An Open-label Study to Define the Safety, Tolerability and Clinical Activity of Deutetrabenazine (AUstedo) in Adult Study Subjects With DYsTonia

Study Overview
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Brief Summary
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This is a single-center, open-label study of AUSTEDO in study subjects with dystonia. The study will provide preliminary experience of the safety, tolerability, and clinical activity of AUSTEDO in study subjects with dystonia. Study duration will be up to 13 weeks from screening (Visit 1) to the post treatment evaluation (Visit 5). Treatment period from drug initiation to final on-treatment Visit will be 12 weeks, or less, as follows: during the ramp-up period, study drug will start at 12 mg/day (6 mg twice daily) and will be titrated weekly by 6 mg/day increments until either 1) the maximal allowable dose (48 mg/day) is reached, or 2) dose-limiting side-effects occur. In study subjects receiving a strong CYP2D6 inhibitor, the maximum allowed dose of AUSTEDO will be 36 mg/day, reducing study duration (due to a reduction in the ramp-up period) to 11 weeks. Study subjects who experience dose-limiting side effects will be maintained on their maximum tolerated dose. Once the maximal dose is established for each participant, they will complete 6 continuous weeks on this dose (maintenance period), followed by a 1-week washout. For study subjects unable to titrate up to 48 mg/day due to side effects, the 6 weeks of maintenance will start once they reduce the study drug back to the maximum well-tolerated dose. Adverse events will be monitored throughout the study and will be reported after drug initiation. Dose reductions, suspensions, and withdrawals due to adverse events will be recorded. ECG readings will be measured at screening, during week 2, during the first week of the maintenance period (whenever this is established to be, typically week 7 for subjects able to titrate up to 48 mg/day), immediately before washout (week 12 for those study subjects who are able to titrate up to 48 mg/day) and during week 13. Assessment of Columbia Suicide Severity Rating Scale and Epworth Sleepiness Scale scores will occur at screening and all clinic Visits. The Mini Mental (MMSE) Scale will be performed at screening and at the final on-treatment Visit (week 12). A video examination of the study subjects will be made at screening (right before initiation of the study drug), and after 6 weeks on AUSTEDO at a steady dose (right before drug cessation). Part III of the MDS-UPDRS will be performed at both of these Visits as well to screen for the appearance of drug-induced parkinsonism. Videos will be sent to raters blinded to treatment, Visit number and recording date.

Official Title
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The AUDYT Trial: An Open-label Study to Define the Safety, Tolerability and Clinical Activity of Deutetrabenazine (AUstedo) in Adult Study Subjects With DYsTonia

Conditions
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Dystonia, Primary

Intervention / Treatment
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* Drug: Deutetrabenazine 6 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study subjects with definite dystonia, as established by a movement disorder specialist. Study subjects of any race and either gender, age 18 or more on the date the informed consent form (ICF) is signed and with the capacity to provide voluntary informed consent. Study subjects able to read and understand English and the ICF and are willing to comply with all study procedures, treatment and follow-up. Study subjects who are taking any central nervous system acting medications (e.g., benzodiazepines, antidepressants, hypnotics), including medications for the treatment of dystonia, will be on a stable regimen for at least 30 days prior to the screening Visit, and will willing to remain on the same dose for the duration of the study. Female of child-bearing potential will not be pregnant and will be using an acceptable method of contraception. Study subjects with an MMSE >24. Exclusion Criteria: Exposure to dopamine blockers prior to the onset of dystonia that could, in the investigator's opinion, have caused dystonia. Study subjects with genetically-confirmed dopa-responsive dystonia. Study subjects with a diagnosis of Parkinson's or an atypical parkinsonian syndrome. Study subjects with a history of bipolar disorder or major depression, or the presence of active depression. Study subjects with a history of a suicide attempt or suicidal ideations, as well as the presence of active suicidal ideation as detailed on the C-SSRS administered during Visit 1. Study subjects with a history of schizophrenia or schizophrenia spectrum disorders. Treatment with tetrabenazine, reserpine, valbenazine, a monoamino oxidase inhibitor, a-methyl-p-tyrosine, strong anticholinergic medications, metoclopramide, antipsychotics, dopamine agonists, levodopa, and/or stimulants within 30 days of screening. Treatment with botulinum toxin less than 11 weeks prior to screening (Visit 1); subjects receiving injections sooner than every 12 weeks will be excluded if their next injection is scheduled farther than 6 days from screening. Presence of a neurologic condition that could confound dystonia assessments. Study subjects with a history of clinically relevant hepatic disease. Study subjects with a history of renal insufficiency. Any unstable medical illness. A corrected QT (Bazett) interval of 450 (458) milliseconds in men or 460 (472) milliseconds in women on 12-lead ECG at screening, or a history of cardiac arrhythmias. Study subjects participating in any drug or device clinical investigation concurrently or within 30 days prior to screening for this study. Study subjects with a known hypersensitivity or contraindication to the study drug or its components.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention arm - Oral Deutetrabenazine<br>This is the only arm for this trial. All subjects will receive oral Deutetrabanazine. | Drug: Deutetrabenazine 6 MG<br>* Increasing doses of Deutetrabenazine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of study subjects able to titrate up to the maximum tolerated dose | Proportion of study subjects able to titrate up to 48 mg/d (or up to 36 mg/d if receiving a strong CYP2D6 inhibitor) and able to complete the study at this dosage | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Suicidality | Documentation of change in the Columbia Suicide Severity Rating Scale. Items on this scale are both binary (Yes/No) and numeric (0-5). No answers and lower numeric values indicate a better outcome. | 3 months | 
| Change in Daytime Somnolence | Documentation of change in the Epworth Sleepiness Scale. Items on this scale are numeric (0-3). Lower numeric values indicate a better outcome. | 3 months | 
| Change in Cognition | Documentation of change in the Mini Mental Scale. The higher the total score on this scale, the better the outcome. Values range from 0 to a maximum of 30. | 3 months | 
| Development of Parkinsonism | Documentation of change in the MDS-Unified Parkinson's Disease Rating Scale, Part III. The lower the total score on this scale, the better the outcome. Values range from 0 to a maximum of 128. | 3 months | 
| Change in the PGI-I | Documentation of change in the Patient Global Impression of Improvement Scale (PGI-I). This is a Likert scale, with values from 1-7. A value of 1 indicates the best outcome. | 3 months | 
| Change in Dystonia Severity | Documentation of change in the Global Dystonia Rating Scale. The lower the total score on this scale, the better the outcome. Values range from 0 to a maximum of 140. | 3 months |