A Study to Evaluate the Efficacy and Safety of Adjunctive KarXT for the Treatment of Mania, With or Without Mixed Features, in Participants With Bipolar-I Disorder Taking Lithium, Valproate, or Lamotrigine

Official title

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

Overview

The purpose of this study is to evaluate the efficacy and safety of adjunctive KarXT for the treatment of mania in participants with Bipolar-I Disorder.

Interventions

• Drug Xanomeline/Trospium Chloride
  Specified dose on specified days
• Drug Placebo
  Specified dose on specified days

Primary outcome measures

• Change from baseline in Young Mania Rating Scale (YMRS) at Week 5 [Time frame: At Week 5]

Secondary outcome measures (11)

• Change from baseline in Clinical Global Impressions Bipolar (CGI-BP) at Week 5 [Time frame: At Week 5]
• Occurrence of response at Week 5 assessed as the number of participants with a ≥ 50% decrease from baseline in Young Mania Rating Scale (YMRS) score [Time frame: At Week 5]
• Occurrence of response at Week 5 assessed as the number of participants with a ≥ 1 change from baseline in CGI-BP [Time frame: At Week 5]
• Number of participants with Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to Week 7]
• Number of participants with Serious Adverse Events (SAEs) [Time frame: Up to Week 7]
• Number of participants with TEAEs leading to treatment discontinuation [Time frame: Up to Week 5]
• Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) [Time frame: Up to Week 7]
• Change from baseline in Barnes Akathisia Rating Scale (BARS) at Week 5 [Time frame: At Week 5]
• Change from baseline in Simpson Angus Scale (SAS) at Week 5 [Time frame: At Week 5]
• Change from baseline in Abnormal Involuntary Movement Scale (AIMS) at Week 5 [Time frame: At Week 5]
• Change from baseline in International Prostate Symptom Score (IPSS) at Week 5 [Time frame: At Week 5]

Eligibility criteria

Inclusion criteria

• Individuals have a primary diagnosis of Bipolar-I disorder established by a comprehensive psychiatric evaluation based on the DSM-5-TR criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI) version 7.0.2.
• Individual is experiencing an acute exacerbation or relapse of manic episode, with or without mixed features (≤ 3 weeks).
• The individual requires hospitalization for the acute exacerbation or relapse of mania.
• Body mass index ≥ 18 and ≤ 40 kg/m2.
• Currently experiencing an acute episode of mania or mania with mixed features with a therapeutic dose of lithium, valproate, or lamotrigine. The dose of the mood stabilizer must have remained stable for at least two weeks prior to screening. Additionally, participants on valproate must have been receiving treatment with valproate for a minimum of seven months.
• YMRS Total Score of ≥ 18 at Screening and at Baseline, and < 20% reduction in YMRS from screening to baseline.

Exclusion criteria

• Any primary DSM-5-TR disorder other than BP-I within 12 months before screening (confirmed using MINI version 7.0.2 at screening) including BP-I depression (for previous 3 months only), BP-I with rapid cycling, first manic episode, BP-II, primary psychotic disorder, borderline personality disorder, and major depressive disorder, with the exception of mild anxiety disorders.
• Individual has a DSM-5-TR diagnosis of moderate to severe substance use disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current use as determined by urine toxicology screen or alcohol test.
• Risk for suicidal behavior at screening as determined by the investigator's clinical assessment and the C-SSRS with an answer "Yes" to item 4 or 5 within 6 months before screening or between screening and baseline, or "Yes" to any of the 5 items (C-SSRS behavior) with an event occurring within the 12 months before screening, or between screening and baseline.
• History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months.
• History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma.
• Participants with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on either medical history or the LFT results.
• Elevations in hepatic transaminases at screening ≥ 2 × ULN for ALT or AST and/or bilirubin > 1.5× ULN, unless in the context of Gilbert's syndrome.
• All grades of hepatic impairment (mild \[Child-Pugh Class A\], moderate \[Child-Pugh Class B\], and severe \[Child-Pugh Class C\]).
• Other protocol-defined Inclusion/Exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 20 centers

• Pillar Clinical Research - Bentonville — Bentonville
• Pillar Clinical Research- Little Rock — Little Rock
• Clinical Innovations, Inc. dba CITrials — Bellflower
• Inland Psychiatric Medical Group. — Chino
• Proscience Research Group — Culver City
• Omega Clinical Trials - La Habra — La Habra
• Catalina Research Institute, LLC — Montclair
• NRC Research Institute — Orange
• … and 12 more centers

Japan · 13 centers

• Okehazama Hospital — Toyoake
• Local Institution - 0205 — Ichikawa
• Local Institution - 0172 — Iizuka
• Local Institution - 0141 — Kitakyushu-shi
• Goryokai Medical Corporation - Goryokai Hospital — Sapporo
• Local Institution - 0107 — Yokohama
• Rainbow and Sea Hospital — Karatsu
• Juntendo University Hospital — Bunkyo-ku
• … and 5 more centers

Ukraine · 12 centers

Center list to be confirmed — check the primary protocol.

China · 11 centers

• Local Institution - 0185 — Beijing
• Local Institution - 0190 — Beijing
• Local Institution - 0191 — Guangzhou
• Local Institution - 0193 — Baoding
• Local Institution - 0187 — Shijiazhuang
• Local Institution - 0196 — Nanjing
• Local Institution - 0186 — Xi'an
• Local Institution - 0192 — Chengdu
• … and 3 more centers

Romania · 11 centers

Center list to be confirmed — check the primary protocol.

Argentina · 6 centers

• Local Institution - 0011 — ABB
• Local Institution - 0010 — Córdoba
• Local Institution - 0012 — Córdoba
• Local Institution - 0008 — Córdoba
• Local Institution - 0009 — Mendoza
• Local Institution - 0114 — Santiago del Estero

Bulgaria · 5 centers

• Local Institution - 0184 — Kazanlak
• State Psychiatric Hospital Sv. Ivan Rilski Novi Iskar — Novi Iskar
• "University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski" EAD — Pleven
• Local Institution - 0181 — Sliven
• Local Institution - 0086 — Targovishte

France · 5 centers

• Local Institution - 0126 — Nice
• Local Institution - 0085 — Clermont-Ferrand
• Local Institution - 0087 — Marseille
• Local Institution - 0129 — Montpellier
• Local Institution - 0089 — Paris

Israel · 5 centers

• Local Institution - 0052 — Hod HaSharon
• Sheba Medical Center — Ramat Gan
• Local Institution - 0053 — Ashkelon
• Be'er Sheva Mental Health Center — Beersheba
• Local Institution - 0083 — Jerusalem

Italy · 5 centers

• Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico — Milan
• Local Institution - 0005 — Pisa
• Azienda Ospedaliero Universitaria Senese — Siena
• Local Institution - 0004 — Ancona
• Local Institution - 0002 — Genova

India · 4 centers

• Local Institution - 0121 — Mangalore
• Local Institution - 0123 — Madurai
• Local Institution - 0118 — Kolkata
• Local Institution - 0116 — Kolkata

Poland · 4 centers

• Instytut Psychiatrii i Neurologii — Warsaw
• Uniwersyteckie Centrum Kliniczne — Gdansk
• Local Institution - 0103 — Rybnik
• … and 1 more center

Denmark · 3 centers

• Local Institution - 0088 — Hillerød
• Local Institution - 0054 — Aalborg
• Local Institution - 0091 — Glostrup Municipality

Identifiers

NCT: NCT07140913 · CN012-0046 · 2025-521845-26 · U1111-1321-1513

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗