Safety Evaluation of Long-Term Maintenance Therapy with (+)-α-Dihydrotetrabenazine in Patients with Moderate to Severe Tardive Dyskinesia

The primary objective of this clinical trial is to evaluate the **safety** and tolerability of long-term maintenance therapy with ADE513, also known as (+)-α-dihydrotetrabenazine, in patients with moderate to severe **tardive dyskinesia**. This is clinically relevant as it aims to ensure that the therapeutic regimen is safe for prolonged use, which is crucial for managing a chronic condition like tardive dyskinesia.

Secondary objectives include evaluating the long-term effects of ADE513 (+)-α-DHTBZ in the same patient population. This will provide insights into the sustained impact of the treatment on the condition, further informing its potential benefits and risks over an extended period.

The clinical trial focuses on evaluating the safety and tolerability of long-term maintenance therapy with ADE513 (+)-α-DHTBZ in individuals diagnosed with **tardive dyskinesia**. The study population comprises both male and female subjects aged between 18 and 75 years. Participants are required to have completed treatment within a parent study, either open-label or double-blind, placebo-controlled, followed by a washout period of at least one week. Subjects must be in a stable psychiatric status, with no changes in psychoactive medications within the 30 days preceding the baseline. They should also be compliant with their prescribed treatment regimen and live in a stable environment with adequate supervision to ensure adherence to study procedures. Female participants of childbearing potential are required to use a highly effective form of contraception throughout the study. The trial does not include a vulnerable population, and participants must have a body weight of at least 45 kg for females and 55 kg for males. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the safety and tolerability of long-term maintenance therapy with **(+)-α-dihydrotetrabenazine** in patients diagnosed with moderate to severe **tardive dyskinesia**. This is a Phase 4, open-label study, which will involve a total duration of 54 weeks. The trial will follow a structured methodology, including a **randomized** and **controlled** approach, although it is not double-blind. Participants will be administered the investigational product in the form of an oral solution, with a maximum daily dose of 25 mg and a total dose not exceeding 12.5 mg per administration.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are assessed. Participants must be between 18 and 75 years of age, have a clinical diagnosis of tardive dyskinesia, and meet other specific criteria, such as stable psychiatric status and compliance with treatment regimens. Following the screening, participants will undergo a baseline assessment before commencing the treatment phase. Regular follow-up visits will be scheduled throughout the trial to monitor safety, efficacy, and any adverse events. These visits will include assessments such as the Abnormal Involuntary Movement Scale (AIMS) and other clinical evaluations.

The end-of-study visit will occur at Week 54, where the primary endpoint will be the change in AIMS score from baseline, assessed by a blinded central video rating. Secondary endpoints include the incidence of adverse events, changes in clinical laboratory parameters, vital signs, ECG parameters, and treatment success based on Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). Participant involvement is expected to last the entire 54-week period unless early termination is warranted due to severe adverse events, non-compliance, or withdrawal of consent. The trial aims to provide comprehensive data on the long-term safety and efficacy of the investigational product in the target population.

The clinical trial involves the administration of the experimental medication **(+)-α-Dihydrotetrabenazine** (also known as **(+)-DHTBZ**), which is an oral solution. The active substance in this medication is **(2R,3R,11BR)-1,3,4,6,7,11B-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ol**, a chemical compound. The medication is provided by Adeptio Pharmaceuticals Limited and is identified by the sponsor product code ADE513. The pharmaceutical form of the medication is an oral solution, and it is administered via oral use. The maximum daily dose is 25 mg, with a maximum total dose of 12.5 mg. The treatment period extends up to 54 weeks. The medication is not a pediatric formulation and is not classified as an orphan drug.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety and tolerability of long-term maintenance therapy with **(+)-α-Dihydrotetrabenazine** in patients with moderate to severe tardive dyskinesia. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial is designed to assess the safety profile of the medication over an extended period, providing valuable data on its long-term use.

Efficacy in this clinical trial will be assessed primarily through the **Abnormal Involuntary Movement Scale (AIMS)** score, focusing on items 1 through 7. The primary endpoint is the change in AIMS score from Baseline to the end of long-term therapy at Week 54, as evaluated by a blinded central video rating. Secondary endpoints include the incidence of adverse events (AEs), serious adverse events (SAEs), drug-related AEs, severe AEs, and AEs leading to discontinuation during the overall period, titration period, and long-term treatment. Additionally, observed values and changes in clinical laboratory parameters, vital signs, ECG parameters, and abnormal findings will be monitored. The Hospital Anxiety and Depression Scale (HADS) and the Columbia-Suicide Severity Rating Scale (C-SSRS) will also be utilized to assess changes. The proportion of subjects achieving treatment success, defined as "Much" or "Very Much Improved" on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54, will be evaluated. Furthermore, the proportion of subjects with a ≥3-point reduction in AIMS score and the percent change in AIMS score from Baseline to Week 54 will be analyzed. These assessments will provide a comprehensive evaluation of the efficacy of the treatment in patients with moderate to severe tardive dyskinesia over the course of the trial.