| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Tardive Dyskinesia |
| Tardivné dyskinézie |
|
| 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 efficacy of fixed doses of SD-809 to reduce the severity of abnormal involuntary movements of TD
• To evaluate the safety and tolerability of fixed doses of SD-809 in subjects with TD |
|
| 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 between 18 and 80 years of age, inclusive.
2. 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).
3. Subject has a clinical diagnosis of TD, and has had symptoms for at least 3 months prior to Screening.
4. The subject's TD symptoms are bothersome to the subject or cause functional impairment.
5. At the Screening and Baseline visits, the subject has:
• Moderate or severe abnormal movements as judged by the Investigator based on Item 8 of the AIMS, AND
• A total motor AIMS score of ≥6 (based on Items 1 through 7) as assessed by the Investigator. Note: A video recording of the AIMS assessment at Screening will be reviewed by a blinded central rater to confirm eligibility based on Items 1 through 7 of the AIMS prior to randomization.
6. For subjects with underlying psychiatric illness:
• Subject is psychiatrically stable and has had no change in psychoactive medications (including, but not limited to neuroleptics, benzodiazepines, anticonvulsants, and mood stabilizers) for ≥30 days before Screening (45 days for antidepressants).
• Subjects on long-acting (depot) medications have been on stable therapy (dose, frequency) for ≥3 months before Screening.
• Subject has a mental health provider who is aware of the subject's participation in the trial, and does not anticipate any changes to the subject's treatment regimen (drug, dose, frequency) in the next 3 months.
7. Subject has a history of being compliant with prescribed medications.
8. Subject is able to swallow study drug whole.
9. 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 written assent.
10. 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.
11. Subject is in good general health, is expected to attend all study visits and is expected to complete all study assessments, in the opinion of the Investigator.
12. Subject has sufficient reading skills to comprehend the
subjectcompleted rating scales.
13. Female subjects of childbearing potential a 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 any of the following medications within 30 days of Screening or Baseline:
• Tetrabenazine, reserpine, α-methyl-p-tyrosine (AMPT), botulinum toxin (within 3 months of Screening), medications with strong anticholinergic activity (trihexyphenidyl, benztropine, orphenadrine, procyclidine, and biperiden)
• Metoclopramide, prochlorperazine, or promethazine
• Stimulants(i.e., methylphenidate, amphetamine/dextroamphetamine, lisdexamphetamine, etc.), or monoamine oxidase inhibitors (MAOIs)
• Levodopa or dopamine agonists
2. Subject has previously participated in a study with SD-809.
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 Screening or a Baseline.
5. Subject has active suicidal ideation at Screening or Baseline.
6. Subject has history of any of the following within 6 months of Screening:
• Previous intent to act on suicidal ideation with a specific plan (positive answer to question 5 on C-SSRS)
• 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 Screening or Baseline.
8. Subject has dementia.
9. Subject has an unstable or serious medical illness at Screening or 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 ECG at Screening.
12. Subject has evidence of hepatic impairment at Screening, 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 >4 seconds 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 tetrabenazine or to any of the excipients of SD-809.
15. Subject has participated in an investigational drug or device trial and received study drug 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-V, or subject is unable to refrain from substance abuse throughout the study.
19. Subject has a positive urine drug screen (for amphetamines, barbiturates, benzodiazepine, phencyclidine, cocaine, or opiates) at Screening or Baseline, except if subject is receiving a stable dose of a benzodiazepine. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change in AIMS score from Day 0 to Week 12, as assessed by blinded central video rating. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint: The proportion of subjects who are a treatment success at Week 12, based on the Clinical Global Impression of Change (CGIC). A treatment
success is defined as Much or Very Much Improved on the CGIC at the Week 12 visit. The CGIC is a 7-point Likert Scale, ranging from very much worse to very much improved.
Additional Secondary Endpoints:
• The change in the modified Craniocervical Dystonia Questionnaire (CDQ-24) from Day 0 to Week 12.
• The proportion of subjects who are a treatment success at Week 12, based on the Patient Global Impression of Change (PGIC). A treatment success is defined as Much or Very Much Improved on the PGIC at the Week 12 visit.
• The proportion of subjects who have a 50% or greater reduction in AIMS score from Day 0 to Week 12.
• The percent change in AIMS score from Day 0 to Week 12.
• Based on the change in AIMS score from Day 0 to Week 12, as assessed by blinded central video rating, the cumulative proportion of responders will be
displayed for responder definitions ranging from a 10% improvement from Baseline to a 90% improvement from Baseline in steps of 10 percentage points. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | 4 |
| 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 | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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