ARC-HD

Overview

Status: Recruiting
Keywords: Huntington's Disease (HD) , Chorea , Movement Disorder , First-HD , SD-809
IRB Number: 00071315
Specialty: Neurology, Neurology, Neurology
Sub Specialties: Movement Disorders, Chorea, Huntington Disease

Brief Summary

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
 
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 a 54-week period. 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 30 centers in the U.S. and Canada. 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. For subjects who complete the study, overall study participation will be up to 58 weeks.
 
This is an open-label, single-arm study in which subjects with manifest 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 (First-HD) 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. However, Utah is not a site for this arm.  Please reference attached study protocol for complete details, if necessary.
 
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 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, Protocol Pages 14-15). 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), 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, 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.
 
Long-Term Treatment Period (up to 52 weeks): 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, 41 and 54 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 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 and in increments
of 6 mg per day. Dose adjustments should be based on all available information including the subject’s and caregiver’s reports of adverse events and chorea control, as well as information from rating scales and safety evaluations, when available.
 
Post-Treatment Safety Follow Up: All subjects will discontinue study drug at the Week 54 visit and return for their final clinic visit at Week 55 for evaluation of safety, chorea and motor function. During this one week washout, subjects should not take prohibited concomitant medications. Between the Week 55 visit and the Week 58 telephone contact, concomitant medication use is per the discretion of the investigator. Subjects will also have a follow up telephone contact at Week 58, four weeks after their last dose of study drug, to evaluate adverse events and concomitant medication usage.

 

Detailed Description

This is an open-label, single-arm study in which subjects with manifest 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. 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 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) 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]) , 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. 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), 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.

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. U.S.: 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 on Screening.
 
3. Subject meets either of the following:
• Has successfully completed participation in Study SD-809-C-15 OR
• Has been receiving an FDA approved dose of tetrabenazine 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 Protocol Section 6.12).
 
8. 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 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 Screening, Baseline and Week 4, 8, 15, 28, 41
   and 54 visits. 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

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 11 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 Protocol Appendix 12)
• Metoclopromide
• Monoamine oxidase inhibitors (MAOI)
• Levodopa or dopamine agonists
• Reserpine
• Amantadine
• Memantine
• 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.
  • 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 Protocol Appendix 19 for Celexa and Lexapro (Cipralex) dosing information. 
  • See Appendix 11 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)
NoteSubjects with Gilbert’s Syndrome are eligible to participate if approved by the Clinical Monitor.
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.
 
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.