A Phase 3, Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of Adjunctive KarXT for the Treatment of Mania, With or Without Mixed Features, in Individuals with Bipolar-I Disorder Taking Lithium, Valproate, or Lamotrigine

The primary objective of this study is to evaluate the superiority of adjunctive KarXT (comprising xanomeline tartrate and trospium chloride) in combination with lithium, valproate, or lamotrigine compared with placebo plus the same mood stabilizers in reducing the severity of acute mania, with or without mixed features, in participants with bipolar I disorder. This assessment aims to establish whether the addition of KarXT to standard mood stabilizer therapy provides clinically meaningful reduction in manic symptom severity and overall symptomatology in this patient population.

The secondary objective is to determine whether participants with mania associated with bipolar I disorder experience overall improvement in their condition when treated with KarXT plus lithium, valproate, or lamotrigine compared with placebo plus these mood stabilizers.

This clinical trial enrolled a total of **239 participants** diagnosed with **Bipolar I disorder** (BP-I) experiencing an acute episode of **mania** or **mania with mixed features**. The study population included both male and female participants aged **18 to 65 years**. All individuals had a primary diagnosis of BP-I established through comprehensive psychiatric evaluation based on **DSM-5-TR criteria** and confirmed by the **Mini International Neuropsychiatric Interview (MINI)** version 7.0.2. Participants were required to be experiencing an acute exacerbation or relapse of a manic episode lasting no more than three weeks and requiring hospitalization. All enrolled individuals were currently receiving a stable therapeutic dose of **lithium**, **valproate**, or **lamotrigine** for at least two weeks prior to screening, with those on valproate having received treatment for a minimum of seven months. The trial population was selected based on specific clinical criteria including a **Young Mania Rating Scale (YMRS)** Total Score of at least 18 at both screening and baseline with less than 20% reduction between these timepoints, and a **Clinical Global Impression-Bipolar (CGI-BP)** Severity scale score of at least 4. Participants were required to have a **body mass index** between 18 and 40 kg/m².

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of adjunctive KarXT in individuals with Bipolar I disorder experiencing mania or mania with mixed features. Participants will be taking a stable dose of lithium, valproate, or lamotrigine as background mood stabilizer therapy. The investigational product KarXT contains trospium chloride and xanomeline tartrate as active substances and is administered orally in capsule form. A matching placebo will be used as the comparator. The maximum treatment period is 5 weeks, with a maximum daily dose of 25099960 mg and a maximum total dose of 79509991900 mg. The trial is expected to commence recruitment in January 2026 and is estimated to conclude in June 2027.

The primary objective is to determine the superiority of KarXT plus mood stabilizer compared with placebo plus mood stabilizer in reducing the severity of acute mania, with or without mixed features, in participants with Bipolar I disorder. The primary endpoint is the change from baseline in Young Mania Rating Scale (YMRS) score at Week 5, which evaluates manic symptoms. The secondary endpoint is the change from baseline in Clinical Global Impression-Bipolar (CGI-BP) scale at Week 5, which assesses daily functioning.

Eligible participants must be between 18 and 65 years of age at the time of informed consent. A primary diagnosis of Bipolar I disorder must be established by comprehensive psychiatric evaluation based on DSM-5-TR criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) version 7.0.2. Participants must be experiencing an acute exacerbation or relapse of a manic episode, with or without mixed features, lasting 3 weeks or less. Hospitalization is required for the acute exacerbation or relapse of mania. Participants must be receiving a therapeutic and stable dose of lithium, valproate, or lamotrigine for at least two weeks prior to screening. Additionally, participants on valproate must have been receiving treatment for a minimum of seven months. At screening and baseline, participants must have a YMRS total score of 18 or higher, with less than 20% reduction in YMRS from screening to baseline, and a CGI-BP severity score of 4 or higher. Body mass index must be between 18 and 40 kg/m² inclusive.

Participant involvement in the study includes a screening visit to assess eligibility, followed by a baseline visit where randomization occurs and treatment is initiated. Follow-up visits are conducted to monitor efficacy and safety throughout the 5-week treatment period. The end-of-study visit occurs at Week 5 or upon early termination. Early termination from the study may occur if a participant withdraws consent, experiences adverse events requiring discontinuation, demonstrates lack of efficacy, or meets protocol-defined discontinuation criteria.

The experimental medication KarXT (sponsor product code BMS-986510) is administered as a capsule formulation for oral administration. The product contains two active substances of chemical origin: trospium chloride and xanomeline tartrate. The maximum daily dose amount is 25099960 milligrams, with a maximum total dose amount of 79509991900 milligrams over a maximum treatment period of 5 years. KarXT serves as the test product in this clinical trial and is administered as adjunctive therapy in combination with lithium, valproate, or lamotrigine.

KarXT Matching Placebo is utilized as the comparator treatment in this randomized, double-blind, placebo-controlled study. The placebo is designed to match the experimental medication to maintain blinding throughout the trial. The placebo contains no active pharmaceutical ingredients and serves as the control arm against which the efficacy and safety of KarXT are evaluated. Participants receiving placebo also continue their background therapy with lithium, valproate, or lamotrigine.

All study participants receive concomitant standard-of-care therapy consisting of lithium, valproate, or lamotrigine as background treatment for bipolar I disorder. The investigational product or matching placebo is administered as adjunctive therapy to these mood stabilizers. This study design allows for the evaluation of KarXT's efficacy and safety when added to existing therapeutic regimens for the treatment of acute mania, with or without mixed features, in individuals with bipolar I disorder.

Efficacy will be assessed through the evaluation of changes in manic symptom severity and overall clinical functioning in participants with Bipolar-I disorder experiencing acute mania, with or without mixed features. The primary efficacy endpoint is the change from baseline in the Young Mania Rating Scale (YMRS) score at Week 5. The YMRS is a validated instrument used to evaluate manic symptoms in individuals with bipolar disorder. The secondary efficacy endpoint is the change from baseline in the Clinical Global Impression-Bipolar scale (CGI-BP) at Week 5, which is utilized to assess daily functioning and overall clinical severity. Both endpoints will be measured at Week 5 to determine the superiority of KarXT plus lithium, valproate, or lamotrigine compared with placebo plus the same mood stabilizers in reducing the severity of acute mania and associated symptoms. Baseline assessments require a YMRS Total Score of at least 18 at both screening and baseline, with less than 20% reduction between these timepoints, and a CGI-BP score of at least 4, ensuring that participants meet criteria for moderate to severe symptom severity at study entry.