A Study Evaluating the Efficacy of Xanomeline/Trospium (XT) on Cognitive Impairment After 24 and 52 Weeks of Treatment in Adult Participants With Schizophrenia

Official title

A Prospective, Open-label, Single-arm, Multicenter Study Evaluating the Efficacy of Xanomeline/Trospium (XT) on Cognitive Impairment After 24 and 52 Weeks of Treatment in Adult Participants With Schizophrenia

Overview

Schizophrenia is a long-lasting and serious mental health disorder that affects about 1% of people worldwide. It can cause symptoms such as hallucinations and delusions (called positive symptoms), confused or disorganized thinking, reduced motivation and emotional expression (negative symptoms), difficulties with memory and concentration (cognitive symptoms), and movement problems like restlessness or slowed activity. Current treatments, called antipsychotics, mainly work by blocking dopamine in the brain. These medicines are helpful for hallucinations and delusions, but they do little to improve negative or cognitive symptoms. A new medicine, Xanomeline/Trospium (XT), works differently. It targets a brain system called the muscarinic acetylcholine receptors while limiting side effects elsewhere in the body. Clinical trials have shown that XT reduces psychotic symptoms effectively and is generally well tolerated. The FDA approved XT in 2024 for adults with schizophrenia. Importantly, early results also suggest that XT may help improve thinking and memory (cognition domains), though this has not yet been studied in depth. Most schizophrenia drug studies pay little attention to long-term changes in cognition, often using only short screening tests. This study will be the first to take a deep look at cognitive function over a full year of XT treatment. It will also examine how changes in thinking skills connect with other aspects of life, such as symptom control, daily functioning, and quality of life. By making cognition a central outcome, the study responds to an urgent need in schizophrenia research: moving beyond just controlling hallucinations and delusions toward improving real-world recovery. The results could help shape future treatment strategies and support the idea that cognition should be a core treatment target in schizophrenia.

Detailed description

This is a phase III, prospective, open-label, single-arm, international, multicenter study. At visit 1, the informed consent is signed and screening is performed to confirm eligibility. At visit 2, baseline measures are performed, and the new treatment is initiated. Max. 14 days after the baseline visit, the pre-study antipsychotic treatment is withdrawn via tapering. At visit 3, 4, 5, 7 and 9 participants' general wellbeing and safety is assessed. At visit 6, 8 and 10, baseline measures are repeated. Between visit 6-7, visit 7-8, visit 8-9 and visit 9-10, a phone call is planned to assess general psychopathology, adverse events and concomitant medication. The treatment duration is one year for each participant; with a safety follow up 4 weeks after the end of the trial. All participants are treated with XT open label.

Interventions

• Drug Xanomeline/trospium
  Participants will receive oral xanomeline/trospium during the trial (target dose 125/30 BID).

Primary outcome measures

• Change in cognitive performance after 24 weeks of treatment, relative to baseline. [Time frame: 24 weeks]

Secondary outcome measures (1)

• Change in negative symptoms after 24 weeks of treatment, relative to baseline. [Time frame: 24 weeks]

Eligibility criteria

Inclusion criteria

• Be between 18 and 55 years of age.
• Be willing and able to provide informed consent, after the nature of the study has been fully explained. This includes being able to understand the locally approved informed consent (and information letter) in the local language.
• Have a current DSM-5 diagnosis of schizophrenia, which needs to be confirmed by MINI.
• Have all PANSS positive items + G8 and G10 ≤4 at screening.
• Be on a stable dose of oral antipsychotic medication(s) for at least 4 weeks prior to Screening. Participants should be on monotherapy oral AP for baseline visit.
• Have a SCIP total below 70.
• Test negative for pregnancy at the screening visit and must be using a highly effective contraceptive method during the study and 30 days after the study, if being a female of childbearing potential.

Exclusion criteria

• Be pregnant, lactating, or less than 3 months postpartum.
• Be at significant risk of committing suicide. This is defined as: participants with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the participant to participate in the study.
• Currently meet DSM-5 criteria for a manic episode or major depressive disorder as confirmed by the MINI.
• Currently meeting DSM-5 criteria for severe substance and/or alcohol use disorder as confirmed by the MINI (≥6 on module K for alcohol use disorder and/or ≥6 on module J for substance use disorder, unless being in early or sustained remission).
• Have a positive urine toxicology for phencyclidine, amphetamines, opiates (unless participant has a valid prescription for short-term use), cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator). Nicotine and caffeine use is allowed. Stimulants and cannabis is allowed when used sporadically and recreationally as per the judgement of the clinician.
• Present with an intellectual disability, drug-induced psychosis, or history of clinically significant brain trauma as per the judgement of the clinician.
• Have current or past use of clozapine (used for at least 6 weeks in an effective dose range) and/or current use of a long-acting injectable antipsychotic, or anticholinergic treatment that cannot be discontinued before the baseline visit.
• Be expected to require more than the allowed psychotropic concomitant medication during the study (from baseline on). This is defined as: needing benzodiazepines of more than 2 mg lorazepam equivalent (daily), quetiapine, antidepressants, mood stabilizers or benzodiazepines at a dose exceeding the allowed threshold. If these treatments are used at the screening visit, they must be tapered down before the baseline visit.
• Have clinically significant abnormal finding on the physical examination, medical history, ECG (at screening), or clinically significant laboratory results at screening.
• Participated in any cognitive remediation/training program or completed the BACS within 4 weeks of Screening.
• Having a known allergy to xanomeline, trospium chloride or any of the ingredients of XT.
• Have current presence of clinically significant cardiovascular, pulmonary, renal, hematologic, gastrointestinal (e.g., 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. This includes:

12a. Have history or high risk of urinary retention. 12b. All grades of hepatic impairment (mild \[Child-Pugh Class A\], moderate \[Child-Pugh Class B\], and severe \[Child-Pugh Class C\]).

12c. Elevations in hepatic transaminases at screening ≥ 2× ULN for ALT and AST and/or bilirubin > 2 × ULN, unless in the context of Gilbert's syndrome.

12d. Have a history or high risk for narrow-angle glaucoma. 12e. Active biliary disease (e.g., symptomatic gallstones). Participants with other biliary histories are eligible and should be discussed with the sponsor.

12f. Participants with a history of bladder stones . 12g. Participants with a history of recurrent urinary tract infections. 12h. For all male participants, serum prostate-specific antigen >10 ng/mL at screening.

12i. For male participants ≥ 45 years of age, an IPSS score of 5 (i.e, "almost always") on items 1, 3, 5, or 6, and/or for male participants ≥ 45 years of age, an IPSS score ≥ 9 for the sum of items 1, 3, 5, and 6.

12j. An eGFR of < 60 mL/min (which indicates renal dysfunction). 12k. History of unstable hypertension or tachycardia as evidenced by a blood pressure of ≥ 160/100 mmHg at screening and/or a heart rate of ≥ 110 bpm at screening.

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 4 centers

• University of Augsburg — Augsburg
• University Hospital Cologne — Cologne
• Central Institute of Mental Health — Mannheim
• Ludwig Maximilian University — München

Spain · 3 centers

• Hospital Clínic de Barcelona — Barcelona
• Hospital Universitario La Paz — Madrid
• Hospital Universitario Virgen del Rocío — Seville

Italy · 2 centers

• University of Campania Luigi Vanvitelli — Naples
• AOU Città della Salute e della Scienza di Torino — Torino

Austria · 1 center

• Medical University Innsbruck — Innsbruck

Belgium · 1 center

• UPC KU Leuven — Leuven

Czechia · 1 center

• National Institute of Mental Health — Klecany

Denmark · 1 center

• Psykiatrisk Center Glostrup — Glostrup Municipality

Hungary · 1 center

• Semmelweis University — Budapest

Israel · 1 center

• Sheba Medical Center — Ramat Gan

Netherlands · 1 center

• University Medical Center Groningen — Groningen

Identifiers

NCT: NCT07084831 · 2025-523060-20-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗