of Events A and B.  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. 
6.4 
Post-Treatment Safety Follow Up 


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Following discontinuation of study medication, subjects will have a clinic visit one week after 
the last dose for evaluation of safety, chorea and motor function and a telephone contact four 
weeks after the last dose for review of adverse events and concomitant medication use.  During 
the first week after stopping study drug, subjects should not take prohibited concomitant 
medications.  Between the one-week and four-week post-treatment follow up visits, concomitant 
medication use is per the discretion of the investigator. 
6.4.1 Clinic Visit (1-week follow up ± 3 days) 
See the Schedule of Events A and B for a detailed summary of activities. 
All subjects will return one week after the End of Treatment, or Early Termination visit, for 
evaluation of safety, chorea and motor function.  The following activities should be performed: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver) and concomitant medication use  
 
 Vital signs 
 Weight 
 Hospital Anxiety and Depression Scale (HADS) 
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Montreal Cognitive Assessment (MoCA©)  
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o Motor  
o Cognitive 
o Behavior 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Barnes Akathisia Rating Scale (BARS) 
 Epworth Sleepiness Scale (ESS) 
 Swallowing Disturbance Questionnaire (SDQ) 
 Next telephone contact will be scheduled/reconfirmed  
6.4.2 Telephone Contact (4-week follow up ± 3 days) 
All subjects will have a follow up telephone contact four weeks after their last dose of study 
medication.  During the telephone contact, subjects and caregivers will be questioned about 
adverse events and concomitant medication use since the subject’s last evaluation. 
6.5 
Unscheduled Visit(s) 
See the Schedule of Events A and B for a detailed summary of activities. 
Unscheduled visits may be performed for Dose Adjustment or evaluation of intercurrent 
events.   Visits for Dose adjustment should focus on evaluating chorea control, adverse events 


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and adjusting the dose of study medication, if indicated.  Additional safety measures may be 
performed at the investigator’s discretion.   
For unscheduled clinic visit(s) conducted during the course of the study, the following activities 
should be performed: 
 Assessment of adverse events, chorea control (in consultation with the subject and 
caregiver), and concomitant medications 
 Vital signs and weight 
 Unified Huntington’s Disease Rating Scale (UHDRS) 
o Motor  
 Evaluation of study drug dose level and adjustment, if necessary 
 
The following assessments are at the Investigator’s discretion and should be performed if 
indicated: 
 12-lead ECG 
 Clinical laboratory tests: serum chemistry, hematology, and urinalysis 
 Single PK Blood Sample (for Unscheduled Visits due to SAE, if within 48 hours, if 
possible) 
 Hospital Anxiety and Depression Scale (HADS) 
 Columbia Suicide Severity Rating Scale (C-SSRS): Since Last Visit version 
 Unified Parkinson’s Disease Rating Scale (UPDRS): dysarthria item 
 Barnes Akathisia Rating Scale (BARS) 
 Epworth Sleepiness Scale (ESS) 
 Swallowing Disturbance Questionnaire (SDQ) 
 
 Re-order study medication 
For unscheduled telephone visit(s) needed during the course of the study, the following 
activities should be performed: 
 Assessment of adverse events, chorea control and concomitant medications in 
consultation with the subject and caregiver. 
 Evaluation of study drug dose level and adjustment, if necessary (at the Investigator’s 
discretion) 
 
 Re-order study medication (at the Investigator’s discretion) (See Operations Manual for 
further details) 


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6.6 
Safety Evaluations 
6.6.1 Demographics and Medical History 
The subject’s gender, date of birth, race, ethnic origin, and medical and surgical history will be 
obtained at Screening for C-16 Switch subjects and recorded in the electronic Case Report Form 
(eCRF) and transferred from data collected in C-15 for Rollover subjects.  The subject’s medical 
and surgical history will be updated at Baseline for C-16 Rollover subjects. 
6.6.2 Physical Examination 
A complete physical examination will be performed as specified in the SCHEDULE OF 
EVENTS A – SUBJECTS SWITCHING FROM TETRABENAZINE or SCHEDULE OF 
EVENTS B – SUBJECTS ROLLING OVER FROM SD-809-C-15.  A complete examination 
includes evaluation of the following systems/regions: 
 General Appearance 
 Skin 
 Head, Eyes, Ears, Nose, Throat 
 Neck: Lymph Nodes, pulses 
 Cardiovascular* 
 Respiratory* 
 Musculoskeletal 
 Abdominal* 
 Extremities 
 
* Systems evaluated in brief physical examination  
A brief physical examination includes evaluation of the cardiovascular, respiratory, and 
abdominal systems. 
6.6.3 Complete Neurological Examination 
A complete neurological examination will be performed as specified in the SCHEDULE OF 
EVENTS A – SUBJECTS SWITCHING FROM TETRABENAZINE or SCHEDULE OF 
EVENTS B – SUBJECTS ROLLING OVER FROM SD-809-C-15.  The neurological 
examination includes evaluation of the following: 
 Mental status  
 Cranial nerves  
 Motor system (strength, tone posture)  
 Coordination 
 Gait and balance  
 Tendon reflexes  
 Sensation 
6.6.4 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.   
6.6.5 Orthostatic Blood Pressure and Pulse 
Orthostatic blood pressure and pulse will be recorded at Baseline, Week 8 and End of 
Treatment/ET. 


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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 assure 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. 
6.6.6 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. 
Serum Chemistry 
 
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) 
 
Screening Labs 
Other  
 
Urine and serum pregnancy tests (women of 
childbearing potential only) 
 
Follicle Stimulating Hormone (FSH) for post-
menopausal women only. 
 
Hepatitis B surface antigen (HBsAg) 
 
CYP2D6 genotype (blinded) 
 
CAG repeat (blinded) 
 
Prothrombin Time (PT) 
International Normalized Ratio (INR)         
6.6.7 12-lead Electrocardiogram (ECG) 
All ECGs will be performed after at least 5 minutes rest in a supine or semi-supine position.   
12-lead ECGs to assess safety will be recorded according to the SCHEDULE OF EVENTS A – 
SUBJECTS SWITCHING FROM TETRABENAZINE or SCHEDULE OF EVENTS B – 


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SUBJECTS ROLLING OVER FROM SD-809-C-15 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.    
6.6.8 Detecting Adverse Events 
The occurrence of adverse events (AEs) 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 AEs.   
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?” 
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 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 eCRF page for 
subjects who are enrolled.  
6.7 
Rating Scales 
Subject completed assessments will be available in English, Spanish and French. 
6.7.1 Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-administered instrument reliable for detecting states of depression and 
anxiety in an outpatient medical setting (14).  The HADS is recommended by the National 
Institute of Neurological Disorders & Stroke (NINDS) Common Data Elements for Huntington 
Disease 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 four 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. 
6.7.2 Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an FDA endorsed questionnaire to 
screen for suicidality in trials of central nervous system (CNS) active compounds (15, 16).  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”) and subsequent visits use a C-SSRS 
termed “Since the Last Visit”. 
6.7.3 Unified Huntington’s Disease Rating Scale (UHDRS) 
The UHDRS is a research tool which has been developed by the HSG to provide a uniform 
assessment of the clinical features and course of HD (17).  As the authors sought to develop a 


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tool for evaluating interventions that modify disease progression, they suggested the UHDRS 
may be suitable for tracking longitudinal changes.  The instrument was not intended to assess the 
impact of short-term treatment effects, although it has often been used for such purposes. The 
components of the UHDRS are: 
 Motor Assessment 
 Cognitive Assessment 
 Behavioral Assessment 
 Independence Scale 
 Functional Assessment 
 Total Functional Capacity (TFC)   
6.7.4 Montreal Cognitive Assessment (MoCA©) 
The Montreal Cognitive Assessment (MoCA©) 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.  
There are 3 versions in the English language.  Given the relatively frequent use of this 
instrument, the versions will be rotated at each visit. Additionally, Spanish and French language 
versions may be utilized.  
6.7.5 Unified Parkinson’s Disease Rating Scale (UPDRS) 
The Unified Parkinson's Disease Rating Scale (UPDRS) 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 dysarthria will be utilized to screen and monitor study subjects for 
parkinsonism. 
6.7.6 Barnes Akathisia Rating Scale (BARS) 
The Barnes Akathisia Rating Scale (BARS) 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 (18).    
6.7.7 Epworth Sleepiness Scale (ESS) 
The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire comprised of eight 
questions that provides a measure of a subject’s general level of daytime sleepiness (19).  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 lives.  The total ESS score is the sum of 8 item-scores and can range between 0 and 24 with 
a higher the score indicating a higher level of daytime sleepiness.  Most people can complete the 
ESS, without assistance, in 2 or 3 minutes. 
6.7.8 Swallowing Disturbance Questionnaire (SDQ) 


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The Swallowing Disturbance Questionnaire is a self-administered questionnaire comprised of 15 
questions that assess frequency of swallowing disturbance (20).  It has been validated in subjects 
with Parkinson’s disease and has been shown to be a sensitive and accurate tool for identifying 
subjects with swallowing disturbances arising from different etiologies.  A sensitivity and 
specificity analysis demonstrated that a threshold score of 11 was the optimal score for 
identifying subjects with dysphagia that had underlying pathology confirmed on fiberoptic 
endoscopic evaluation of swallowing (FEES) (21). 
6.8 
Pharmacokinetic Evaluations 
A pharmacokinetic (PK) sub-study will be conducted in subjects switching from TBZ to SD-809 
ER.  Blood samples will be obtained for measurement of plasma concentrations of SD-809, 
tetrabenazine and their respective α HTBZ, β-HTBZ, total (α+β)-HTBZ and other metabolites, as 
required.  Approximately one third of the population will have rich samples drawn and the 
remaining two thirds will have sparse sampling.  The rich sampling cohort should be enrolled 
first.  Subjects who are unable or unwilling to participate in the rich sampling cohort may be 
assigned to the sparse sampling cohort.  
Subjects in the rich sampling cohort must have a morning visit in which the AM dose of 
tetrabenazine or SD-809 ER is administered in clinic.  If the subject is assigned to the rich group 
at the Screening Visit but forgets to hold tetrabenazine dose the morning of the Baseline visit, the 
subject must be re-consented to undergo sparse sampling.  Subjects in the sparse sampling cohort 
may have a morning or an afternoon visit.  If sparse sample subjects have a morning visit, the 
AM dose of tetrabenazine or SD-809 ER should be administered in clinic as with the rich 
sampling cohort.  If sparse sampling subjects have an afternoon visit, tetrabenazine or SD-809 
ER should be taken at home per their usual schedule.   Blood samples will be collected at 
Baseline (on tetrabenazine) and at Week 8 (on SD-809 ER) as follows: 
Cohort 
Visit 
Day 0 (TBZ) 
Week 8* (SD-809 ER) 
Rich Sampling 
(N=12) 
Morning 
only 
Pre-dose, 0.5, 1, 2 and 6 hours 
post-dose 
Pre-dose, 1.5, 2.5, 4 and 6 
hours post-dose 
Sparse Sampling 
(N=24) 
Morning 
Pre-dose and 1-2 hours post-
dose 
Pre-dose and 2-4 hours post-
dose  
Afternoon 
1st sample during the visit and 
2nd at least 1 hr† afterward 
1st sample during the visit and 
2nd at least 2 hrs† afterward 
* If a subject requires a dose change at Week 8, the Week 8 visit assessments should be conducted except for PK 
sampling which should be postponed until Week 15. 
† The second PK sample for sparse sampling (afternoon) should be taken as late as possible during the visit. 
Subjects in the rich sampling cohort and those in the sparse sampling cohort who have a 
morning visit should be reminded not to take their morning dose at home prior to their 
Baseline visit (tetrabenazine) and prior to their Week 8 visit (SD-809 ER) as it will be 
administered in clinic. Morning clinic visits should be scheduled early in the day to allow 
sufficient time for PK blood sampling. 
Samples should be collected as close to the target time as possible.  The pre-dose specimen 
should be taken within one hour prior to drug administration.  The actual sample collection time 
will be recorded in the source document worksheets.    


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At each time point, four (4) mL of blood will be collected into lithium heparin tubes and 
processed to plasma.  After centrifugation, the plasma will be split into 2 aliquots and stored 
frozen in polypropylene plasma storage tubes at -70°C or below.   If a subject requires a dose 
change at Week 8, the Week 8 visit assessments should be conducted except for PK sampling 
which should be postponed until Week 15. 
Switch subjects will be provided with a diary at the Screening and Week 4 visits to record meal 
and dosing times before PK sampling at Baseline and Week 8.  Prior to clinic visits subjects will 
be reminded to record the start time of their last meal and the time of their last dose in their diary 
card and to bring the diary card with them to the clinic visit.   Switch subjects will be reminded 
to bring their tetrabenazine to the Baseline visit and the SD-809 ER to the Week 8 visit.   
Subjects who withdraw early from the study should have a single blood sample collected for PK 
at the Early Termination Visit if the last dose was within the prior 48 hours, if possible. 
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 medication should be recorded along with the date and 
time of the sample collection. 
6.9 
Subject Restrictions  
6.9.1 Concomitant Medications 
The following products should not be used within 4 weeks of Screening or Baseline and 
throughout the study: 
 Antipsychotics (See Appendix 13) 
 Metoclopromide  
 MAO Inhibitors 
 Levodopa or dopamine agonists 
 Reserpine 
 Amantadine 
 Memantine (Rollover subjects only) 
o Switch subjects may receive Memantine if on a stable, approved dose for at least 30 
days. 
Subjects discontinuing anti-psychotics (See Appendix 13) or the other concomitant medications 
noted above in order to enroll in the trial must be stable off therapy for at least 30 days before 
Screening. 
Subjects receiving antidepressant therapy must be on a stable dose for 8 weeks before Screening.  
Additionally, subjects switching or discontinuing SSRIs in order to enter the trial, must be stable 
on their new regimen for at least 8 weeks before Screening. 
The drugs listed above and other drugs which are known to cause QT prolongation (See 
Appendix12) should not be taken concomitantly with study medication.  A washout period of 
5 half-lives is recommended or other duration as approved by the Clinical Monitor. 


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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.   
6.9.2 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 ER may have additive effects 
and cause or worsen somnolence.  Until subjects are receiving a stable dose of SD-809 ER and 
understand how the drug affects them, alcohol should be used with caution.  
6.9.3 Other Restrictions 
Subjects should be advised to not drive a car or operate dangerous machinery until they 
understand how SD-809 ER affects them. 
Use of illicit drugs is prohibited from the time of signing of the Informed Consent Form or 
Assent and throughout study participation. 
6.10 Caregiver Responsibilities 
Each subject participating in the study must have a reliable caregiver.   The caregiver must 
interact on a daily 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.  Note: 
 Subjects with a TFC score of 5-7 at Screening must have a live-in caregiver. 
 Subjects with a TFC score of 5-7 at Screening or those who enrolled with the consent of 
an LAR, must have caregivers present at all study visits. 
 For subjects with a TFC score of 8-13 at Screening who did not require an LAR to 
provide informed consent, the caregiver must attend the following visits: Screening, 
Baseline, Weeks 4, 8, 15, 28 and visits every 13 weeks thereafter through the end of the 
Long Term Treatment Period.  Caregivers will be encouraged to attend other visits. 
The caregiver must also make him/herself available for telephone contacts in order to report 
chorea control and adverse events to determine whether dose adjustment of study drug will be 
made.  As subjects may have agnosia to chorea, telephone contacts should involve the subject 
and caregiver at the same time, if possible. 
6.11 Capacity Assessment 
In order to determine if a subject can provide informed consent to participate in the trial, an 
assessment of capacity must be made by a qualified healthcare provider who is not directly 
involved with other aspects of the study (e.g., cannot be the Site Investigator).  The qualified 
individual must be a health care professional with documented training and experience who has 
an established role for assessing capacity for treatment consent at the institution.  A written 
assessment verifying the subject has the capacity to provide consent must be maintained in the 
subject’s source documentation. 


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6.12 Research Advance Directive 
During the consenting process, subjects who have the capacity to provide informed consent will 
be required to provide a research advance directive specific for this trial and will expire when the 
subject completes participation.  A research advance directive will specify whether a subject 
wishes to continue participation in the study should he or she lose capacity.  In the event that a 
subject loses the capacity to provide consent during the course of the trial, it would allow the 
subject to continue participation, if so expressed (22, 23). 
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; 
 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 
Clinical 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 early termination 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 for safety reasons at any time in collaboration with the Sponsor. 
7 ADVERSE EVENTS 
Throughout the course of the study, all adverse events will be monitored and reported on an 


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adverse event case report form, 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 investigational product(s) can be found 
in the Investigator’s Brochure (IB) and will be included in the subject informed consent form. 
The Investigator and site staff are responsible for detection, recording and reporting of events 
that meet the criteria and definition of an AE or SAE (listed below). 
7.1 
Definitions 
7.1.1 Adverse Event 
An adverse event (AE) 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 AE 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 investigational product administration even 
though it may have been present prior to the start of the study. 
 Abnormal safety assessments if they lead to investigational product dose modification, 
investigational product 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 
investigational product or a concurrent medication. 
Examples of an AE do not include: 
 A medical or surgical procedure (e.g. endoscopy); a condition that leads to the procedure 
is an AE. 
 Situations where an untoward medical occurrence did not occur (social and/or 


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convenience admission to hospital) or scheduled elective procedures like cosmetic 
surgery are not AEs.  However, if the procedure results in an unexpected complication, 
the complication is an AE. 
 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 investigator brochure 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 investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure 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 investigator brochure 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 (SAE) 
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 AE 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 


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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 
o Social reasons and/or respite care in the absence of any deterioration of the 
subject’s general condition.   
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 AEs.  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 medication 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 AE rather than 
individual signs or symptoms.  Similarly, the unifying diagnosis should be recorded as the AE 
rather than the abnormal laboratory result (i.e. “anemia” instead of “low hemoglobin”).   
If the AE is a worsening of a past medical condition, the AE 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 (AEs) 
Collection of AEs 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 
AEs.  Adverse findings detected at the Screening visit (e.g., abnormalities on clinical laboratory 
testing, ECGs, physical/neuro 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 AE CRF and considered non-treatment emergent. 


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7.2.2 Recording of Serious Adverse Events (SAEs) 
Collection of SAEs 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 
SAEs.  Serious adverse events occurring after signing the informed consent form but before 
starting study treatment will be considered non-treatment emergent. 
If a new SAE comes to the attention of the Investigator after the completion of the final study 
visit, information regarding the SAE 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 SAE 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 SAE.  This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
SAEs that remain ongoing past the subject’s last protocol-specified follow-up visit will be 
evaluated by the Investigator and Sponsor. All SAEs 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 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 medication 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 


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The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study.  The assessment will be based on the Investigator’s clinical judgment.  The intensity of 
each AE and SAE recorded in the eCRF should be assigned to one of the following categories: 
 Mild:  
Awareness of sign or symptom that is easily tolerated. 
 Moderate: 
Sign or symptom intense enough to interfere with usual activity 
 Severe: 
Interferes significantly with ability to do work or usual activity 
An AE that is assessed as severe should not be confused with a SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.  
An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in 
“Definition of a SAE.” 
7.3.2 Relationship to Study Drug 
The Investigator is obligated to assess the relationship between study drug and the occurrence of 
each AE.  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 AE 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 investigational product should be considered and 
investigated, if appropriate. The Clinical Monitor’s opinion may be sought in those cases in 
which the Site Investigator is unable to make an independent judgment.  The Clinical 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 5.2.5 for guidance in contacting Clinical Monitor) 
 Drug permanently discontinued 
7.3.4 Treatment Required 
Treatment required as a result of an AE will be recorded in the subject’s source documents, and 
if medication is required, on the Concomitant medications log: 
 None 


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 Medication Required (record on Concomitant Medications eCRF) 
 Hospitalization Required 
 Other (specify) 
If a diagnosis has been entered as an AE, the treatment(s) recorded may represent the 
treatment(s) given for one or more sign(s) or symptoms(s) (e.g. Naproxen for the AE “fracture”, 
without recording “pain due to fracture” or “inflammation due to fracture” as separate AEs).   
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 
 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 Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) as required by the IRB/IEC, local regulations, and the governing health 
authorities. 
7.4.1 Completion and Transmission of the SAE Report 
Once an Investigator becomes aware that an SAE has occurred in a study subject, she/he will 
report the information to the Sponsor (or designee) within 24 hours.  The SAE 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 an SAE, 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 SAE 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 SAEs 
The Investigator must promptly report all SAEs to the Sponsor in accordance with the 
procedures describe above.  Prompt notification of SAEs by the Investigator to the appropriate 
project contact for SAE receipt is essential so that legal obligations and ethical responsibilities 


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towards the safety of other subjects are met.  The Investigator will be responsible for reporting 
SAEs to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) per local 
regulatory requirements.   
The Sponsor (or designee) is responsible for reporting serious adverse events (SAEs) to the 
relevant regulatory authorities in accordance with local regulations.  That is, SAEs 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 AE or SAE, any pregnancy complications should be recorded as AEs or 
SAEs.  Any pregnancy will be followed through its conclusion for observation of any SAEs 
including congenital anomalies/birth defects. 
 
8 STATISTICAL PROCEDURES AND DATA ANALYSIS 
This section describes the statistical analysis strategy and procedures for the study.  Summary 
statistics will be provided by treatment.  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 will be summarized descriptively in the Safety 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: 


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 Adverse events (AEs)  
 Clinical laboratory tests  
 Physical examination  
 Vital signs 
 12- lead ECGs  
 Epworth Sleepiness Scale 
(ESS) 
 Columbia Suicide Severity Rating Scale (C-SSRS)  
 Unified Huntington’s Disease Rating Scale (UHDRS)  
 Swallowing Disturbance Questionnaire (SDQ) 
 Unified Parkinson’s Disease Rating Scale (UPDRS), 
dysarthria item  
 Barnes Akathisia Rating Scale (BARS)  
 Hospital Anxiety and Depression Scale (HADS)  
 Montreal Cognitive Assessment (MoCA©) 
Safety data will be summarized descriptively for the overall population and based on prior 
treatment [SD-809 ER or placebo (Rollover subjects) or tetrabenazine (Switch subjects)].  
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 
for Rollover subjects will utilize the Baseline from Study SD-809-C-15 (C-15 Baseline) and the 
Baseline from the present study (C-16 Baseline), as appropriate, and will be specified in the 
Statistical Analysis Plan. 
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 
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: 
 Incidence of adverse events (AEs), serious AEs, severe AEs, drug related AEs, AEs leading 
to withdrawal during the following periods: 
 Overall 
 During titration in Rollover subjects (up to 8 weeks) 
 During dose adjustment in Switch subjects (up to 4 weeks)  
 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 > 450ms, > 480ms, > 500ms 
 Observed values and changes in UHDRS, UPDRS (dysarthria), BARS, HADS, ESS,           
C-SSRS, and MoCA©  
 Duration of time to achieve stable doing of SD-809 ER 
8.5 
Sample Size 


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Because this is an open label safety study, the sample size is not based on statistical 
considerations. 
8.6 
Pharmacokinetics 
A population pharmacokinetic analysis will be performed using data from all subjects switching 
from TBZ to SD-809 in this study together with data obtained from subjects in Study SD-809-C-
15 to examine the pharmacokinetics of SD-809 and TBZ and to explore the potential effect of 
various covariates on the pharmacokinetics of SD-809 and TBZ.  The population 
pharmacokinetic analysis will be discussed in detail in a prospective Statistical Analysis Plan. 
8.7 
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.  
Significant protocol deviations (e.g. inclusion/exclusion criteria) will be reported to the Sponsor 
and to the IRB/IEC in accordance with its reporting policy. 
8.8 
Data Recording 
Source data will be transcribed onto source document worksheets and will then be entered into 
an electronic Case Report Form (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. 
8.9 
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. 
8.10 Data Management 
The data will be entered into a validated FDA 21 CFR part 11 compliant database maintained by 
sponsor or designee. The data management group for the will be responsible for data processing, 
in accordance with agreed procedures. The Site 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 Site 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) Standard Operating Procedures 
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Complete details of data management will be described in a separate Data Management Plan. 
9 ADMINISTRATIVE ISSUES 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
regulations and guidelines including the International Conference on Harmonization Guideline 
on Good Clinical Practice. 
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 (IEC)/Institutional Review Board (IRB) 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 
typed 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 one 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 (as determined by an independent assessment by a 
qualified healthcare provider not directly involved in other study activities), a legally authorized 
representative 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 Site 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 Site 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 


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Form/Informed Consent Form to retain. 
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 International Conference on 
Harmonization (ICH) Good Clinical Practice (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 testing, will be destroyed after testing is complete 
in accordance with each laboratory’s standard procedures.  
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 Steering Committee and 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. 
9.3 
Records Retention 
Following closure of the study, the Site 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 


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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: Two 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 
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. 
9.4.1 Steering Committee 
A Steering Committee (SC) has been established to provide overall supervision of the study and 
ensure that it is being conducted in accordance with the principles of Good Clinical Practice 
(GCP), Huntington Study Group constitutional bylaws, and the relevant regulations.  The SC has 
reviewed the protocol, and will review and approve any protocol amendments, and provide 
advice to the investigators on the conduct of the trial.  The SC members include representatives 
from Auspex, a biostatistician, the study PI and Co-PI, an experienced HD study coordinator, a 
psychiatrist and a HD patient advocate. 
9.4.2 Clinical Monitoring 
The Clinical Monitor for the study will review safety data on a monthly basis during study 
conduct, including aggregate laboratory and adverse event data, and laboratory alert values.  The 
Clinical Monitor will review all Serious Adverse Events as they are reported.  In addition, the 
Clinical Monitor will:  Authorize enrollment based on review of eligibility information; approve 
enrollment of subjects with possible Gilbert’s syndrome or two or more abnormal liver tests.   
The investigative sites are to contact the Clinical Monitor to: 
 Review drug suspensions and dose reductions, according to the procedures outlined in 
Section 5.2.5;  
 Review all withdrawals from the study for medical reasons, as outlined in Section 6.14. 
9.5 
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 


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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. 
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 
1. 
Baillie TA. The use of stable isotopes in pharmacological research. Pharmacol Rev. 
1981;33(2):81-132. 
2. 
Guyton AC.  Textbook of Medical Physiology, 8th Ed. Philadelphia, PA: W.B. Saunders; 
1991. p. 274. 
3. 
Chang R. Chemistry, 9th Ed.: McGraw-Hill; 2007. 
4. 
Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy 
water and deuterated compounds. Can J Physiol Pharmacol. 1999;77(2):79-88. 
5. 
Di Costanzo L, Moulin M, Haertlein M, Meilleur F, Christianson DW. Expression, 
purification, assay, and crystal structure of perdeuterated human arginase I. Arch Biochem 
Biophys. 2007;465(1):82-9. 
6. 
Fisher SJ, Helliwell JR. An investigation into structural changes due to deuteration. Acta 
Crystallogr A. 2008;64(Pt 3):359-67. 
7. 
Blagojevic N, Storr G, Allen JB. Role of heavy water in boron neutron capture therapy. 
In: Zamenhof R, Solares G, Harling O, editors. Dosimetry and treatment planning for neutron 
capture therapy. Madison, WI1994. 
8. 
Collins ML, Eng S, Hoh R, Hellerstein MK. Measurement of mitochondrial DNA 
synthesis in vivo using a stable isotope-mass spectrometric technique. J Appl Physiol. 
2003;94(6):2203-11. 
9. 
Kassis AN, Jones PJ. Changes in cholesterol kinetics following sugar cane policosanol 
supplementation: a randomized control trial. Lipids Health Dis. 2008;7(1):17. 
10. 
Leitch CA, Jones PJ. Measurement of human lipogenesis using deuterium incorporation. 
J Lipid Res. 1993;34(1):157-63. 
11. 
Neese RA, Misell LM, Turner S, Chu A, Kim J, Cesar D, et al. 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. 2002;99(24):15345-50. 
12. 
Strawford A, Antelo F, Christiansen M, Hellerstein MK. Adipose tissue triglyceride 
turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. Am J 
Physiol Endocrinol Metab. 2004;286(4):E577-88. 
13. 
Hellerstein MK, Hoh RA, Hanley MB, Cesar D, Lee D, Neese RA, et al. Subpopulations 
of long-lived and short-lived T cells in advanced HIV-1 infection. The Journal of clinical 
investigation. 2003;112(6):956-66. 
14. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta psychiatrica 
Scandinavica. 1983;67(6):361-70. 
15. 
The Columbia Suicide Severity Rating Scale  [cited 2012 May 18]. Available from: 
http://www.cssrs.columbia.edu/about_cssrs.html. 
16. 
Guidance for Industry Suicidality: Prospective Assessment of Occurrence in Clinical 
Trials, DRAFT GUIDANCE. September 2010. 
17. 
Huntington-Study-Group. Unified Huntington disease rating scale: reliability and 
consistency. Mov Disord. 1996;11:136-42. 


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18. 
Barnes TR. A rating scale for drug-induced akathisia. The British journal of psychiatry : 
the journal of mental science. 1989;154:672-6. 
19. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness 
scale. Sleep. 1991;14(6):540-5. 
20. 
Manor Y, Giladi N, Cohen A, Fliss DM, Cohen JT. Validation of a swallowing 
disturbance questionnaire for detecting dysphagia in patients with Parkinson's disease. Mov 
Disord. 2007;22(13):1917-21. 
21. 
Cohen JT, Manor Y. Swallowing disturbance questionnaire for detecting dysphagia. The 
Laryngoscope. 2011;121(7):1383-7. 
22. 
Stocking CB, Hougham GW, Danner DD, Patterson MB, Whitehouse PJ, Sachs GA. 
Speaking of research advance directives: planning for future research participation. Neurology. 
2006;66(9):1361-6. 
23. 
Commission NBA. Research involving persons with mental disorders that may affect 
decision-making capacity. Vol. 2. Commissioned Papers. Rockville, MD: US Government 
Printing Office; 1999. 
 
 
 
 


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12 APPENDICES 
 
 


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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 this protocol in its entirety and I agree to all aspects. 
 
Principal Investigator: 
 
 
Print Name 
 
 
 
 
 
 
Signature 
 
Date 
 


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Appendix 2: Unified Huntington’s Disease Rating Scale (UHDRS) 
 
































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Appendix 3: Hospital Anxiety and Depression Scale (HADS) 




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Appendix 4: Columbia Suicidality Severity Rating Scale (C-SSRS) – Baseline 








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Appendix 5: Columbia Suicidality Severity Rating Scale (C-SSRS) – Since Last Visit 








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Appendix 6: Unified Parkinson’s Disease Rating Scale (UPDRS): Speech 
Fahn S, Elton RL, Members of the UPDRS Development Committee. The Unified Parkinson’s Disease Rating 
Scale. In Fahn S, Marsden CD, Calne DB, Goldstein M, eds. Recent developments in Parkinson’s disease, vol 2. 
Florham Park, NJ: Macmillan Health Care Information, 1987:153-163, 293-304 


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Appendix 7: Montreal Cognitive Assessment (MoCA©) 








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Appendix 8: Epworth Sleepiness Scale (ESS) 




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Appendix 9: Barnes Akathisia Rating Scale (BARS) 




Citation:  Barnes TR: A Rating Scale for Drug-Induced Akathisia.  British Journal of Psychiatry 154:672-676, 
 1989. 


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Appendix 10: Swallowing Disturbance Questionnaire (SDQ) 




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Appendix 11: Strong CYP2D6 Inhibitors 
Subject’s receiving any of these strong CYP2D6 inhibitors will have a maximal dose of SD-809 
ER of 42 mg per day. 

Bupropion

Fluoxetine

Paroxetine


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Appendix 12: Prohibited or restricted QT Prolonging Drugs 
Generic 
Brand Name 
Class/Clinical Use 
Note 
Amiodarone 
Cordarone®, 
Pacerone® 
Anti-arrhythmic / abnormal heart rhythm 
Arsenic trioxide Trisenox® 
Anti-cancer / Leukemia 
Azithromycin 
Zithromax® 
Antibiotic / bacterial infection 
Bepridil 
Vascor® 
Anti-anginal / heart pain 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Chlorpromazine Thorazine® 
Anti-psychotic/ Anti-emetic / 
schizophrenia 
Citalopram 
Celexa® 
Anti-depressant / depression 
 See Appendix 16 
for dosing 
information 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
Disopyramide 
Norpace® 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Anti-arrhythmic / abnormal heart rhythm 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Not available in 
U.S. 
Droperidol 
Inapsine® 
Sedative;Anti-nausea/anesthesia adjunct, 
nausea 
Erythromycin 
E.E.S.®, Erythrocin® 
Antibiotic; GI stimulant; GI motility 
Escitalopram 
Lexapro®, Cipralex® 
Anti-depressant / Anxiety disorders 
See Appendix 16 
for dosing 
information 
Flecainide 
Tambocor® 
Anti-arrhythmic / abnormal heart rhythm 
Halofantrine 
Halfan® 
Anti-malarial / malaria infection 
Haloperidol 
Haldol® 
Anti-psychotic / schizophrenia, agitation 
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart rhythm 
Levomethadyl 
Orlaam® 
Opiate agonist/pain control, narcotic 
dependence 
Not available in 
U.S. 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
Methadone 
Dolophine® 
Opiate agonist/pain control, narcotic 
dependence 
Methadone 
Methadose® 
Opiate agonist/pain control, narcotic 
dependence 
Moxifloxacin 
Avelox® 
Antibiotic / bacterial infection 
Pentamidine 
NebuPent®, Pentam® 
Anti-infective / pneumocystis pneumonia 
Pimozide 
Orap® 
Anti-psychotic / Tourette's tics 
Probucol 
Lorelco® 
Antilipemic / Hypercholesterolemia 
Not available in 
U.S. 
Procainamide 
Pronestyl®, Procan® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Quinaglute,Cardioquin Anti-arrhythmic / abnormal heart rhythm 
Quetiapine 
Seroquel®, Seroquel 
XR® 
Anti-psychotic / schizophrenia 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general / anesthesia 
Sotalol 
Betapace® 
Anti-arrhythmic / abnormal heart rhythm 
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection 
Not available in 
U.S. 
Thioridazine 
Mellaril® 
Anti-psychotic / schizophrenia 


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Vandetanib 
Caprelsa® 
Anti-cancer / Thyroid cancer 
Vardenafil 
Levitra® 
Phosphodiesterase inhibitor / vasodilator 
Appendix 13: Prohibited Antipsychotic Drugs 
Typical/First Generation Antipsychotics 
Atypical/Second Generation Antipsychotics 
Chlorpromazine (Thorazine, Largactil) 
Aripiprazole (Abilify) 
Fluphenazine (Prolixin) 
Asenapine Maleate (Saphris) 
Haloperidol (Haldol, Serenace) 
Clozapine (Clozaril) 
Loxapine (Loxapac, Loxitane) 
Iloperidone (Fanapt) 
Molindone (Moban) 
Lurasidone (Latuda) 
Perphenazine (Trilafon) 
Olanzapine (Zyprexa) 
Pimozide (Orap) 
Olanzapine/Fluoxetine (Symbyax) 
Prochlorperazine (Compazine) 
Paliperidone (Invega) 
Thioridazine (Mellaril) 
Quetiapine (Seroquel) 
Thiothixene (Navane) 
Risperidone (Risperdal) 
Trifluoperazine (Stelazine) 
Ziprasidone (Geodon) 
Promethazine (Phenergan) containing 
compounds 


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Appendix 14:  Simulated Exposures of Total (α+β)-HTBZ for Tetrabenazine and 
SD-809 
Comparison of Simulated Exposures (AUC0-24) of Total (α+β)-HTBZ for Tetrabenazine 
(pink) and SD-809 ER (blue) at Steady State for Various Dose Regimens in CYP2D6 
Extensive/Intermediate Metabolizers 
Note: Box plots represent 25/50(median)/75th percentiles and whiskers represent 95% CI 
Dose information on x-axis: SD-809 ER (blue text) is dose regimen and TBZ (red text) is total daily dose 


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Appendix 15:  Simulated Exposures (AUC24) of Total (α+β)-HTBZ for Initial SD-809 
Regimens at Steady State in CYP2D6 Poor Metabolizers 
Scenarios 
Treatment 
Total daily 
dose 
Regimens 
AUC24SS (h•ng/mL) 
1 
TBZ 
25 mg 
12.5 mg BID 
1510 
[819-2943] 
SD-809 
12 mg 
6 mg BID 
1061 
[635-2034] 
2 
TBZ 
37.5 mg 
12.5 mg TID 
25/12.5 
12.5/25 
2750 
[1499-5326] 
2768 
[1563-5250] 
SD-809 
18 mg 
12/6 mg 
1740 
[1058-3105] 
3 
TBZ 
50 mg 
25 mg BID 
25/12.5/12.5 
12.5/25/12.5 
12.5/12.5/25 
4200 
[2296-8155] 
4228 
[2394-8030] 
SD-809 
24 mg 
12 mg BID 
2435 
[1451-4723] 


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Appendix 16: Celexa and Lexapro (Cipralex) 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 

SAP_001.pdf: 
Statistical Analysis Plan
An Open-Label, Long Term Safety Study of SD-809 ER in Subjects with Chorea 
Associated with Huntington Disease
Study SD-809-C-16
NCT01897896
Date: 15 September 2017


Protocol SD-809-C-16 
    Teva Pharmaceuticals, Inc. 
Page 1 of 37 
STATISTICAL ANALYSIS PLAN 
Protocol SD-809-C-16 
An Open-Label, Long Term Safety Study 
of SD-809 ER in Subjects with Chorea 
Associated with Huntington Disease 
Final Clinical Study Report 
15 September 2017
Prepared for 
Teva Pharmaceuticals, Inc.  
3333 N. Torrey Pines Court, Suite 400 
La Jolla, CA 92037 
Prepared by 
 
 
Biostatistical Consulting Inc. 
91 Hartwell Avenue 
Lexington, MA 02421 


 
                                                                                                       
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
                                    
 
 
 
 
 
                                         
 
 
 
 
 
 
 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
 
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TABLE OF CONTENTS  
APPENDIX 1: INTERIM ANALYSIS ...........................................................................4 
LIST OF TABLES ............................................................................................................5 
1 
INTRODUCTION.....................................................................................................8 
2 
PURPOSE OF THE ANALYSES............................................................................8 
3 
STUDY OBJECTIVES .............................................................................................8 
4 
STUDY DESIGN .......................................................................................................8 
5 
DATA MANAGEMENT ........................................................................................18 
6 
DEFINITION OF POPULATION ........................................................................18 
7 
ENDPOINTS AND RATING SCALES ................................................................18 
7.1 
Efficacy Endpoints ......................................................................................... 18 
7.2 
Safety Endpoints ............................................................................................ 18 
7.3 
Rating Scales ................................................................................................... 19 
7.3.1 
Hospital Anxiety and Depression Scale (HADS) ........................................19 
7.3.2 
Columbia Suicide Severity Rating Scale (C-SSRS) ....................................19 
7.3.3 
Unified Huntington Disease Rating Scale (UHDRS) ..................................19 
7.3.4 
Montreal Cognitive Assessment (MoCA©) .................................................20 
7.3.5 
Unified Parkinson Disease Rating Scale (UPDRS) ....................................20 
7.3.6 
Barnes Akathisia Rating Scale (BARS) ......................................................20 
7.3.7 
Epworth Sleepiness Scale (ESS) .................................................................20 
7.3.8 
Swallowing Disturbance Questionnaire (SDQ) ..........................................20 
8 
STATISTICAL METHODS ..................................................................................20 
8.1 
Hypothesis Testing ......................................................................................... 20 
8.2 
Sample Size ..................................................................................................... 21 
8.3 
Subject Withdrawal ....................................................................................... 21 
8.4 
Final Analyses and Reporting ....................................................................... 21 
8.5 
Handling of Missing Data .............................................................................. 21 
8.5.1 
Missing Data for Individual Items of an Instrument ...................................21 
8.5.2 
Missing Endpoint Data ................................................................................21 


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8.6 
Interim Analysis ............................................................................................. 22 
8.7 
Comments on Statistical Analysis ................................................................. 22 
8.8 
Time Periods for Analyses ............................................................................. 23 
8.9 
Visit Windows ................................................................................................. 23 
8.10 
Changes to Protocol-Specified Analyses ...................................................... 24 
9 
STATISTICAL ANALYSES .................................................................................25 
9.1 
Subject Disposition ......................................................................................... 25 
9.2 
Demographic and Baseline Characteristics ................................................. 25 
9.3 
Medical History .............................................................................................. 25 
9.4 
Concomitant Medications ............................................................................. 26 
9.5 
Study Drug Exposure and Compliance ........................................................ 26 
9.6 
Protocol Deviations ........................................................................................ 27 
9.7 
Efficacy Analyses ........................................................................................... 27 
9.9 
Safety Analyses ............................................................................................... 28 
9.9.1 
Adverse Events ............................................................................................28 
9.9.2 
Vital Signs and Weight ................................................................................30 
9.9.3 
Orthostatic Vital Signs ................................................................................31 
9.9.4 
Physical and Neurological Examinations ....................................................31 
9.9.5 
Electrocardiogram (ECG) ............................................................................31 
9.9.6 
Clinical Laboratory Assessments ................................................................32 
9.9.7 
Other Safety Assessments ...........................................................................33 
9.10 
Pharmacokinetic Assessments ...................................................................... 35 
10 REFERENCES ........................................................................................................36 
APPENDIX 1: Interim Analysis 
 
 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
 
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LIST OF TABLES 
TABLE 1: SCHEDULE OF EVENTS A – SUBJECTS SWITCHING FROM 
TETRABENAZINE ...........................................................................11 
TABLE 2: SCHEDULE OF EVENTS B – SUBJECTS ROLLING OVER FROM SD-
809-C-15 ..............................................................................................15 
TABLE 3: VISIT WINDOW .........................................................................................24 
TABLE 4: CLINICAL LABORATORY TESTS ........................................................33 


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GLOSSARY OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
ARC-HD 
Study SD-809-C-16 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body Mass Index 
CAG 
Cytosine Adenine Guanine 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESS 
Epworth Sleepiness Scale 
ET 
Early Termination 
FDA 
Food and Drug Administration 
First-HD 
Study SD-809-C-15 
HADS 
Hospital Anxiety and Depression Scale 
HD 
Huntington’s Disease 
HDBZ 
Dihydrodeutetrabenazine 
HSG 
Huntington Study Group 
HTBZ 
Dihydrotetrabenzine 
ICH 
International Conference on Harmonization 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA© 
Montreal Cognitive Assessment 
NDA 
New Drug Application 
PK 
Pharmacokinetic 
PR 
PR interval - measured from the beginning of the P wave to the 
beginning of the QRS complex 
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 


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Abbreviation 
Definition 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDQ 
Swallowing Disturbance Questionnaire 
SOC 
System Organ Class 
TBZ 
Tetrabenazine 
TEAE 
Treatment-Emergent Adverse Event 
TFC 
Total Functional Capacity 
TMC 
Total Maximal Chorea score 
UHDRS 
Unified Huntington Disease Rating Scale 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
WHODRUG 
World Health Organization drug dictionary 
 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be performed 
for the analysis of data from Protocol SD-809-C-16, “An Open-Label, Long Term Safety Study 
of SD-809 ER in Subjects with Chorea Associated with Huntington Disease.”  All of the 
analyses specified in this SAP will be included in the final Clinical Study Report (CSR). 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): Guidance on Statistical 
Principles in Clinical Trials.  The following documents were reviewed in preparation of this 
SAP: 
 Final Clinical Protocol SD-809-C-16, Amendment 03, issued 02 March 2015 
 Case report forms (CRFs) for Protocol SD-809-C-16, issued 18 January, 2017  
Throughout this SAP, SD-809 extended release will be denoted simply as SD-809.  
2 
Purpose of the Analyses 
The purpose of this SAP is to outline the planned analyses to be completed to support the final 
Clinical Study Report (CSR) for Protocol SD-809-C-16.  The planned analyses identified in this 
SAP will be included in regulatory submissions and/or future manuscripts.  Also, exploratory 
analyses not necessarily identified in this SAP may be performed to support the clinical 
development program.  Any post-hoc or unplanned analyses not identified in this SAP will be 
clearly identified in the CSR. 
3 
Study Objectives 
The objectives of this study are as follows:  
 Evaluate the safety and tolerability of titration and maintenance therapy with SD-809 
 Evaluate the safety and tolerability of switching subjects from tetrabenazine to SD-809  
 Evaluate the pharmacokinetics of tetrabenazine, SD-809 and their respective α- and β- 
metabolites in subjects switching from tetrabenazine to SD-809 
4 
Study Design 
This is an open-label, single-arm study in which subjects with manifest Huntington’s disease 
(HD) who are receiving FDA-approved doses of tetrabenazine (TBZ) for the treatment of chorea 
associated with HD or have successfully completed the SD-809-C-15 efficacy study will be 
invited to participate.  Successful completion of Study SD-809-C-15 is defined as (1) study 
participation through Week 13, (2) the subject has generally been compliant with study drug and 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
 
Page 9 of 37 
 
procedures, in the opinion of the Investigator, and (3) the subject has no ongoing adverse events 
that are serious (SAE), severe in intensity or are expected to interfere with safety evaluations in 
this study.  Two groups of subjects will be enrolled into this trial:  
Switch subjects are those subjects who are currently receiving stable doses of TBZ for treatment 
of chorea associated with HD and convert to SD-809 based on an algorithm designed to achieve 
comparable exposure to total (α+β)-dihydrotetrabenazine (HTBZ) and (α+β)-
dihydrodeutetrabenzine (HDBZ) metabolites. 
Rollover subjects are those subjects who have successfully completed Study SD-809-C-15 and 
continue on long-term SD-809 after a 1-week washout period. 
Subjects Switching from Tetrabenazine (Switch):  Subjects who are currently receiving an 
FDA-approved dose of TBZ that is providing a therapeutic benefit for control of chorea 
associated with HD will be eligible to participate in the study.  These subjects will be converted 
from their TBZ regimen to an SD-809 regimen that is predicted to provide comparable exposure 
to total (α+β)-HTBZ and (α+β)-HDBZ.  Subjects will continue taking their TBZ regimen 
through midnight at the end of Day 0 and then switch to their assigned SD-809 regimen the next 
morning.  The dose of SD-809 may be adjusted weekly (upward or downward) in increments of 
6 mg per day (each week) (6 mg/day or up to 12 mg/day after a total daily dose of 48 mg is 
reached), until there is adequate control of chorea, the subject experiences a protocol defined 
“clinically significant” adverse event (defined as related to study medication and either a) is 
moderate or severe in intensity or b) meets the criteria for a Serious Adverse Event [SAE]), or 
the maximal allowable dose (72 mg) 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.  The Investigator, in consultation with the subject and caregiver, will 
determine when an adequate level of chorea control has been achieved.  Although subjects will 
enter the long-term treatment period after Week 2, dose adjustment (upward or downward) may 
continue through Week 4 to optimize dose level.  If clinically indicated, additional dose 
adjustments may be made after Week 4. 
Subjects Enrolled from the SD-809-C-15 Study (Rollover):  Subjects who have successfully 
completed Study SD-809-C-15 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-15.  To 
reduce subject burden, the Week 13 evaluation will provide some Baseline data for the present 
study.  Additional evaluations required as part of the SD-809-C-16 study may be completed on 
the same day as the Week 13 visit of the SD-809-C-15 study after SD-809-C-16 informed 
consent/assent is obtained.  If subjects are unable to enroll at the Week 13 visit they will have up 
to 3 weeks to complete the additional evaluations for Baseline or the subject will not be eligible 
to enroll in this study.  In addition, following informed consent/assent, prior data from Study SD-
809-C-15 can be used in this study as part of the subject’s medical history information.      


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
 
Page 10 of 37 
 
As Rollover subjects will have discontinued study drug (SD-809 or placebo) for at least 1 week 
at completion of the SD-809-C-15 study, they will undergo titration on SD-809.  During titration, 
the Investigator, in consultation with the subject and caregiver, will determine when an adequate 
level of chorea control has been achieved.  The dose of SD-809 may be adjusted (upward or 
downward), in increments of 6 mg per day (each week) (6 mg/day or up to 12 mg/day after a 
total daily dose of 48 mg is reached), until there is adequate control of chorea, the subject 
experiences a protocol defined “clinically significant” adverse event, as outlined above, 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.  Although subjects will enter the long-term treatment period after Week 2, titration 
may occur through Week 8 to optimize dose level.  Additional dose adjustments may be made 
after Week 8 if clinically indicated.  
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.  Dose adjustments should be 
based on all available information including the subject's and caregiver's reports of adverse 
events and chorea control, information from rating scales, and all safety evaluations.  The Long-
Term Treatment Period will continue until SD-809 becomes commercially available in the U.S. 
Post-Treatment Safety Follow Up:  All subjects will discontinue study drug at the End of 
Treatment visit and return for their final clinic visit one week later for evaluation of safety, 
cognition, behavior, chorea, 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 four weeks after their last dose of study drug, to evaluate adverse events and 
concomitant medication usage. 
PK Sub-Study (Switch subjects only):  A sub-study will be conducted to evaluate the 
pharmacokinetics (PK) of TBZ and SD-809 in Switch subjects.  Approximately 12 subjects will 
have rich PK sampling and approximately 24 subjects will have sparse PK sampling.  The PK of 
TBZ and metabolites will be assessed at the Baseline visit, and the PK of SD-809 and 
metabolites will be assessed at the Week 8 visit.  If a subject requires a dose change at Week 8, 
the Week 8 visit assessments should be conducted except for PK sampling, which should be 
postponed until Week 15.  
 
Table 1 contains the schedule of events for Switch subjects, and Table 2 contains the schedule of 
events for Rollover subjects. 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 11 of 37 
 
Table 1: SCHEDULE OF EVENTS A – SUBJECTS SWITCHING FROM TETRABENAZINE 
 
Screening 
 
Long Term Treatment 
Follow up 
Unscheduled 
Dose Adjustment 
 
 
Study Week→ 
Up to -4 
-1 
Baseline
1 
1 
2 
3 
4 
7 
8 
15 
28 
28 + q13 
wks 
End of 
Treatment 
1 wk FU 4 wk FU
 
 
Visit Window (days)  → 
 
± 3 
0 
± 1 
 
± 3 
n/a 
Visit →   Screenin
g 
T1 
V1 
V2 
T2 
T3 
V3 
T4 
V4 
V5 
V6 
Vx17 
End Tx/ET 
FU 
FFU 
UV18 
UT
C 
Activity Visit type → 
V 
TC 
V 
V 
TC 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
Evaluate/Adjust Dose  
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X3 
Evaluate Capacity for 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Subject ID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Unique ID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Advance 
Directive** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selection Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight 
X 
 
X2 
X 
 
 
X 
 
X2 
X 
X 
X 
X2 
X 
 
X 
 
Physical Examination 
X4 
 
X 
 
 
 
 
 
 
 
X4 
 
X 
 
 
 
 
Complete Neurological 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X16 
 
 
X16 
 
X 
 
 
 
X 
 
 
 
 
Blood sampling for PK 
 
 
X12 
 
 
 
 
 
X13 
 
 
 
X5 
 
 
X5 
 
Provide/Remind/Review 
diary Card for meal/dosing 
times 
X9 
X9 
X11 
 
 
 
X10 
X10 
X11 
 
 
 
 
 
 
 
 
Chemistry/Hematology/UA 
X* 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
CAG Repeat 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded CYP2D6 Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Screen (HBsAg) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test/FSH6 
S 
 
U 
 
 
 
 
 
 
 
U 
U 
U 
 
 
 
 
HADS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
C-SSRS7 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
MoCA© 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Motor 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
UHDRS - Cognitive 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Behavior 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Functional 
Assessment 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS - Independence 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS - TFC 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
UHDRS - Summary 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UPDRS -  Dysarthria 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
SDQ 
X 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 12 of 37 
 
 
Screening 
 
Long Term Treatment 
Follow up 
Unscheduled 
Dose Adjustment 
 
 
Study Week→ 
Up to -4 
-1 
Baseline
1 
1 
2 
3 
4 
7 
8 
15 
28 
28 + q13 
wks 
End of 
Treatment 
1 wk FU 4 wk FU
 
 
Visit Window (days)  → 
 
± 3 
0 
± 1 
 
± 3 
n/a 
Visit →   Screenin
g 
T1 
V1 
V2 
T2 
T3 
V3 
T4 
V4 
V5 
V6 
Vx17 
End Tx/ET 
FU 
FFU 
UV18 
UT
C 
Activity Visit type → 
V 
TC 
V 
V 
TC 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
BARS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
ESS 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/Order Study Drug8 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
X3 
Drug Acct/Compliance 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Assess Adverse Events 
 
 
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 
Administer TBZ or SD-809 
ER   
 
 
X14 
 
 
 
 
 
X15 
 
 
 
 
 
 
 
 
Evaluate Chorea Control 
(subject/caregiver) 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Return Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 13 of 37 
 
SCHEDULE OF EVENTS KEY SUBJECTS SWITCHING FROM TETRABENAZINE 
[V]  
Clinic Visit 
[TC]  
Telephone Contact 
[ET]   
Early Termination Visit 
 
[FU]  
Follow Up Visit one week after end of treatment 
[FFU] 
Final Follow Up Visit four weeks after end of treatment 
[S]  
Serum pregnancy test for women of childbearing potential only 
[U]  
Urine pregnancy test for women of childbearing potential only 
 
*     Screening labs to include Prothrombin Time (PT) with INR 
**   Subjects who have the capacity to provide informed consent only (See Section 6.12 of the protocol) 
1    Baseline visit (Day 0) will occur on the day before the scheduled first dose of SD-809 ER (Day 1) 
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    Subjects who withdraw early from the study should have a single blood sample collected for PK at the Early Termination Visit if the last dose was within the prior 
48 hours, if possible. Subjects who experience an SAE should have a single blood sample collected for metabolites of SD-809 within 48 hours of SAE, if possible 
6    Serum follicle stimulating hormone (FSH) level to be assessed in post-menopausal females only (at Screening only). 
7    At Screening, administer the C-SSRS Baseline version.  At Baseline and every visit thereafter, administer the C-SSRS Since Last Visit version. 
8    Study medication supply will be ordered. (See Operations Manual for further details).  
9    Provide Diary Card to record meals and tetrabenazine dosing times for upcoming PK sampling day.  Subjects should be reminded approx. 7 days before next 
scheduled visit to complete diary card. Subjects in the “Rich” cohort and “Sparse” cohort, scheduled for a morning visit, will be reminded to hold dose of 
tetrabenazine on the day of their Baseline visit. Subjects in the “Sparse” cohort, scheduled for an afternoon visit, will be reminded to take their usual dose(s) of 
tetrabenazine at home per their usual schedule on the day of their Baseline visit. 
10    Provide diary card to record the start time of the subject’s last meal and the time of their last dose of SD-809 ER prior to the Week 8 visit and ask the subject to 
bring the diary card with them to the next clinic visit. Subjects should be reminded approx. 7 days before next scheduled visit to complete diary card.  Subjects in 
the “Rich” cohort and “Sparse” cohort, scheduled for a morning visit, will be reminded to hold dose of SD-809 ER on the day of their Week 8 visit. Subjects in the 
“Sparse” cohort, scheduled for an afternoon visit, will be reminded to take their usual dose(s) of SD-809 ER at home per their usual schedule on the day of their 
Week 8 visit. 
11    Collect and review diary card 
12    PK blood sample for tetrabenazine and metabolites 
13    PK blood sample for SD-809 and metabolites.  If subject requires a dose change at Week 8, PK sampling should be postponed until Week 15. 
14    Administer tetrabenazine in clinic if subject scheduled for morning visit. If subject is scheduled for afternoon visit, they will take their usual dose of tetrabenazine at 
home.  
15    Administer SD-809 ER in clinic if subject scheduled for morning visit. If subject is scheduled for afternoon visit, they will take their usual dose of SD-809 ER at 
home. 
16    For subjects on allowed doses of citalopram or escitalopram: 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 14 of 37 
 
 
Week 1: A 12-lead ECG is required at this visit. 
 
Week 4: If the dose of study drug has been increased since the last ECG, a 12-lead ECG is required at this visit. 
17 After Week 28, perform clinic visits every 13 weeks until the End of Treatment Visit.  Obtain safety labs and urine pregnancy test every 26 weeks after Week 28, 
and perform UHDRS-TFC every 52 weeks after Week 28. 
18   For subjects requiring an Unscheduled Clinic Visit for any reason, assessments denoted with X should be performed; all other assessments are as indicated at  
       Investigator’s discretion (see Section 6.5 of the protocol). 
 
 
 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 15 of 37 
 
Table 2: SCHEDULE OF EVENTS B – SUBJECTS ROLLING OVER FROM SD-809-C-15 
 
 
Screening 
                 
Long Term Treatment 
Follow up 
Unscheduled 
Titration Period 
 
Study Week →   
 
Baseline‡ 
1 
2 
3 
4 
5 
8 
15 
28 
28 + 
q13 wks 
End of 
Treatment 
1 wk 
FU 
4 wk FU
 
 
Visit Window (days)  → 
 
 +3 
± 1  
 
± 3 
n/a 
                                            
Visit  → 
Prior Data 
from  
Study C-15† 
V1 
T1 
V2 
T2 
V3 
T3 
V4 
V5 
V6 
Vx9 
End Tx/ET 
FU 
FFU 
UV10 
UTC 
Activity Visit type  → 
 
V 
TC 
V 
TC 
V 
TC 
V 
V 
V 
V 
V 
V 
TC 
V 
TC 
Evaluate/Adjust Dose   
 
 
X 
X 
X 
X 
X 
X  
 
 
 
 
 
 
X 
X3 
Evaluate Capacity for 
consent 
 
 X§# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
 
X§ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Advance 
Directive†† 
 
X§ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selection Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Update Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs/Weight 
 
** 
 
X 
 
X 
 
X2 
X 
X 
X 
X2 
X 
 
X 
 
Physical Examination 
* 
 
 
 
 
 
 
 
 
X4 
 
X 
 
 
 
 
Complete Neurological 
Exam 
* 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
* 
 
 
X8 
 
X8 
 
X 
 
 
 
X 
 
 
 
 
Blood sampling for PK 
 
 
 
 
 
 
 
  
 
 
 
X7 
 
 
X7 
 
Chemistry/Hematology/UA 
* 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
CAG Repeat1 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded CYP2D6 Genotype1 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
U 
 
 
 
 
 
 
 
U 
U 
U 
 
 
 
 
HADS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
C-SSRS5 
 
** 
 
X  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
MoCA© 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Motor 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
UHDRS – Cognitive 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS – Behavior 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
UHDRS - Functional 
Assessment 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS – Independence 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UHDRS – TFC 
* 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
UHDRS - Summary 
* 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
UPDRS - Dysarthria 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
SDQ 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
BARS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
ESS 
 
** 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 16 of 37 
 
Dispense/Order Study Drug6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X3 
Drug 
Accountability/Compliance 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Assess Adverse Events 
* 
 
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 
Evaluate Chorea Control 
(subject/caregiver) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Return Study Drug 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


Protocol SD-809-C-16                                                                                                                   Teva Pharmaceuticals, Inc.                                                                                                    
 
 
 
Page 17 of 37 
 
SCHEDULE OF EVENTS KEY – SUBJECTS ROLLING OVER FROM SD-809-C-15 
 
[V]  
Clinic Visit 
[TC]  
Telephone Contact 
[ET]   
Early Termination Visit 
 
[FU]  
Follow Up Visit one week after end of treatment 
[FFU] 
Final Follow Up Visit four weeks after end of treatment 
 [U]  
Urine pregnancy test for women of childbearing potential only 
 
† 
After Informed Consent is obtained, data from Study SD-809-C-15 will be utilized in this study as part of screening information as detailed in the informed 
consent/assent. 
††  
Subjects who have the capacity to provide informed consent only (See Section 6.12 of the protocol)  
‡ 
Data from the Week 13 evaluation of Study SD-809-C-15 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 
# 
For subjects who were determined to have the capacity to provide informed consent in Study SD-809-C-15. 
* 
Data (Week 12 or earlier) from Study SD-809-C-15 will be utilized in this study as part of screening information.  
** 
Data (Week 13) from Study SD-809-C-15 will be utilized 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 Study SD-809-C-15 
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 for Rollover subjects 
6    Study medication supply will be ordered (See Operations Manual for further details). 
7    Subjects who withdraw early from the study should have a single blood sample collected for PK at the Early Termination Visit if the last dose was within the prior 
48 hours, if possible. Subjects who experience an SAE should have a single blood sample collected for metabolites of SD-809 within 48 hours of SAE, if possible. 
8    For subjects on allowed doses of citalopram or escitalopram: 
 
Week 2: A 12-lead ECG is required at this visit. 
 
Week 4: If the dose of study drug has been increased since the last ECG, a 12-lead ECG is required at this visit. 
9 
After Week 28, perform clinic visits every 13 weeks until the End of Treatment Visit.  Obtain safety labs and urine pregnancy test every 26 weeks after Week 28, 
and perform UHDRS-TFC every 52 weeks after Week 28. 
10 For subjects requiring an Unscheduled Clinic Visit for any reason, assessments denoted with X should be performed; all other assessments are as indicated at 
Investigator’s discretion (see Section 6.5 of the protocol). 
 
 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 18 of 37 
 
5 
Data Management 
Complete details of data management will be described in a separate Data Management Plan. 
6 
Definition of Population 
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 CSR.   
Unless specified otherwise, all data will be summarized for the Safety Population.  In addition, 
two subsets of the Safety Population are defined: 
 Rollover Cohort:  Successfully completed SD-809-C-15 (First-HD) prior to enrollment 
into SD-809-C-16 (ARC-HD) 
 Switch Cohort:  Switched from TBZ to SD-809 for enrollment in SD-809-C-16 (ARC-
HD) 
7 
Endpoints and Rating Scales 
7.1 
Efficacy Endpoints 
The changes from baseline (see sec. 8.7) and from week 8 in total maximal chorea score and 
total motor score from the UHDRS motor assessment are the efficacy endpoints for this study. 
7.2 
Safety Endpoints 
Safety and tolerability will be assessed throughout the study by monitoring the following: 
 Incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, drug-related AEs, 
and AEs leading to withdrawal during the following periods: 
o The entire post-baseline period 
o During the Titration Period (from Day 1 to the end of Week 8) in Rollover subjects 
o During the Dose-Adjustment Period (from Day 1 to the end of Week 4) in Switch 
subjects 
o During the Extended Dose-Adjustment Period (from Day 1 to the end of Week 8) in 
Switch subjects who undergo dose adjustment between Weeks 4 and 8 (if at least 
10% of Switch subjects have had a dose adjustment between Week 4 and Week 8)  
o During the Stable-Dose Period (Week 8 to end of study) 
 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 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 19 of 37 
 
 Numbers of subjects with QTcF values > 450 msec, > 480 msec, > 500 msec 
 Counts and percentages for Columbia Suicide Severity Rating Scale (C-SSRS) 
 Observed values and changes from baseline in the following: 
o Unified Huntington Disease Rating Scale (UHDRS) 
o Unified Parkinson’s Disease Rating Scale (UPDRS) (dysarthria) 
o Barnes Akathisia Rating Scale (BARS) 
o Hospital Anxiety and Depression Scale (HADS) 
o Epworth Sleepiness Scale (ESS) 
o Montreal Cognitive Assessment (MoCA©)    
o Swallowing Disturbance Questionnaire (SDQ) 
 Duration of time to achieve a stable dose of SD-809, defined as the number of days from 
Day 1 until the first day at which the subject was taking the dose level they were 
receiving at Week 8. 
7.3 
Rating Scales 
7.3.1 
Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-administered instrument reliable for detecting states of depression and 
anxiety in an outpatient medical setting.  The scale consists of 14 items (7 each for anxiety and 
depression).  Each item is rated on a four-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. 
7.3.2 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an FDA endorsed questionnaire to screen for suicidality in trials of central 
nervous system active compounds.  The C-SSRS is an interview by trained study personnel that 
should be done at Screening, Baseline (Day 0), and during the study as outlined in the Schedule 
of Events.  The form provided at Screening collects the history of suicide using a C-SSRS form 
version termed “Baseline”, and subsequent visits use a C-SSRS form version termed “Since the 
Last Visit.” 
7.3.3 
Unified Huntington Disease Rating Scale (UHDRS) 
The UHDRS is a research tool which has been developed by the HSG to provide a uniform 
assessment of the clinical features and course of HD.  The components of the UHDRS are: 
 Motor Assessment, which includes the total maximal chorea (TMC) score and the 
parkinsonism subscale score (sum of finger taps, pronate/supinate - hands, rigidity - arms, 
bradykinesia - body, gait, tandem walking, and retropulsion pull test scores) 
 Cognitive Assessment 
 Behavioral Assessment 
 Independence Scale 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 20 of 37 
 
 Functional Assessment 
 Total Functional Capacity (TFC) 
 Clinical Summary  
7.3.4 
Montreal Cognitive Assessment (MoCA©) 
The MoCA© 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.  
The total possible score is 30 points; a score of 26 or above is considered normal.  There are 3 
versions in the English language.  Given the relatively frequent use of this instrument, the 
versions will be rotated at each visit. 
7.3.5 
Unified Parkinson Disease Rating Scale (UPDRS) 
The UPDRS 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 
speech/dysarthria will be utilized to screen and monitor study subjects for parkinsonism. 
7.3.6 
Barnes Akathisia Rating Scale (BARS) 
The BARS 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.    
7.3.7 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire, composed of eight questions, that provides a 
measure of a subject’s general level of daytime sleepiness.  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 lives.  The total ESS score 
is the sum of 8 item-scores and can range between 0 and 24, with higher scores indicating a 
higher level of daytime sleepiness.   
7.3.8 
Swallowing Disturbance Questionnaire (SDQ) 
The SDQ is a self-administered questionnaire comprising 15 questions that assess the frequency 
of swallowing disturbance.  Scores range from 0.5 (normal) to 44.5 (severe impairment). 
8 
Statistical Methods 
8.1 
Hypothesis Testing 
Because this is an open-label, single-arm trial, no formal statistical analyses will be conducted.   


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 21 of 37 
 
8.2 
Sample Size 
This is an open-label, single-arm safety study, and the sample size is not based on statistical 
considerations. 
8.3 
Subject Withdrawal 
Subjects may withdraw from the study at any time.  Subjects may be withdrawn from study 
treatment or the study at the request of the Investigator or Sponsor. 
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 early termination evaluations should 
be performed at the time of discontinuation, if possible.   
8.4 
Final Analyses and Reporting 
For Rollover subjects from the First-HD study, the subject's prior treatment assignment (SD-809 
or placebo) will remain blinded until that study's final database has been locked and unblinded. 
The final databases for this study may not be locked until this SAP has been approved.  The 
analyses outlined in this SAP will be carried out after: 
 The SAP has been approved; 
 The corresponding study database has been authorized by the sponsor clinical team as 
complete and finalized.  
Further exploratory analyses not necessarily identified in this SAP may be performed to support 
the clinical development program.  Any post-hoc or unplanned analyses performed and not 
identified in this SAP will be clearly identified in the CSR. 
8.5 
Handling of Missing Data 
8.5.1 
Missing Data for Individual Items of an Instrument 
For the Total Motor Score and the TMC Score of the UHDRS, missing data items will be 
imputed, provided that at least 80% of the items for the corresponding score are nonmissing.  In 
such cases, the value(s) of the missing item(s) will be imputed by carrying forward the most 
recent nonmissing value of the corresponding item.  However, if more than 20% of the items for 
the score are missing, the score will be treated as missing. 
For all other missing data items, the missing data items will remain missing and will not be 
imputed, and only observed data will be summarized. 
8.5.2 
Missing Endpoint Data 
Missing endpoint data will not be imputed, and only observed data will be summarized. 


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8.6 
Interim Analysis 
An interim analysis of the safety and open-label efficacy data was conducted to assess the 
adequacy of the dose conversion strategy and the activity of SD-809 in treating chorea.  Details 
can be found in Appendix 1. 
8.7 
Comments on Statistical Analysis 
The following general comments apply to all statistical analyses and data presentations: 
 Unless otherwise specified, all data will be summarized separately for the Rollover 
Cohort and the Switch Cohort.   
 Summaries will include frequencies and percentages for categorical data and the number 
of observations, mean, standard deviation, median, minimum, and maximum for 
continuous data. 
 Duration variables will be calculated using the general formula:  (end date – start date) + 
1. 
 Unless specified otherwise, for subjects in the Switch cohort, the baseline value is the 
last available value prior to the first administration of SD-809 on Day 1.  For Rollover 
subjects from the First-HD study, for assessments that were scheduled to be performed at 
Week 13 of that study or the Baseline visit of the ARC-HD study, the baseline value is 
the last available off-treatment (at least 4 days after the last administration of study drug) 
value prior to administration of SD-809 on Day 1. For assessments that were not 
scheduled to be performed at Week 13 of the First-HD study or at the Baseline visit of 
the ARC-HD study, the baseline value is the last available value prior to administration 
of study drug on Day 1 of the First-HD study. For the Switch cohort, the baseline value 
used for calculating change from baseline for TMC and the total motor score will be the 
mean of the values from the Screening and Baseline visits. 
 If the reported value of a clinical laboratory parameter cannot be used in a statistical 
summary table (e.g., a character string is reported for a parameter of the numeric type), a 
coded value must be appropriately determined and used in the statistical analyses.  In 
general, a value or lower or upper limit of normal range such as ‘<10’ or ‘<5’ will be 
treated as ‘10’ or ‘5’, respectively, and a value such as ‘>100’ will be treated as ‘100.’  
However, the actual values as reported in the database will be presented in data listings. 
 Individual subject listings of all data represented on the eCRFs will be provided to 
facilitate the investigation of tabulated values and to allow for the clinical review of all 
data. 
 Version 9.4 of SAS statistical software package will be used to provide all summaries, 
listings, and graphs described in this document. 


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 All raw data will be presented to the original number of decimal places.  Means and 
medians will be presented to one more decimal place than the raw data.  Standard 
deviations will be presented to two more decimal places than the raw data.   
 The denominator for percentages will be based on the number of subjects or observations 
with non-missing data appropriate for summary purposes.  Unless otherwise noted, all 
percentages will be presented to one decimal place. 
8.8 
Time Periods for Analyses 
Some analyses will be performed by time period.  For these analyses, the following definitions 
will be used: 
 Screening Period (Switch subjects only) - from informed consent until the first dose of 
study drug  
 Dose-Adjustment Period (Switch subjects only) – Baseline through Week 4 
 Extended Dose-Adjustment Period (Switch subjects only) – Baseline through Week 8 
 Titration Period (Rollover subjects only) – Baseline through Week 8 
 Stable-Dose Period - from Week 8 through the last dose of study drug 
 Entire Treatment Period - Baseline through last dose of study drug 
 Follow-up Period - from the last dose of study drug through the end of the study 
Subjects who withdraw from the study during the Titration Period or the Extended Dose-
Adjustment Period will not have a Stable-Dose Period.  For the analyses of adverse events, to be 
conservative, all follow-up adverse events will be counted as events that occurred during the last 
available treatment period prior to the Follow-up period. 
8.9 
Analysis Visit Windows 
For efficacy and safety by-visit analyses, data collected at post baseline scheduled visits will be 
included using their nominal visit. Data collected at early termination, end of treatment, and 
unscheduled visits will be assigned to a visit window as described below. All scheduled visits 
will be assigned a target study day; for the determination of target days, weeks will be assumed 
to have 7 days. Thus, Week 4 would have a target day of 4*7=28 days. For each visit, a visit 
window will be assigned so that anything from the midpoint to the prior target day to the 
midpoint to the following target day will be assigned to that visit window as shown in Table 3 
below.  The following rules concerning visit windows and selecting records for analysis will be 
used: 
1.  Scheduled visit has precedence. 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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2.  If there are multiple records of the same scheduled visit, the record closest to the target day 
will be used for analysis. If two records are equidistant, then the earlier one will be used. 
3.  For a given visit, if there is no data from a scheduled visit, data from an unscheduled visit that 
occurs in the visit window will be used for analysis.  
Table 3: Analysis Visit Window 
 
 
 
8.10 
Changes to Protocol-Specified Analyses 
The protocol stated that a subject would be deemed compliant if the subject has taken 80% to 
100% of the expected tablets; however, this was changed, and a subject will be deemed to be 
compliant if the subject has taken 80% to 105% of the expected tablets. 
Visit 
Target Day 
Visit Window 
Screening 
-5 
( --, -5) 
Screening Telephone Contact 
-2 
(-4, -2) 
Baseline 
-1 
(-1, -1) 
Week 1 
7 
(1,10) 
Week 2 
14 
(11-17) 
Week 3 
21 
(18, 24) 
Week 4 
28 
(25, 31) 
Week 5 
35 
(32, 38) 
Week 7 
49 
(39, 52) 
Week 8 
56 
(53, 80) 
Week 15 
105 
(81, 150) 
Week 28 
196 
(151, 241) 
Week 41 
287 
(242, 332) 
Week 54 
378 
(333, 423) 
Week 67 
469 
(424, 514) 
Week 80 
560 
(515, 605) 
Week 93 
651 
(606, 697) 
Week 106 
742 
(698, 787) 
Week 119 
833 
(788, 879) 
Week 132 
924 
(880, 970) 
Week 145 
1015 
(971, 1060) 
Week 158 
1106 
(1061, 1152) 
Week 171 
1197 
(1153, --) 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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TMC and the total motor score from the UHDRS were listed as safety parameters in the protocol; 
however, these parameters were changed to efficacy endpoints for this SAP. 
9 
Statistical Analyses 
9.1 
Subject Disposition 
The number and percent of enrolled subjects who were screen failures, who were included in the 
Safety Population, who completed the study, and who withdrew from the study, and their 
primary reason for withdrawal, will be summarized.  Subject disposition will be summarized 
using all enrolled subjects.  Enrolled subjects are those subjects who signed the informed consent 
form. 
For screen failures, the reason that subjects were declined and the reason that subjects were 
excluded from the study will be summarized using counts and percentages.  
A listing summarizing whether subjects completed or discontinued from the study will also be 
presented, and the primary reason for discontinuation will be provided for those subjects who 
withdrew. 
9.2 
Demographic and Baseline Characteristics 
Descriptive statistics or counts and percentages, as appropriate, will be used to summarize 
demographic and baseline characteristics in the Safety Population.  Subject demographics 
include age, gender, race, ethnicity, education (years), CAG repeat length, height, weight, and 
body mass index (BMI) at screening, whether or not the subject was a CYP2D6 poor 
metabolizer, and disease duration (in years).  Age (in years) will be calculated from the date of 
birth to the date of informed consent in Protocol SD-809-C-16 for both Switch and Rollover 
subjects.  Age will be reported as an integer.  BMI will be calculated using the following 
formula: BMI (kg/m2) = weight (kg)/(height (m))2. Only the year of diagnosis is collected in the 
CRF, so disease duration (years) will be calculated using the following formula: (Date of 
Informed Consent - July 1 of Year of Diagnosis)/365.25.  
All demographic and baseline characteristics will also be listed. 
9.3 
Medical History 
Medical history will be obtained at Screening for C-16 Switch subjects and recorded in the eCRF 
and transferred from data collected in C-15 for Rollover subjects. 
Medical history information will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) high level group term and preferred term using counts and percentages.  Medical 
history information will also be listed. 


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9.4 
Concomitant Medications 
Concomitant medications are defined as medications taken any time after the start of dosing until 
the final visit.  Medications are also considered concomitant if their stop date is unknown or 
marked as continuing.  Medications with missing start dates will be considered ongoing on the 
first day of study drug administration, except where positive confirmation is available that the 
medication was stopped before study drug administration.   
The World Health Organization Drug Dictionary (WHODRUG) will be used to classify prior 
and concomitant medications by therapeutic class and preferred term.  The WHODRUG version 
will be noted in the CSR.  The number and percentage of subjects receiving concomitant 
medications will be summarized by Anatomical Therapeutic Chemical (ATC) level 3 and 
preferred term.  Subjects will be counted only once for an ATC class, even if the subject took the 
same medication on multiple occasions or more than one medication in the same ATC class.  
Similarly, subjects will be counted at most once for a preferred term, even if they took the same 
medication on multiple occasions or more than one medication with the same preferred term.  
The number and percentage of subjects receiving concomitant medications at baseline will also 
be summarized by ATC level 3 and preferred term.  
A listing of concomitant medications will also be presented. 
9.5 
Study Drug Exposure and 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 obtained from 
returned study drug containers and must be reviewed at every visit while the subject is still in the 
clinic to determine if the subject is taking study drug as directed. 
Percent compliance in the interval between visits will be calculated as 100·(number of tablets 
used/number of tablets expected to be used), where number of tablets used = number of tablets 
dispensed minus number of tablets returned.  A subject will be deemed compliant if the subject 
has taken 80% to 105% of the expected number of tablets of study drug; this definition of 
compliance supersedes the definition specified in the study protocol. 
For Switch subjects, percent compliance will be summarized for the following time periods using 
descriptive statistics: from Day 1 to the Week 4 visit, from Day 1 to the Week 8 visit, and from 
Day 1 to the last dose of study drug.  For Rollover subjects, percent compliance will be 
summarized for the following time periods using descriptive statistics: from the Day 1 to the 
Week 8 visit and from Day 1 to the last dose of study drug. Compliance will be summarized for 
these same time periods using counts and percentages. 
 
The length of time (in days) that each subject is exposed to SD-809 will be summarized using 
descriptive statistics. For subjects who complete the study through Week 8, the duration of time 
in days from Day 1 until the day of first receiving the SD-809 dose received at Week 8 (i.e., the 
duration of time to achieve a stable dose of SD-809) will be summarized using descriptive 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 27 of 37 
 
statistics. For Switch subjects who complete the study through Week 8, the number and 
percentage of subjects who achieve a stable dose by Week 4 (i.e., received the same dose of SD-
809 at Week 4 that they received at Week 8) will be presented. 
For each subject, the initial dose, titrations, and investigator-initiated dose changes that occur 
during the study will be listed.   
9.6 
Protocol Deviations 
Deviations from the protocol will be recorded appropriately.  Protocol deviations will include the 
following: 
 Subjects who did not give appropriate Informed Consent 
 
Subjects enrolled who did not meet the inclusion/exclusion criteria 
 
Subjects who took disallowed or prohibited medications 
 
Subjects who were not 80% - 105%  treatment compliant 
 
Key endpoint non-compliance: TMC, UHDRS Behavior, HADS, C-SSRS, UPDRS, 
SDQ, BARS or ESS not performed for 2 or more consecutive expected visits 
 
Subjects who were administered the wrong study treatment 
 Subjects who were administered an incorrect dose or an incorrect starting dose for switch 
cohort subjects (a dose adjustment would not be considered an incorrect dose) 
 Missing safety endpoints at any visit: SDQ, BARS, HADS, or C-SSRS  
 Missing lab tests, PK sampling, vital sign and ECG at any visit 
 Out of protocol-specified window visits 
A listing of protocol deviations will be provided. 
9.7 
Efficacy Analyses 
For TMC and the total motor score of the UHDRS, the Rollover and Switch cohorts will be 
analyzed separately through Week 8. Descriptive statistics will be presented by visit for the 
actual data and for the changes from baseline, including 95% confidence intervals for the true 
mean changes from baseline.  For the Switch cohort, the baseline value used for calculating 
change from baseline for TMC and the total motor score will be the mean of the values from the 
Screening and Baseline visits. These analyses will be repeated for TMC using data at scheduled 
visits only and also only using subjects with a TMC score at all scheduled visits up to Week 15.   
In addition, for TMC and the total motor score, descriptive statistics will be presented by visit for 
the actual data and the changes from Week 8, including 95% confidence intervals for the true 
mean changes from Week 8. Subjects without a Week 8 assessment will be excluded from the 
analysis. This analysis will be done for the prior SD-809 subjects in the rollover cohort, prior 
placebo subjects in the rollover cohort, the switch cohort, and the two cohorts combined. 
9.8 
Analysis of Dose Level 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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Total daily dose level (mg) at Week 1 (Switch cohort)/Week 2 (Rollover cohort), and each 
scheduled visit will be summarized for each cohort using descriptive statistics. The baseline 
tetrabenazine dose level will be summarized for the Switch cohort.  In addition, the number and 
percentage of subjects at each dose level will be summarized for each visit.  
The total daily dose level will also be summarized by visit using descriptive statistics for the 
subjects with a corresponding TMC score at the given visit.      
9.9 
Safety Analyses 
Safety will be assessed using the Safety Population.   
9.9.1 Adverse Events 
Adverse events will be coded using version 16.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA); the MedDRA version will be noted in the CSR.  Treatment-emergent AEs 
(TEAEs) are events that 1) begin after treatment with study drug in the current study and that are 
not present at baseline or 2) if present at baseline, have worsened in severity.  For AEs with 
missing start dates, the AE will be considered treatment-emergent unless there is additional 
information indicating that the AE started prior to the first treatment.  All analyses of TEAEs 
will be performed separately for TEAEs that occurred during the titration period (for Rollover 
subjects only), during the dose-adjustment period (for Switch subjects only), during the extended 
dose-adjustment period (for Switch subjects only), during the stable dose period, and during the 
entire treatment period. To be conservative, all adverse events that occurred during the follow-up 
period will be counted as events that occurred during the last available treatment period. In order 
to be included in the analysis for a given time period, a subjects must have at least one visit 
during the time period.  
For the Switch cohort, an overview of AEs occurring during the Screening period will present 
the number and percentage of subjects in the following categories: 
 Any AEs 
 Any serious AEs (SAEs) 
 Any severe AEs  
 Any AE(s) leading to death 
An overview of TEAEs will present the number and percentage of subjects in the following 
categories: 
 Any TEAEs 
 Any serious TEAEs 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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 Any severe TEAEs  
 Any treatment-related TEAEs 
 Any TEAEs resulting in dose reduction  
 Any TEAEs resulting in dose suspension  
 Any TEAEs resulting in withdrawal from the study 
 Any treatment-related TEAEs resulting in withdrawal from the study 
 Any TEAEs resulting in dose reduction, dose suspension, or withdrawal from the study 
 Any TEAE(s) leading to death 
TEAEs, serious TEAEs, TEAEs that led to dose reduction, TEAEs that led to dose suspension, 
TEAEs that led to withdrawal from the study, TEAEs that occurred in at least 4% of Rollover or 
Switch cohort subjects in the Safety Population across all time periods,will be summarized at the 
subject level by MedDRA system organ class (SOC) and preferred term using frequencies and 
percentages.  
Exposure adjusted incidence rates (number of patients with an event per person-year) will also be 
presented for the above TEAE overview categories, all preferred terms, and selected AEs of 
interest by patient cohort and study (First Active in C15, First Placebo in C15, Rollover in C16, 
and Switch in C16). AEs of agitation, somnolence, insomnia, anxiety and fall will be defined as 
events with matched preferred terms. In addition, AEs with selected preferred terms will be 
combined into the AEs of interest as follows:  
 Akathisia and Restlessness: Akathisia, Hyperkinesia, Psychomotor hyperactivity, 
Restlessness, Agitation 
 Dysphagia: Aphagia, Dysphagia  
 Parkinsonism: Akinesia, Bradykinesia, Cogwheel rigidity, Freezing phenomenon, 
Hypertonia, Masked facies, Muscle rigidity, On and off phenomenon', Parkinsonian 
crisis, Parkinsonian gait, Parkinsonian rest tremor, Parkinsonism, Parkinson's disease, 
Resting tremor 
 Suicidality: Completed suicide, Depression suicidal, Intentional overdose, Intentional 
self-injury, Poisoning deliberate, Self-injurious ideation, Suicidal behavior, Suicidal 
ideation, Suicide attempt. 
 Depression: all preferred terms containing “depression” 
Incidence rate will be calculated as:  


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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Number of patients with given event/ Person-years for the event  
Person-years for a selected event are defined as the sum of exposure days across all subjects 
divided by 365.25. Subjects with an event of the given type contribute days from the date of their 
first treatment dose until the date of the first event of the given type. Subjects without an event of 
the given type contribute days from date of their first treatment dose until their treatment end 
date. Events that occurred after the last dose date of each study period were not included.  
TEAEs and treatment-related TEAEs, categorized by system organ class, preferred term, and 
maximum severity (mild, moderate, or severe), will be summarized by study period using counts 
and percentages.  In addition, TEAEs, categorized by system organ class, preferred term, and 
relationship to study drug (unrelated, related), will be summarized by study period using counts 
and percentages.  TEAEs that are classified as possibly, probably, or definitely related to study 
drug on the AE eCRF, or for which the relationship to study drug is missing, will be considered 
treatment related.  Unrelated AEs include those classified as unrelated or unlikely related on the 
AE eCRF.  
Subjects receiving a strong CYP2D6 inhibitor or who are poor CYP2D6 metabolizers are 
considered to have impaired CYP2D6 function. The following AE analyses will be repeated by 
impaired CYP2D6 function category at baseline (subjects receiving a strong CYP2D6 inhibitor 
at Baseline, subjects not receiving a strong CYP2D6 inhibitor at Baseline, CYP2D6 poor 
metabolizers, non-CYP2D6 poor metabolizers, subjects with impaired CYP2D6 function, and 
subjects without impaired CYP2D6 function): 
 Overview of TEAEs 
 TEAEs by SOC and preferred term  
For TEAE summaries, if a subject has more than one TEAE within a preferred term, the subject 
is counted once in that preferred term at the maximum severity and at the closest relationship to 
study drug.  If a subject has more than one TEAE within a system organ class, the subject is 
similarly counted once in that system organ class. 
Complete listings of all AEs will be provided.  In addition, data listings of all SAEs, AEs leading 
to withdrawal from the study, and AEs leading to death will also be provided. 
9.9.2 Vital Signs and Weight 
Respiration rate (breaths/minute), temperature (°C), and weight (kg) will be obtained at each 
clinic visit.  Supine and standing systolic and diastolic blood pressure (mmHg) and supine and 
standing heart rate (beats/minute) will be collected at the Baseline, Week 8, and End-of-
Treatment/Early Termination visits.  Seated blood pressure and heart rate will be collected at all 
other visits.   


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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Weight, respiration rate, temperature, seated/supine systolic and diastolic blood pressure, and 
seated/supine heart rate, and the corresponding change from baseline, will each be summarized 
by visit using descriptive statistics.  
A listing of weight and vital sign assessments will also be provided. 
9.9.3 Orthostatic Vital Signs 
Orthostatic blood pressure and heart rate will be recorded at Baseline and Week 8.  The Baseline 
and Week 8 differences between supine and standing systolic and diastolic blood pressure and 
heart rate, and the change from Baseline to Week 8 in these differences will be summarized 
using descriptive statistics.   
9.9.4 Physical and Neurological Examinations 
Physical examination findings will be listed. 
A complete neurological examination will include evaluation of the following categories: 
 Cranial nerves 
 Motor system (muscle strength, coordination) 
 Sensory (sensation) 
 Reflexes (muscle strength reflexes, plantar response) 
Neurological examination findings will be listed.   
9.9.5 Electrocardiogram (ECG) 
A safety electrocardiogram (ECG) will be recorded at Screening and the Week 8 visit for all 
subjects.  For subjects on allowed doses of citalopram or escitalopram, additional ECGs will be 
performed at Week 1 (Switch subjects) or Week 2 (Rollover subjects) and at Week 4 if the dose 
of study drug has been increased since the last ECG.  
A cardiologist will provide a clinical interpretation of each ECG that will be recorded in the 
eCRF. ECG parameters that will be recorded include heart rate, PR interval, QRS duration, QT 
interval, and QTcF (QT interval corrected for heart rate using Fridericia’s formula). 
Descriptive statistics will be used to summarize ECG parameters at Screening and the Week 8 
visit.  Descriptive statistics will also be used to summarize QTcF values at Screening and the 
Week 8 visit for subjects with a QTcF value >450 msec at any visit. These analyses will be 
repeated for the Screening, Week 1 (Switch subjects) or Week 2 (Rollover subjects), Week 4, 
and Week 8 visits for subjects receiving allowed doses of citalopram or escitalopram at Baseline.  


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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The number and percentage of subjects with normal, abnormal not clinically significant, 
abnormal clinically significant, and abnormal with clinical significance not specified ECGs will 
be summarized at Screening and the Week 8 visit.  The number and percentage of subjects with 
PR >200 msec, QRS >100 msec, QT >500 msec, QTcF >450 msec, QTcF >480 msec, and QTcF 
>500 msec, will be similarly summarized. These analyses will be repeated for the Screening, 
Week 1 (Switch subjects) or Week 2 (Rollover subjects), Week 4, and Week 8 visits for subjects 
receiving allowed doses of citalopram or escitalopram at Baseline.  
ECG results will also be listed. 
9.9.6 Clinical Laboratory Assessments 
Serum chemistry, hematology, and urinalysis laboratory tests will be performed at Screening 
(Switch subjects only), Baseline (Switch subjects only), Week 8, Week 28, Week 41, Week 54, 
and every 26 weeks thereafter.  For Rollover subjects, the screening assessment will be prior data 
from study SD-809-C-15.  Laboratory parameters that will be assessed include the following: 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
Page 33 of 37 
 
Table 4: Clinical Laboratory Tests 
Serum Chemistry 
 
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) 
 
Screening Labs 
Other  
 
Urine and serum pregnancy tests (women 
of childbearing potential only) 
 
Follicle Stimulating Hormone (FSH) for 
post-menopausal women only. 
 
Hepatitis B surface antigen (HBsAg) 
 
CYP2D6 genotype (blinded) 
 
CAG repeat 
 
Prothrombin Time 
 
Serum chemistry and hematology results and changes from screening/baseline will be 
summarized at each visit using descriptive statistics.  In addition, all serum chemistry and 
hematology results will be categorized into the following categories using the laboratory 
reference ranges:  below lower limit of normal, normal, above upper limit of normal. Shift tables 
summarizing changes in status from screening/baseline to each post-baseline visit will be 
presented.  All laboratory results including urinalysis results will be listed. 
9.9.7 Other Safety Assessments 
Other safety outcomes include the following: 
 HADS (HADS Anxiety subscale [HADS-A] score and HADS Depression subscale 
[HADS-D] score) 
 C-SSRS  


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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 MoCA© (total score) 
 UHDRS  
o Parkinsonism subscore 
o Verbal fluency test score,  
o Symbol digit modalities test score 
o Stroop interference test scores of the cognitive exam, including raw color naming 
score, raw word reading score, raw interference score, as well as the adjusted 
interference score1.   The adjusted interference score can be calculated by 
subtracting a “predicted score”, calculated as (raw color naming *raw word 
reading)/(raw color naming + raw word reading), from the raw interference score.  
o Behavioral assessment item scores (the product of frequency and severity) 
(depressed mood, apathy, low self-esteem/guilt, suicidal thoughts, anxiety, 
irritable behavior, disruptive or aggressive behavior, perseverative/obsessional 
thinking, compulsive behavior, delusions, hallucinations), behavioral assessment 
total score (sum of frequency × severity item scores) 
o Functional assessment score 
o Independence scale score 
o Total functional capacity (TFC) score 
o Question 78 and 79 scores of the clinical summary section (Part VII)]  
 UPDRS dysarthria (speech score) 
 SDQ (total score) 
 BARS (summary score and global clinical assessment of akathisia score) 
 ESS (total score) 
 Duration of time to achieve a stable dose of SD-809 
For all quantitative data (which includes all of these assessments except for the C-SSRS and the 
Question 78 and 79 scores of the UHDRS), except the duration of time to achieve a stable dose 
of SD-809, descriptive statistics will be presented by visit for the actual data and for the changes 
from baseline.  For the ESS total score, SDQ, UPDRS (speech) and the BARS scores, 95% 
confidence intervals will be presented for the true mean changes from baseline.  Descriptive 
statistics (and 95% confidence intervals for the true mean changes from Week 8 for the ESS total 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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score, SDQ, UPDRS (speech) and the BARS scores) will also be presented by visit for the actual 
data and for the changes from Week 8 for the UHDRS parkinsonism subscore, the UHDRS 
cognitive exam scores, the behavioral assessment item scores and total score, the SDQ total 
score, the UPDRS dysarthria speech score, the HADS scores, the BARS scores, the ESS total 
score, and the MoCA© total score.  Analyses of the UHDRS cognitive exam scores will be 
repeated excluding sites with conflict of interest or good clinical practice violations. Results of 
Questions 78 and 79 from the Clinical Summary section (Part VII) of the UHDRS will be 
summarized by visit using counts and percentages.  
For C-SSRS, the number and percentage of subjects with suicidal ideation at any post-baseline 
time point (overall and by individual question), suicidal behavior at any post-baseline time point 
(overall and by individual question), suicidal ideation or behavior at any post-baseline time point 
(overall and by individual question), and self-injurious behavior without suicidal intent at any 
post-baseline time point will be presented for each treatment group.  The number and percentage 
of subjects with suicidal ideation [affirmative ("YES") answer to questions 1 or 2 at any post-
baseline time point], with suicidal behavior [affirmative ("YES") answer to questions 6, 7, 8 or 9 
at any post-baseline time points], and who completed suicide [affirmative ("YES") answer to 
question 10 at any post-baseline time point] post-baseline will also be presented.   
9.10 
Pharmacokinetic Assessments 
Blood samples will be obtained for measurement of plasma concentrations of alpha (α)-HTBZ, 
beta-(β)-HTBZ, total (α+β)-HTBZ, alpha (α)-HDBZ, beta-(β)-HDBZ, total (α+β)-HDBZ, and 
other metabolites, as required in subjects switching from TBZ to SD-809.   
Plasma concentrations will be listed at each measured time point.  Plasma concentrations will be 
used in a separate population PK analysis.  
 
 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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10 
References 
1   The Stroop Color and Word Test Manual. 1998, 2002. Stoelting Co., Wood Dale, IL.  
 
 


Protocol SD-809-C-16                                                                                                       Teva Pharmaceuticals, Inc. 
 
 
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APPENDIX 1: Interim Analysis