First Time Use of SD-809 ER in HD (First-HD)

Overview

Status: Recruiting
Keywords: Huntington's Disease (HD) , Chorea , SD-809 , First-HD , Movement Disorder
IRB Number: 00067316
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Movement Disorders, Chorea, Huntington Disease

Brief Summary

This is a randomized, double blind, placebo controlled parallel group study in which subjects with chorea associated with HD will be invited to participate. Subjects will undergo an independent evaluation by a qualified healthcare provider to determine their capacity to provide informed consent. Subjects who qualify for the study will be randomized to receive either SD-809 ER or placebo in a 1:1 (SD-809 ER to placebo) ratio and the randomization will be stratified by prior exposure to tetrabenazine (previously exposed versus not previously exposed to tetrabenazine). Subjects will be titrated to an optimal dose level of study drug, followed by maintenance therapy at that dose. The overall treatment period will be 12 weeks in duration. The titration period will last 8 weeks, the maintenance period will be 4 weeks, followed by a washout period of 1 week. To provide a systematic examination for independent rating of chorea, a limited motor examination will be video recorded using a standard protocol at Screening, Baseline and at Weeks 9 and 12.

Approximately 90 subjects will be randomized (1:1) into the study, with approximately 45 subjects receiving SD-809 ER and 45 subjects receiving placebo. The study will be conducted at approximately 30 centers in the U.S. and Canada. The study is divided into a screening period, a titration period, a maintenance period and a post-treatment safety follow up period. For subjects who complete the study, overall study participation will be up to 20 weeks.

The objectives of this study are:

 • To evaluate the efficacy of SD-809 ER to reduce the chorea associated with HD

 • To evaluate the safety and tolerability of titration and maintenance therapy with SD-809 ER 

Titration period (8 weeks): All subjects and caregivers will interact weekly with the clinical site, either by telephone contact or clinic visit, through Week 8 of the titration period, in order to evaluate safety and establish a dose of study drug that adequately controls chorea and is well tolerated. Safety evaluations during titration include Unified Huntington Disease Rating Scale (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. See protocol for SoE (p. 12-13) .

In person study visits will be scheduled at Weeks 2, 4, and 6 after initiating therapy and telephone contacts will be scheduled for Weeks 1, 3, 5, 7 and 8 after initiating therapy. 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 increased on a weekly basis 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  adequate control of chorea has been achieved, the dose of study drug should not be increased further. If a subject experiences a “clinically significant” 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 and caregiver’s reports of adverse events and chorea control, the clinical assessment of safety and efficacy by the investigator, as well as information from rating scales including the Unified Huntington Disease Rating Scale (UHDRS), the Hospital Anxiety and Depression Scale (HADS), the Swallowing Disturbance Questionnaire (SDQ), the Unified Parkinson’s Disease Rating Scale (dysarthria item) (UPDRS [dysarthria]), the Barnes Akathisia Rating Scale (BARS), the Epworth Sleepiness Scale (ESS), and the Columbia Suicide Severity Rating Scale (C-SSRS). At the end of the titration period, the subject’s dose will be established for the maintenance period.

Maintenance period (4 weeks): Subjects will continue to receive their maintenance dose over the next 4 weeks (dose reductions for adverse events are allowed) and will return for in person visits at Weeks 9 and 12 for evaluation of safety, efficacy and pharmacokinetics. In addition, there will be a telephone contact at Week 10 to evaluate safety. At the end of the maintenance period (Week 12), subjects will undergo a complete evaluation, including physical and neurological exam, safety labs and 12-lead ECG and performance of all rating scales. If a subject requires a dose reduction based on a telephone contact during the maintenance period, an unscheduled clinic visit should be conducted. 

Washout (1 week): All subjects will discontinue study drug after the Week 12 visit and will return at Week 13 for evaluation of safety, chorea and motor function. Subjects who complete the study and were tolerating study drug may be eligible to participate in a long term safety study of SD-809 ER. 

Subjects not participating in the long term safety study of SD-809 ER will have a follow up telephone contact at Week 16, four weeks after their last dose of study drug.

Principal Investigator: David Shprecher
Department: Neurology
Co Investigator:

Contact Information

Name:Paola Wall
Phone: 801-581-4543
Email: paola.wall@hsc.utah.edu

Inclusion Criteria

Inclusion Criteria

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 Screening.

3. Subject has a Total Maximal Chorea Score (TMC) ≥ 8 at Screening and Baseline. (Note: The Baseline TMC may be < 8 if the average of the Screening and Baseline scores is ≥ 8 and the difference between the Screening and Baseline scores is no more than 4).

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. Female subjects of childbearing potential 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 enrollment.

  • Stable hormonal contraception (with approved oral, transdermal, or depot regimen) for at least 3 months prior to screening.

8. 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 Screening, Baseline and Weeks 4, 9 and 12 Visits. Caregivers will be encouraged to attend other visits.

9. 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).

 

Exclusion Criteria

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 Protocol Appendix 16 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 Screening or Baseline.

5. Subject has an unstable or serious medical or psychiatric illness at Screening or Baseline.

6. Subject has received tetrabenazine within 6 months prior to Screening.

7. Subject has received any of the following concomitant medications within 30 days of Screening or Baseline:

  • Antipsychotics (See Protocol Appendix 17)

  • Metoclopromide

  • Monoamine oxidase inhibitors (MAOI)

  • Levodopa or dopamine agonists

  • Reserpine

  • Amantadine

  • Memantine

8. Subject has a score of ≥11 on the Swallowing Disturbance Questionnaire (SDQ) at Screening.

9. Subject has a Unified Parkinson’s Disease Rating Scale (UPDRS) dysarthria score of ≥3 at Screening.

10. Subject requires treatment with drugs known to prolong the QT interval. Note:
• Quetiapine (Seroquel) is not allowed.
• Escitalopram (Lexapro or Cipralex) is allowed when administered according to approved labeling.
• Citalopram (Celexa) is allowed when administered according to approved labeling.
• See Appendix 19 for Celexa and Lexapro (Cipralex) dosing information
• See Appendix 17 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 medical 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 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.
 
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.