Clinical trial designs

The COBENFY clinical trial program evaluated more than 1250 patients across 5 clinical trials1-5

Three 5-week studies* evaluated mean change in PANSS total score in adult patients with schizophrenia experiencing acute psychosis.6†

Cobenfy clinical trial design

Primary end point6:

  • Change in PANSS total score from baseline at Week 5

Prespecified secondary end points1-3:

  • Change from baseline at Week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, and CGI-S score
  • Proportion of participants with at least a 30% reduction from baseline to Week 5 in PANSS total score (EMERGENT-2 & -3 only)
* Pivotal 5-week trials were placebo controlled.3,9
† Patients who were newly diagnosed or were experiencing their first treated episode of schizophrenia were excluded.1,6,7,10
‡ Markedly ill=symptoms that impair social or occupational function or cause intrusive levels of distress.11
§ Day 34 for EMERGENT-1.7
|| Safety follow-up only occurred in 2 out of the 3 clinical trials.7

Two 52-week, open-label studies evaluated long-term safety and efficacy4,5

EMERGENT-4 and EMERGENT-5 52-week clinical trial design
  • Two long-term, 52-week, phase 3, open-label studies4,5,7
  • EMERGENT-4 included patients who previously completed the treatment period of EMERGENT-2 or EMERGENT-34
  • EMERGENT-5 included a patient population with the following select characteristics7:
    • Aged 18 to 65 years at time of screening
    • No psychiatric hospitalization, acute crisis intervention, or other inpatient care within 8 weeks prior to screening
    • PANSS score of ≤80
    • CGI-S score of ≤4
    • Received an oral antipsychotic medication within 30 days prior to screening
    • Antipsychotic down-taper, if clinically appropriate in the opinion of the investigator, may occur during the screening phase
  • The primary objective of these studies was to assess the long-term safety and tolerability of COBENFY4,5
  • The secondary objective was to assess the long-term efficacy and evaluate plasma concentrations of xanomeline and trospium chloride after administration of COBENFY7
  • Patients with a history of treatment resistance to antipsychotic medications were excluded from these trials6,7,¶
Failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) within the past 12 months or having received clozapine within the past year (for EMERGENT-4) or 3 years (for EMERGENT-5).7
   
  BID=twice daily; CGI-S=Clinical Global Impression - Severity Scale; PANSS=Positive and Negative Syndrome Scale.

View the PANSS total score data in phase 3 trials

References: 

  1. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.
  2. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry 2024;81(8):749-756.
  3. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726.
  4. Kaul I, Claxton A, Sauder C, et al. Long-term safety and efficacy of xanomeline and trospium chloride in schizophrenia: results from the 52-week, open-label EMERGENT-4 trial. Poster presented at: Psych Congress; October 29-November 2, 2024; Boston, MA.
  5. Kaul I, Claxton A, Sauder C, et al. Long-term safety, tolerability, and efficacy of xanomeline and trospium chloride in people with schizophrenia: results from the 52-week, open-label EMERGENT-5 trial. Poster presented at: Psych Congress; October 29- November 2, 2024; Boston, MA.
  6. Kaul I, Sawchak S, Claxton A, et al. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials. Schizophrenia (Heidelb). 2024;10(1):102.
  7. Data on file. Karuna Therapeutics, Inc., a Bristol Myers Squibb company; Boston, MA.
  8. Mortimer AM. Symptom rating scales and outcome in schizophrenia. Br J Psychiatry Suppl. 2007;50:s7-s14.
  9. COBENFY. Prescribing Information. Bristol-Myers Squibb Company; 2024.
  10. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2024;81(8)(suppl):749-756.
  11. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

COBENFY™ is contraindicated in patients with: urinary retention; moderate or severe (Child-Pugh Class B or C) hepatic impairment; gastric retention; history of hypersensitivity to COBENFY or trospium chloride—angioedema has been reported with COBENFY and trospium chloride; and untreated narrow-angle glaucoma.

WARNINGS AND PRECAUTIONS

Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention.

COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment.

In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated.

Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions.

COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment.

Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment.

Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.

COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated.

Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.

Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride.

Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring.

Increases in Heart Rate: COBENFY can increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY.

Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.

Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.

Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.

Use in Specific Populations:

 
  • Moderate or Severe Renal Impairment: Not recommended
  • Mild Hepatic Impairment: Not recommended

Pregnancy and Lactation: There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications, including COBENFY, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/.

There are no available data on COBENFY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Additionally, there are no data on the presence of xanomeline or trospium in human milk, the effects on the breastfed infant, or the effects on milk production. However, xanomeline and trospium are present in animal milk, suggesting they may also be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COBENFY and any potential adverse effects on the breastfed infant from COBENFY or the underlying maternal condition.

COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules.

INDICATION

COBENFY™ (xanomeline and trospium chloride) is indicated for the treatment of schizophrenia in adults.

Please see U.S. Full Prescribing Information, including Patient Information.

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Cobenfy, Cobenfy Cares, and the Cobenfy logo are trademarks of Karuna Therapeutics, Inc., a Bristol Myers Squibb company.
© 2025 Bristol-Myers Squibb Company.

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