Evaluation of (+)-α-Dihydrotetrabenazine Efficacy in Moderate to Severe Tardive Dyskinesia: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this clinical trial is to evaluate the **efficacy** of ADE513 in reducing abnormal involuntary movements associated with **tardive dyskinesia**. This is clinically relevant as tardive dyskinesia is a debilitating condition characterized by repetitive, involuntary movements, often resulting from long-term use of certain medications. Effective management of these symptoms can significantly improve the quality of life for affected individuals.

Secondary objectives include:

• Evaluating the safety and tolerability of ADE513 during both titration and maintenance therapy in subjects with tardive dyskinesia.
• Confirming pharmacokinetic parameters in the target population during Part I of the study.

The clinical trial focuses on evaluating the efficacy of ADE513 in reducing abnormal involuntary movements associated with **tardive dyskinesia**. The study population includes both male and female subjects aged between 18 and 75 years, who are in good general health and able to attend all study visits and complete assessments. Participants must have a clinical diagnosis of tardive dyskinesia with symptoms that are bothersome or cause functional impairment. They are required to have a total motor AIMS score of 6 or higher, with abnormal movements judged as moderate or severe. Subjects must weigh at least 45 kg for females and 55 kg for males and be in a psychiatrically stable condition with no recent changes in psychoactive medications. The trial includes individuals living in a stable environment, with adequate supervision if necessary, and having a caregiver in regular contact. Both male and female subjects are included, and the trial involves a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **(+)-α-dihydrotetrabenazine** in reducing abnormal involuntary movements in patients with moderate to severe **tardive dyskinesia**. The study is structured in two parts: an open-label Part I and a randomized, double-blind, placebo-controlled Part II. The trial is expected to commence recruitment on November 13, 2023, and conclude by December 1, 2026. Participants will be involved in the study for a maximum treatment period of 18 weeks, with the primary endpoint being the change in the Abnormal Involuntary Movement Scale (AIMS) score from baseline to Week 12.

Study visits are sequenced to include an initial screening visit, followed by regular follow-up visits, and concluding with an end-of-study visit. The screening visit will assess eligibility based on criteria such as age, health status, and a clinical diagnosis of tardive dyskinesia. Participants must have a total motor AIMS score of ≥6 and be in a psychiatrically stable condition. Follow-up visits will monitor the change in AIMS scores and assess the safety and tolerability of the treatment. The end-of-study visit will finalize data collection and evaluate the overall outcomes of the trial.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial employs a double-blind methodology to ensure unbiased results, with neither participants nor investigators aware of the treatment allocation. The use of a placebo control in Part II further strengthens the study's design by providing a comparative baseline for evaluating the efficacy of the investigational product.

The clinical trial involves the administration of **(+)-α-dihydrotetrabenazine**, an investigational medication, to evaluate its efficacy in reducing abnormal involuntary movements associated with moderate to severe tardive dyskinesia. The active substance, chemically known as (2R,3R,11BR)-1,3,4,6,7,11B-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol, is provided in the form of an **oral solution**. The maximum daily dose is 25 mg, with a total dose not exceeding 12.5 mg per administration. The treatment period is set for a maximum of 18 weeks. The medication is administered orally, and participant compliance is monitored throughout the study to ensure adherence to the dosing schedule.

In the randomized, double-blind, placebo-controlled part of the trial, a **placebo** is used as a comparator treatment. The placebo is referred to as ADE513 placebo and is designed to match the investigational product in appearance and administration route, although it contains no active pharmaceutical ingredient. The placebo is utilized to assess the efficacy of the investigational drug by providing a control for comparison. The administration of the placebo follows the same oral route and dosing schedule as the active treatment, ensuring consistency in the trial protocol.

The efficacy of the investigational product, **(+)-α-dihydrotetrabenazine**, in the treatment of moderate to severe tardive dyskinesia will be assessed through a series of predefined endpoints. The primary endpoint is the change in the Abnormal Involuntary Movement Scale (AIMS) score, specifically items 1 through 7, from Baseline (Day 0) to Week 12, as evaluated by central rating. Secondary endpoints in Part I include changes in the AIMS score from Baseline to Week 12, Baseline to Week 9, and Week 6 to Week 12, all assessed by the on-site Investigator. In Part II, secondary endpoints will focus on the dose level associated with adequate control of dyskinesia during the Maintenance period, and the proportion of subjects rated as Much or Very Much Improved on both the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC) at Week 12.