A Phase 3, randomized, double-blind, placebo-controlled, multicenter, inpatient study in participants with bipolar disorder experiencing an acute episode of mania or mania with mixed features.
Scientific Title of Study
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of KarXT for the Treatment of Manic Episodes in Bipolar-I Disorder (BALSAM-2)
Trial Acronym
NILL
Secondary IDs if Any
Secondary ID
Identifier
2024-520195-94
EudraCT
CN012 0037 _Protocol Amend 01 _ Dated 14-Apr-25
Protocol Number
IND: 174480
Other
U1111-1316-7466
UTN
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Shilpi Sinha
Designation
Director, RCO Head
Affiliation
Bristol-Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphistone (W), Mumbai
Mumbai MAHARASHTRA 400013 India
Phone
09833515863
Fax
Email
shilpi.sinha@bms.com
Details of Contact Person Scientific Query
Name
Kartik Doshi
Designation
Associate Director, Head Medical India
Affiliation
Bristol-Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphistone (W), Mumbai Senapati Bapat Marg, Elphistone (W), Mumbai- 400013 Mumbai MAHARASHTRA 400013 India
Phone
912266288600
Fax
Email
Kartik.Doshi@bms.com
Details of Contact Person Public Query
Name
Shilpi Sinha
Designation
Director, RCO Head
Affiliation
Bristol-Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphistone (W), Mumbai
Mumbai MAHARASHTRA 400013 India
Phone
09833515863
Fax
Email
shilpi.sinha@bms.com
Source of Monetary or Material Support
Bristol Myers Squibb India Pvt. Ltd. One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai- 400013 India
Primary Sponsor
Name
BRISTOL MYERS SQUIBB INDIA PRIVATE LIMITED
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphistone (W), Mumbai
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Croatia India Israel Romania Slovakia Spain Sweden United States of America
IEC, Chethana Centre for Neuropsychiatric Rehabilitation
Approved
Institutional Ethics Committee, KLE Academy of Higher Education and Research
Approved
Institutional Ethics Committee;
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: F312||Bipolar disorder, current episodemanic severe with psychotic features,
Intervention / Comparator Agent
Type
Name
Details
Intervention
KarXT Arm
Intervention: KarXT (xanomeline/trospium chloride)
Dosage Levels: Flexible dosing with the following possible strengths, administered orally, twice daily (BID):
50 mg/20 mg (xanomeline/trospium chloride)
100 mg/20 mg
125 mg/30 mg
Dosing Schedule:
Days 1–2: 50 mg/20 mg BID
Days 3–7: 100 mg/20 mg BID
From Day 8 onwards: titrate to 125 mg/30 mg BID as tolerated, with option to reduce to 100 mg/20 mg BID if needed
Comparator Agent
Placebo Arm
Intervention: Matching placebo
Dosage Levels: Not applicable (placebo only)
Administration: Oral, BID, matching schedule to KarXT arm for blinding purposes
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
1) Participants must be able and willing to sign and date an IRB/IEC-approved written ICF in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal participant care. Participant must be fluent in the language of the ICF to consent.
Type of Participant and Target Disease Characteristics
2) Primary diagnosis of Bipolar-I disorder established by a comprehensive psychiatric evaluation based on the DSM-5-TR criteria18 and confirmed by the Mini International Neuropsychiatric Interview (MINI, v7.0.2).
3) Experiencing an acute episode or relapse of mania or mania with mixed features (less than or equal to 3 weeks) based on DSM-5-TR criteria.18
4) Young Mania Rating Scale (YMRS) score of greater than or equal to 20 at Screening and at Baseline.
5) CGI-BP score of greater than or equal to 4 at screening and at baseline.
6) Requires hospitalization for acute exacerbation or relapse of mania.
7) Hospitalized voluntarily before or during Screening with a mania diagnosis not greater than 21 days before Screening. Hospital admission must be a result of the current manic episode. (See Appendix 4 for country-specific requirements).
8) Body mass index greater than or equal to 18 and less than or equal to 40 kg/m2.
9) All psychotropic medications are washed out in no more than 14 days prior to the first dose of the study drug.
10) Able to comprehend and satisfactorily comply with protocol requirements per investigator judgment.
Age of Participant
11) Aged 18 (or the legal age of consent in the jurisdiction in which the study is taking place, if higher) to 65 years of age, inclusive, at the time of signing the ICF.
Reproductive Status
· Note: The investigator or designee shall counsel individuals of childbearing potential (IOCBP) (as defined in APPENDIX 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
· Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
· Note: Local laws and regulations may require the use of alternative and/or additional contraceptive methods (see APPENDIX 4).
12) Female (as assigned at birth) participants:
Note: Female (as assigned at birth) participants who are individuals not of childbearing potential (INOCBP) (as defined in APPENDIX 3) must have documented proof.
Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.
Note: Participants who are INOCBP are exempt from contraceptive requirements.
a) IOCBP must have a negative highly sensitive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.
· Note: A positive serum pregnancy test or an ambiguous urine pregnancy test must be repeated and sent to the central laboratory (serum sample). If either pregnancy test cannot be confirmed as negative (eg, an ambiguous result), the participant must be excluded from participation.
· Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.
b) IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
· IOCBP are permitted to use hormonal contraceptive methods (as described in APPENDIX 3).
c) A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:
· Is an INOCBP
OR
· Is an IOCBP and using a contraceptive method that is highly effective (with a failure rate of less than 1 percent per year), with preferably user independent methods, as described in APPENDIX 3, during the intervention period and for at least 16 days, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.
13) Male (as assigned at birth) participants:
Male (as assigned at birth) participants should maintain their usual practice regarding contraception (if any); however, no specific or additional contraceptive measures are required.
ExclusionCriteria
Details
Psychiatric Conditions
1) Primary diagnosis of BP-I where present mania is first manic episode.
2) Primary diagnosis of BP-I with rapid cycling (ie, greater than or equal to 4 distinct mood episodes in one year).
3) Any primary DSM-5-TR disorder other than BP-I with mania or mania with mixed features within 12 months before screening (ie, primary focus of treatment, confirmed using MINI version 7.0.2 at screening) including BP-I with depression (for previous 3 months only), BP-II disorder, major depressive disorder, and primary psychotic disorder, with the exception of mild anxiety disorders.
4) A DSM-5-TR diagnosis of moderate to severe substance use disorder (except tobacco use disorder) within 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.
a) Participants who test positive for cannabis at screening may be permitted to enroll in consultation with the medical monitor if the participant’s pattern of use is not indicative of a substance use disorder.
5) Risk for suicidal behavior at screening as determined by the Investigator’s clinical assessment, and/or C-SSRS as confirmed by the following:
a) Answer “Yes” on items 4 or 5 (C-SSRS - ideation) within 6 months of screening, or between screening and baseline
b) Answer “Yes” to any of the 5 items (C-SSRS - behavior) within 12 months of screening or between screening and baseline.
6) Currently receiving oral psychoactive drugs that cannot be safely discontinued in the 14 days of screening prior to first dose, or whose half-life is greater than 14 days. For participants receiving monthly long-acting injectables (LAIs), the last injection cannot be less than five weeks before the first dose. Participants on LAIs with a two-month frequency cannot have had their last injection less than 10 weeks before the first dose of study treatment. Participants on LAIs with longer frequency periods will be excluded.
7) Lifetime history of any clozapine use.
8) Had a separate psychiatric hospitalization(s), unrelated to the current manic episode, within 90 days before screening.
9) YMRS total score less than 20 at baseline or greater than or equal to 20% reduction in YMRS from screening to baseline.
10) If, in the opinion of the investigator (and/or Sponsor), participant is unsuitable for enrollment in the study, or the participant has any finding that in the view of the investigator (and/or Sponsor) may compromise the safety of the participant or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements.
General Medical Conditions
11) History or present illness suggestive of uncontrolled hyperthyroidism.
12) History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months.
13) History or high risk of urinary retention, gastric retention, or untreated narrow-angle glaucoma. 14) History or presence of clinically significant cardiovascular (eg, untreated or unstable hypertension, clinically significant tachycardia), pulmonary, renal, hematologic, gastrointestinal (eg, obstructive disorders [including conditions that may decrease GI motility, such as ulcerative colitis, intestinal atony, and myasthenia gravis]), endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the participant or the validity of the study results.
15) Participants with cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on the liver function test results. Note: Participants with any grade of hepatic impairment (Child-Pugh A or higher) will be excluded.
16) Active biliary disease (eg, symptomatic gallstones).
Participants with other biliary histories are eligible and should be discussed with the medical monitor.
17) Participants are excluded from the study if any of the following criteria apply:
a) History of bladder stones
b) History of recurrent urinary tract infections
c) Serum prostate-specific antigen greater than 10 ng/mL at Screening
d) For male participants greater than or equal to 45 years of age, IPSS score of 5 (i.e., “almost always”) on items 1, 3, 5, or 6
e) For male participants greater than or equal to 45 years of age, an IPSS score greater than or equal to 9 for the sum of scores items 1, 3, 5, and 6
18) History of ischemic stroke within 12 months prior to Screening or any evidence of hemorrhagic stroke.
19) History of cerebral amyloid angiopathy, epilepsy, CNS neoplasm, unstable thyroid function, or unexplained syncope, delirium, cognitive disorders (eg, mild cognitive impairment and dementias).
20) History or presence of any of the following:
a) New York Heart Association Class II or greater heart failure
b) Grade 2 or greater angina pectoris (as measured by Canadian Cardiovascular Society [CCS] Grading)
c) Sustained ventricular tachycardia
d) Ventricular fibrillation
e) Torsade de pointes Implantable cardiac defibrillator
21) Myocardial infarction within 6 months prior to Screening.
22) Risk of violent or destructive behavior.
23) Donation of blood to a blood bank or in a clinical study (except a screening visit) within 4 weeks prior to the first dose of study drug (within 2 weeks for plasma only) and until at least 90 days after the end of the study.
24) Blood transfusion within 4 weeks prior to the first dose of study drug.
25) Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, medical history, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population.
26) Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus (HIV)-1 and HIV-2 antibody.
Reproductive Status
27) Individuals who are pregnant, breastfeeding, or less than 3 months postpartum. Prior/Concomitant Therapy
28) Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: Prior and Concomitant Therapy.
29) Pastor intended use of over-the-counter or prescription medication within 1 day or 1 half-life (whichever is longer) prior to dosing. If taking herbal/dietary supplements, subjects must be on a stable dose for at least 6 weeks prior to dosing. Ensure subjects are not taking supplements with known hepatotoxic ingredients.
30) Prior exposure to KarXT.
31) Anticipated use of lorazepam greater than allowed in protocol (see Section 7.7.1).
32) Use of any investigational medicine within 4 weeks or 5 half-lives, whichever is longer, prior to the first dose of the study drug.
Physical and Laboratory Test Findings
33) Elevations in hepatic transaminases at screening greater than or equal to 3 × ULN for ALT and AST and/or bilirubin greater than 2× ULN, unless in the context of Gilbert’s syndrome.
34) Serum creatinine or blood urea nitrogen greater than ULN, at screening, or eGFR at screening less than 60 mL/min.
35) Blood pressure of greater than or equal to 160/100 mmHg (average of triplicate seated measures) at screening
36) Heart rate of greater than or equal to 110 bpm (average of triplicate seated measures) at screening. Allergies and Adverse Drug Reactions
Allergies and Adverse Drug Reactions
37)History of any significant drug allergy (such as anaphylaxis).
38)History of allergy/hypersensitivity to any component (including excipients) of the study
intervention or related compounds.
Other Exclusion Criteria
39)Participant is an employee or first degree relative of the investigator, study site or BMS
employee, with direct involvement in the proposed study or other studies under that direction.
40)Prisoners or participants who areinvoluntarily incarcerated. Note: Under certain specific
circumstances and only in countries where local regulations permit, a person who has been
imprisonedwhile on studymay be permitted to continue as a participant. Strict conditions
apply.(See Appendix 4 for country-specific requirements)
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator and Outcome Assessor Blinded
Primary Outcome
Outcome
TimePoints
Change from baseline in Young Mania Rating Scale (YMRS) total score
3 weeks
Secondary Outcome
Outcome
TimePoints
Change from baseline in Clinical Global Impression-Bipolar (CGI-BP) overall score
Week 3
Occurrence of response based on greater than or equal to 50 present decrease from baseline in YMRS score
Week 3
Occurrence of response based on CGI-BP change from baseline greater than or equal to 1
Week 3
Occurrence of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and TEAEs leading to discontinuation
Treatment Period
Change from baseline in movement disorder scales (BARS, SAS, AIMS, IPSS for males greater than or equal to 45)
Week 3
Change in C-SSRS responses during treatment
Treatment Period
Target Sample Size
Total Sample Size="274" Sample Size from India="25" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Phase of Trial
Phase 3
Date of First Enrollment (India)
31/03/2026
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
13/06/2025
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="0" Months="1" Days="19"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Not Yet Recruiting
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
KarXT (also referred to as BMS-986510)is a novel combined formulation of two drugs,
xanomeline tartrate and trospium chloride. The combination product is being developed to treat
psychiatric disorderswith a cholinergic mechanism to mitigate the peripheral side effects of
xanomeline, a muscarinic agonist, with trospiumchloride,a muscarinic antagonist.Trospium
chloride is a quaternary ammonium compound with a permanent cationic charge that limits its
ability to cross the blood-brain barrier. Due to this property, it does not interfere with the efficacy
of xanomeline despite competing with xanomeline for binding at peripheral receptors to reduce
the negative systemic side effects of xanomeline.
KarXT has the potential to provide a novel mechanism of action for the treatment ofbipolar mania.
Most antimanic agents approved in this century have the same orsimilar mechanisms of action,
perpetuating similar side effect profiles. The goal of this study is to demonstrate the efficacy of
KarXT in BP-I maniaormania with mixed features while exploringa differentiated side effect