Evaluation of the Efficacy and Safety of Trospium Chloride and Xanomeline Tartrate in Treating Manic Episodes in Bipolar-I Disorder: A Phase 3 Randomized Study

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 aspect of the study is important for assessing the broader impact of KarXT on patient-reported outcomes and overall treatment satisfaction.

The clinical trial involves a total of **185 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**. Participants were selected based on a primary diagnosis of Bipolar-I disorder, confirmed through a comprehensive psychiatric evaluation and the Mini International Neuropsychiatric Interview. The trial does not include a vulnerable population. Participants are required to have 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. All psychotropic medications must be discontinued no more than 14 days prior to the first dose of the study drug. The trial 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 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 individuals with **Bipolar-I disorder**. The primary objective is to determine if KarXT is more effective than a placebo in reducing the severity and symptoms of mania. The trial will involve participants aged 18 to 65 years who have a primary diagnosis of Bipolar-I disorder, confirmed by a comprehensive psychiatric evaluation and the Mini International Neuropsychiatric Interview. Participants must be experiencing an acute episode or relapse of mania or mania with mixed features, requiring hospitalization, and must have a Young Mania Rating Scale (YMRS) score of 20 or higher at screening and baseline.

The trial will span approximately three weeks, with the primary endpoint being the change from baseline in the YMRS score at Week 3. Secondary endpoints include changes in the Clinical Global Impressions-Bipolar (CGI-BP) score, the occurrence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes in other scales such as the Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). The study will commence with a screening visit to confirm eligibility, followed by randomization into either the KarXT or placebo group. Participants will receive the study drug orally in capsule form.

Study visits will include baseline assessments, weekly follow-up visits to monitor efficacy and safety, and an end-of-study visit to evaluate overall outcomes. The expected length of participant involvement is three weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is set to begin recruitment on September 15, 2025, with an estimated end date of November 2, 2026. Participants will be closely monitored throughout the study to ensure adherence to the protocol and to assess the impact of the treatment on manic symptoms.

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. KarXT is administered orally, with a maximum daily dose of 25099960 mg and a total maximum dose of 52509991260 mg over a treatment period of up to 3 months. 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 **KarXT Matching Placebo**. This placebo is designed to mimic the appearance of the KarXT capsules but contains no active medicinal ingredients. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. This approach helps to objectively assess the efficacy and safety of KarXT in reducing the severity and symptoms of manic episodes in participants with Bipolar-I Disorder.

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 from baseline 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.