Long-term Safety Evaluation of Trospium Chloride and Xanomeline Tartrate in Treating Mania or Mixed Features in Bipolar-I Disorder: A Phase 3 Open-label Extension Study

The primary objective of this Phase 3 open-label extension study is to assess the long-term **safety** and tolerability of KarXT in participants with **mania** or mania with mixed features associated with Bipolar-I Disorder (BP-I). This is clinically relevant as it aims to ensure that KarXT, which contains the active substances trospium chloride and xanomeline tartrate, can be safely administered over an extended period, providing a potential therapeutic option for managing manic episodes in BP-I.

Secondary objectives include determining the long-term safety and tolerability of KarXT in the treatment of participants with mania or mania with mixed features associated with BP-I. This further evaluation is crucial for understanding the comprehensive safety profile of KarXT, thereby supporting its potential use in clinical practice for individuals with BP-I.

The clinical trial involves a total of **200 participants** diagnosed with **Bipolar-I disorder**, specifically those experiencing **mania or mania with mixed features**. The study population includes both male and female subjects, aged between **18 and 65 years**. Participants were selected based on their ability to safely discontinue all other psychiatric medications within 14 days prior to the commencement of the study medication. The trial does not include a vulnerable population. Participants are required to meet a minimum score on assessments evaluating symptoms and daily functioning. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is designed to evaluate the long-term safety and tolerability of **KarXT**, a combination of **trospium chloride** and **xanomeline tartrate**, in individuals diagnosed with **Bipolar-I disorder** experiencing mania or mania with mixed features. This is a Phase III, open-label extension study, which will involve participants aged 18 to 65 years. The trial will be conducted over an estimated period, with recruitment starting on September 15, 2025, and concluding by June 13, 2028. Participants will be required to discontinue all other psychiatric medications safely and gradually within 14 days prior to the initiation of the study medication.

The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including a diagnosis of Bipolar-I disorder and a minimum score on assessments of symptoms and daily functioning. Following the screening, participants will enter the treatment phase, where they will receive **KarXT** in capsule form, administered orally. The maximum treatment period is set at 51 weeks, with a daily dose not exceeding the specified limits. Regular follow-up visits will be scheduled to monitor the occurrence of adverse events, changes in safety measures, and responses on the Columbia Suicide Severity Rating Scale (C-SSRS).

The primary endpoint of the study is the occurrence of adverse events during the treatment period, while secondary endpoints include adverse events leading to treatment discontinuation and changes in safety measures. Participants' involvement is expected to last for the duration of the treatment period unless early termination is warranted due to adverse events, non-compliance with the study protocol, or withdrawal of consent. The study aims to ensure that **KarXT** is safe and tolerable for long-term use in the specified patient population, contributing valuable data to the understanding of its safety profile in the treatment of **mania** associated with **Bipolar-I disorder**.

The clinical trial involves the administration of the experimental medication **KarXT**, which is formulated as a **capsule**. The active substances in KarXT are **trospium chloride** and **xanomeline tartrate**, both of which are of chemical origin. The medication is produced by Bristol-Myers Squibb International Corporation and is identified by the sponsor product code BMS-986510. The administration route for KarXT is oral, and the dosage varies across different treatment regimens within the trial. The maximum daily dose for the highest regimen is 25,099,960 mg, with a total maximum dose of 127,509,993,060 mg over a treatment period of up to 51 weeks. Other regimens include maximum daily doses of 20,099,940 mg, 15,099,940 mg, and 10,099,940 mg, with corresponding total maximum doses and treatment periods. The trial aims to assess the long-term safety and tolerability of KarXT in participants with mania or mania with mixed features associated with Bipolar-I Disorder.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the available data. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any pediatric formulations or orphan drug designations. The pharmaceutical form of the medication remains consistent as a capsule across all treatment regimens.

The efficacy of the investigational product, KarXT, in the treatment of **Bipolar-I Disorder** with mania or mania with mixed features will be assessed through a series of endpoints. The primary endpoint focuses on the occurrence of adverse events during the treatment period, which will provide insights into the safety profile of the medication. Secondary endpoints include the occurrence of adverse events leading to treatment discontinuation, changes in responses on the Columbia Suicide Severity Rating Scale (C-SSRS), and other safety measures throughout the treatment period.

Data collection will involve the use of validated scales and assessments to monitor adverse events and changes in safety parameters. The Columbia Suicide Severity Rating Scale (C-SSRS) will be employed to evaluate any changes in suicidal ideation or behavior. These assessments will be conducted at specified intervals during the trial to ensure comprehensive monitoring of the participants' safety and the medication's tolerability. The trial is designed as an open-label extension study, allowing for the long-term evaluation of KarXT's safety in the specified patient population.