Phase 2 Study of (+)-α-Dihydrotetrabenazine for Tardive Dyskinesia in Schizophrenia, Schizoaffective, Mood, Gastrointestinal, or Neuroleptic-Induced Disorders

The primary objective of this study is to evaluate the **efficacy**, **safety**, and **tolerability** of different ascending doses of **(+)-α-dihydrotetrabenazine** (10 to 20 mg administered once daily and 25 mg administered twice daily) for the treatment of **tardive dyskinesia** in subjects diagnosed with schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder, or neuroleptic-induced tardive dyskinesia. This evaluation is clinically relevant as it aims to address the therapeutic needs of patients suffering from tardive dyskinesia, a condition characterized by involuntary, repetitive body movements, which can significantly impact the quality of life and is often a side effect of long-term use of neuroleptic medications. The study does not list any secondary objectives.

The clinical trial focuses on evaluating the efficacy, safety, and tolerability of different doses of (+)-αDHTBZ for the treatment of **tardive dyskinesia** in individuals diagnosed with schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder, or neuroleptic-induced tardive dyskinesia. The study population includes both male and female participants aged 18 to 85 years, who are in good general health and have a body mass index (BMI) ranging from 18 to 38 kg/m². Participants are required to have adequate hearing, vision, and language skills, and must have a negative urine drug screen and alcohol breath test at screening and study start, with specific exceptions for stable doses of certain medications. The trial includes individuals who meet the clinical diagnoses as defined in the DSM-V and have been assessed with moderate or severe tardive dyskinesia. Participants must have stable doses of concurrent medications and conditions for at least 30 days prior to the study start and are expected to maintain this stability throughout the study. The trial also requires subjects of childbearing potential to use highly effective contraception methods. The sponsor has not provided information on the total number of participants involved in the study.

The clinical trial is a **single-arm, open-label, dose titration phase 2 study** designed to evaluate the efficacy, safety, and tolerability of **(+)-α-dihydrotetrabenazine** for the treatment of **tardive dyskinesia**. The trial involves administering different ascending doses of the drug, specifically 10 to 20 mg once daily and 25 mg twice daily, to subjects diagnosed with tardive dyskinesia associated with schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder, or neuroleptic-induced tardive dyskinesia. The trial is expected to commence on November 2, 2023, and conclude by November 1, 2025, with a maximum treatment period of 8 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and stable medication use. The primary endpoint is the change in the Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at week 8 compared to baseline. Secondary endpoints include assessments using the Clinical Global Impression of Tardive Dyskinesia (CGI-TD), Calgary Depression Scale for Schizophrenia (CDSS), and other relevant scales. Safety will be monitored through adverse event reporting, clinical laboratory tests, vital signs, physical examinations, and electrocardiograms (ECGs).

Participants will be involved in the study for approximately 8 weeks, with follow-up visits scheduled at regular intervals to monitor progress and collect data. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the treatment of tardive dyskinesia, contributing to the development of effective therapeutic strategies.

The clinical trial involves the administration of the experimental medication **(+)-α-Dihydrotetrabenazine** (also known as **(+)-DHTBZ**), which is provided in the form of an **oral solution**. The active substance in this medication is chemically identified as **(2R,3R,11BR)-1,3,4,6,7,11B-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol**. The medication is administered orally, with a dosing regimen that includes ascending doses ranging from 10 mg to 20 mg once daily (od) and a 25 mg dose administered twice daily (bid). The maximum daily dose is 980 mg, and the treatment period extends up to 8 weeks. The medication is not formulated specifically for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy, safety, and tolerability of the experimental medication **(+)-α-Dihydrotetrabenazine** in subjects with tardive dyskinesia, associated with conditions such as schizophrenia, schizoaffective disorder, mood disorder, gastrointestinal disorder, or neuroleptic-induced tardive dyskinesia. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the clinical trial for the treatment of **tardive dyskinesia** will be assessed using several primary and secondary endpoints. The primary endpoint is the change in the Abnormal Involuntary Movement Scale (AIMS) Dyskinesia Total Score at week 8 compared to baseline. This score evaluates the severity of tardive dyskinesia symptoms, with a total score ranging from 0 to 28, where a higher score indicates increased severity. An exploratory central blinded AIMS video rating will also be conducted in 50% of patients per site at baseline and week 8 to assess the concordance of measurements and feasibility for future clinical development.

Secondary endpoints include the AIMS Dyskinesia Total Score at various weeks specified in the Schedule of Assessments (SoA) compared to baseline, and the Clinical Global Impression of Tardive Dyskinesia (CGI-TD), which is a 7-point scale assessing the clinician's perspective of the participant's overall improvement of TD symptoms over time. Additional secondary endpoints involve the Calgary Depression Scale for Schizophrenia (CDSS), the Columbia-Suicide Severity Rating Scale (C-SSRS), the Positive and Negative Syndrome Scale (PANSS), and the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC), all measured at weeks specified in the SoA compared to baseline. Pharmacokinetics will also be assessed by collecting plasma samples at the end of weeks 2, 4, 6, 8, and 2 weeks after the last dose of the study drug to determine plasma concentrations of (+)-α-DHTBZ and assess treatment compliance.