Study of Trospium Chloride and Xanomeline Tartrate (KarXT) for Treating Mania in Adults with Bipolar I Disorder

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the efficacy of **KarXT** in reducing the severity and symptoms of mania in participants with **Bipolar-I Disorder** (BP-I). This is clinically relevant as it aims to provide a potential therapeutic option for managing manic episodes, which are a significant component of BP-I and can severely impact patients' quality of life.

Secondary objectives include determining whether individuals with mania associated with BP-I experience an overall improvement in well-being when treated with KarXT compared to a placebo. This assessment is crucial for understanding the broader impact of KarXT on patient health beyond symptom reduction.

The clinical trial involves a total of **197 participants** diagnosed with **Bipolar-I disorder** experiencing mania or mania with mixed features. The study population includes both male and female subjects, aged between **18 to 65 years**, who are experiencing an acute episode or relapse of mania requiring hospitalization. Participants were selected based on a primary diagnosis confirmed by a comprehensive psychiatric evaluation and the Mini International Neuropsychiatric Interview. All psychotropic medications were discontinued no more than 14 days prior to the first dose of the study drug. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity were highlighted. Key inclusion criteria include a Young Mania Rating Scale score of 20 or higher and a Clinical Global Impressions-Bipolar score of 4 or higher at both screening and baseline.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of KarXT for the treatment of manic episodes in **Bipolar-I disorder**. The trial aims to determine if KarXT is superior to placebo in reducing the severity and symptoms of mania. The study involves the administration of KarXT, which contains the active substances **trospium chloride** and **xanomeline tartrate**, in capsule form, administered orally. The trial is expected to last until November 2026, with recruitment starting in September 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of Bipolar-I disorder, and current manic episode status. The screening will include a comprehensive psychiatric evaluation and confirmation of diagnosis using the DSM-5-TR criteria and the Mini International Neuropsychiatric Interview. Participants must have a Young Mania Rating Scale (YMRS) score of ≥ 20 and a Clinical Global Impressions-Bipolar (CGI-BP) score of ≥ 4 at both screening and baseline. All psychotropic medications will be washed out no more than 14 days prior to the first dose of the study drug.

The trial will include follow-up visits to assess the primary endpoint, which is the change from baseline in the YMRS score at Week 3. Secondary endpoints include changes in CGI-BP, the occurrence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes in other scales such as BARS, SAS, AIMS, and IPSS for males aged ≥ 45 years. The end-of-study visit will conclude the participant's involvement, which is expected to last approximately three weeks. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or non-compliance with study protocols.

The clinical trial involves the administration of **KarXT**, an experimental medication 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 route of administration for KarXT is **oral**, and the maximum daily dose is specified as 25,099,960 mg, with a total maximum dose of 52,509,991,260 mg over a treatment period of up to 3 weeks. The dosing schedule and participant compliance are monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a **placebo** group, utilizing a KarXT matching placebo. The placebo is designed to mimic the appearance of the KarXT capsules but contains no active medicinal ingredients. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias and enhancing the reliability of the study results.

The efficacy of KarXT in the treatment of manic episodes in **Bipolar-I Disorder** will be assessed through a Phase 3, randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change from baseline in the Young Mania Rating Scale (YMRS) score at Week 3. This scale is a validated tool used to assess the severity of manic symptoms. Secondary endpoints include the change from baseline in the Clinical Global Impressions-Bipolar (CGI-BP) score at Week 3, which evaluates daily functioning, as well as the occurrence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs leading to treatment discontinuation. Additionally, changes in the Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and International Prostate Symptom Score (IPSS) for males aged 45 years and older will be assessed at Week 3.