| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Tardive Dyskinesia |
| Tardivní dyskineze |
|
| E.1.1.1 | Medical condition in easily understood language |
| Involuntary movements of the tongue, lips, face trunk, and extremities. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the safety and tolerability of long-term maintenance therapy with SD-809
• To evaluate the efficacy of long-term maintenance therapy of SD-809 to reduce the severity of abnormal involuntary movements of Tardive Dyskinesia
• To evaluate the persistence of the therapeutic effect of SD-809. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is at least 18 years of age at Screening.
2. Subject has successfully completed Study SD-809-C-18, SD-809-C-23, or any other controlled study of SD-809 for treatment of moderate to severe TD.
3. Subject has a history of using a dopamine receptor antagonist for at least 3 months (or 1 month in subjects 60 years of age and older).
4. Subject has a clinical diagnosis of TD and has had symptoms for at least 3 months prior to Screening.
5. For subjects with underlying psychiatric illness:
• Subject is psychiatrically stable and has had no change in psychoactive medications (including, but not limited to, neuroleptics, benzodiazepines, anticonvulsants, and mood stabilizers) for ≥ 30 days before Screening (45 days for antidepressants).
• Subjects on long-acting (depot) medications been on stable therapy (dose, frequency) for ≥3 months before Screening.
• Subject has a health care who is aware of the subject's participation in the trial, and does not anticipate any changes to the subject's treatment regimen (drug, dose, frequency) in the next 3 months.
6. Subject has a history of being compliant with medications.
7. Subject is able to swallow study drug whole.
8. Subject has provided written, informed consent or, if subject lacks the capacity to provide informed consent, a legally authorized representative (LAR) has provided written informed consent and the subject has provided assent.
9. In the opinion of the Investigator, the subject lives in a stable environment, and has
adequate supervision when necessary to comply with all study procedures, attend all
study visits, and safely participate in the trial.
10. Subject has sufficient reading skills to comprehend the subject-completed rating scales.
11. Female subjects of childbearing potentialb agree to use one of the following´acceptable methods of contraception from Screening through study completion if
sexually active:
• IUD or intrauterine system in place for at least 3 months prior to screening;
• Subject or partner using barrier method (e.g., condom, diaphragm, or cervical cap) with spermicide from Screening through study completion;
• Partner has a documented vasectomy >6 months prior to enrollment;
• Stable hormonal contraception (with approved oral, transdermal, or depot regimen) for at least 3 months prior to Screening. |
|
| E.4 | Principal exclusion criteria |
1. Subject has received tetrabenazine within 7 days of Baseline.
2. Subject has received any of the following medications within 30 days of Baseline:
• Reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of
Baseline), and medications with strong anticholinergic activity (trihexyphenidyl,
benztropine, orphenadrine, procyclidine, and biperiden)
• Metoclopramide, promethazine, and prochlorperazine
• Stimulants(i.e., methylphenidate, amphetamine/dextroamphetamine,
lisdexamphetamine, etc.), or monoamine oxidase inhibitors (MAOIs)
• Levodopa or dopamine agonists
3. Subject has a neurological condition other than TD that may interfere with assessing the severity of dyskinesias.
4. Subject has a serious untreated or undertreated psychiatric illness at Baseline.
5. Subject has active suicidal ideation at Baseline.
6. Subject has history of any of the following within the last 6 months of Baseline:
• Previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence at the time of suicidal thought
• Previous preparatory acts to commit suicide or suicidal behavior
• A previous actual, interrupted or aborted suicide attempt
7. Subject has a score ≥11 on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) at Baseline.
8. Subject is developmentally disabled or has evidence of dementia.
9. Subject has an unstable or serious medical illness at Baseline.
10. Subject has history (within 3 months) or presence of violent behavior.
11. Subject has a QTcF value >450 ms (males) or >460 ms (females), or
>480 ms (with right bundle branch block [RBBB]) on 12-lead electrocardiogram (ECG) at Baseline.
12. Subject has evidence of hepatic impairment at Screening of the parent study, as indicated by:
• Aspartate transaminase (AST) or alanine aminotransferase (ALT) >2.5
times the upper limit of normal (ULN).
• Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the ULN
o Note: Subjects with Gilbert's Syndrome are eligible to participate if
approved by the medical monitor.
o Note: Subjects with abnormalities in two or more of these analytes
(AST, ALT, ALP, TBil) must be approved by the Medical Monitor to be enrolled.
• Prothrombin time >17 seconds (i.e. prothrombin time prolonged >4
seconds over the ULN)
• Positive Hepatitis B surface antigen (HBsAg).
13. Subject has evidence of significant renal impairment at Screening of
the parent study,, indicated by a creatinine clearance <50 mL/min, as estimated by the Cockroft-Gault formula.
14. Subject has known allergy to tetrabenazine or to any of the
components of SD-809.
15. Subject has participated in an investigational drug or device trial (other than Study SD-809-C-18, Study SD-809-C-23 or any other eligible SD-809 parent study) and received study drug within 30 days (or 5 drug half-lives) of Baseline, whichever is longer.
16. Subject is pregnant or breast-feeding at Baseline.
17. Subject acknowledges present use of illicit drugs at Baseline.
18. Subject has a history of alcohol or substance abuse in the previous 12 months, as defined in the DSM-V, or subject is unable to refrain from substance abuse throughout the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Incidence of AEs, SAEs, severe AEs, drug related AEs, AEs leading to withdrawal during the following periods:
o Overall
o During titration
o During long term treatment
• Observed values and changes from baseline in clinical laboratory parameters (hematology, chemistry, and urinalysis)
• Observed values and changes from baseline in vital signs
• Observed values in ECG parameters and abnormal findings
• Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms or a change from Baseline in QTcF of >30ms or 60ms
• Observed values and changes in UPDRS Part III (motor examination), BARS, HADS, C-SSRS, ESS, and MoCA©
• Duration of time to achieve stable dosing of SD-809 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weeks 4, 6, 15, 28, 41, 54, 67, 80, 93, 106, 119, 132, 145 and 158
Weeks 0,1,13 of the new part of the study (part B) |
|
| E.5.2 | Secondary end point(s) |
• The change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 through 7) from Baseline of this study at each visit that this is measured as assessed by blinded central video rating.
• The change in AIMS score (items 1 through 7) from Baseline of this study at each visit that this is measured, as assessed by the site rating.
• The proportion of subjects who are a treatment success, based on the Clinical Global Impression of Change (CGIC) at each visit that this is measured. A treatment success is defined as Much or Very Much Improved on the CGIC from Baseline of this study.
• Change in the modified Craniocervical Dystonia (CDQ-24) score from Baseline of this study at each visit that this is measured.
• The proportion of subjects who have a 50% or greater reduction in AIMS score from Baseline of this study at each visit that this is measured.
• The proportion of subjects who are a treatment success, based on the Patient Global Impression of Change (PGIC) at each visit that this is measured. A treatment success is defined as Much or Very Much Improved on the PGIC from Baseline of this study.
• The percent change in AIMS score from Baseline of this study at each visit that this is measured.
• Based on the change in AIMS score from Baseline of this study at each visit that this is measured, as assessed by blinded central video rating, the cumulative proportion of responders ranging from a 10% improvement from Baseline to a 90% improvement from Baseline in steps of 10 percentage points.
The following secondary safety endpoints will be assessed in Part B:
• Secondary safety endpoints:
- Incidence of adverse events, serious adverse events, severe adverse events, drug-related adverse events, and adverse events leading to withdrawal
- Observed values and changes from start of randomized withdrawal in clinical laboratory parameters (hematology, chemistry, and urinalysis)
- Observed values and changes from start of randomized withdrawal in vital signs
- Observed values in ECG parameters and abnormal findings
- Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500
ms, or a change from Baseline in QTcF of >30 ms or >60 ms
- Observed values and changes in UPDRS Part III (motor examination), BARS,
HADS, C-SSRS, ESS, and MoCA©
• Primary efficacy endpoint: change from Pre-withdrawal Visit AIMS scores (items 1 through 7) as assessed by blinded central video rating to the
Post-withdrawal Visit between subjects treated with SD-809 and subjects treated with placebo.
: During the new part of the study (part C):
- Incidence of adverse events, serious adverse events, severe adverse events, drug related adverse events, and adverse events leading to withdrawal from start of Part C
- Observed values and changes in vital signs from start of Part C
- Observed values and changes in C-SSRS from start of Part C
- Observed values in ECG parameters and abnormal findings from start of Part C
Number of subjects with on-treatment QTcF values >450 ms, >480 ms, >500 ms, or a change from baseline in QTcF of >30 ms or >60 ms from start of Part C
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 4, 6, 15, 28, 41, 54, 67, 80, 93, 106, 119, 132, 145 and 158
For part B Week 0, 1 and 13
And weeks 0,13,26,39,52 of new part of the study (part C) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double blind for one week in part B |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Germany |
| Hungary |
| Poland |
| Slovakia |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| After LVLS is follow up phone contact |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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