Cholinergic Enhancement of Theta

NCT07228338 | Not Yet Recruiting Early Phase 1 FDA Drug

• 1 other identifier: STU20250602
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to learn about the effects of Cobenfy KarXT (xanomeline and trospium chloride) on episodic memory processing, including specific effects on areas of the brain involved in memory and changes it may have on brain activity. The investigators will do this by testing epileptic patients who are already undergoing intracranial surgery for seizure monitoring, and measuring the activity from the brain areas being assessed. The main questions it aims to answer are 1) whether Cobenfy KarXT changes memory activity based on its agonist effect on muscarinic receptors and acetylcholine, and 2) what the nature of these brain activity changes are. This work builds on previous experiments evaluating cholinergic antagonists. Participants will complete two treatment arms. One of these will be with the drug, and the other will be with a placebo pill, so that the participants are unaware which session the actual drug has been received. Patients will complete a verbal serial recall and/or associative recognition task each of the two days. An anesthesiologist or patient nurse will administer either the drug or the placebo at a critical point which addresses both of the research questions. Researchers will compare the brain activity between the two treatment arms to determine what brain activity changes, and whether there is an additional behavioral effect on memory.

Conditions

Epilepsy; Seizures; Cognitive Impairment, Mild; Memory Disorder; Memory Loss

Keywords

oscillatory changest; cholinergic agonist; muscarinic agonist

Outcome Measures

Primary Outcomes (6)

• Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the Free recall memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily theta power and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 1 post-intervention (approx. within 1-3 hrs)

• Memory-related changes in brain electrical activity in participants from baseline at Day 2 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the Free recall memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily theta power and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 2 post-intervention (approx. within 1-3 hrs)

• Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the serial recall memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily thetapower and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 1 post-intervention (approx. within 1-3 hrs)

• Memory-related changes in brain electrical activity in participants from baseline at Day 2 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the serial recall memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily theta power and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 2 post-intervention (approx. within 1-3 hrs)

• Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the associative recognition memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily theta power and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 1 post-intervention (approx. within 1-3 hrs)

• Memory-related changes in brain electrical activity in participants from baseline at Day 2 post-intervention (approx. within 1-3 hrs)

  Memory-related changes in brain electrical activity in participants from baseline at post-intervention (approx. within 1-3 hrs) is measured by comparing the associative recognition memory tasks with the electrical readings collected across all bandwidths, but focusing on primarily theta power and oscillatory changes. Other changes, such as phase amplitude coupling, may also be considered.

  Baseline, at Day 2 post-intervention (approx. within 1-3 hrs)

Study Arms (2)

COBENFY KarXT (50/20 mg)

EXPERIMENTAL

Subjects will receive a dose of COBENFY KarXT (50/20 mg). Approximately 2 hours minutes after administration, the participant will then complete an episodic memory task session. If the patient completed the sham session already, this session will take place minimum of 24 hours following the initial session, or at least four half-lives after the first session.

Drug: COBENFY KarXT (50/20 mg)

Placebo

PLACEBO COMPARATOR

Subjects will receive a placebo. Approximately 2 hours minutes after administration, the participant will then complete an episodic memory task session. If the patient completed the COBENFY KarXT session already, this session will take place minimum of 24 hours following the initial session, or at least four half-lives after the first session.

Drug: Placebo

Interventions

COBENFY KarXT (50/20 mg) DRUG

Patient receives a dose of COBENFY KarXT (50/20 mg) 2 hours prior to episodic memory task.

COBENFY KarXT (50/20 mg)

Placebo DRUG

Patient receives a dose of placebo 2 hours prior to episodic memory task.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 - 75 years, all races/ethnicities, and both genders are eligible.
• Candidates for pre-operative evaluation using stereo intracranial electrodes and admission to the Epilepsy Monitoring Unit (EMU) as determined independently by the patient's treating physician as part of the patient's routine medical care.
• Able to read, understand, and provide written, dated informed consent prior to screening.
• In good general health, aside from a history of epilepsy, as ascertained by medical history, physical examination (PE), clinical laboratory evaluations, and ECG.

You may not qualify if:

• Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results according to the study physician.
• Female that is pregnant, breastfeeding, or has a positive pregnancy test at screening or baseline. We note that pregnant patients are excluded from undergoing iEEG.
• Hepatic impairment (moderate or severe).
• Renal impairment (moderate or severe).
• Clinically significant bladder outlet obstruction or incomplete bladder emptying, such as patients with prostatic hyperplasia (BPH), diabetic cystopathy, pre-existing urinary retention.
• History of hypersensitivity to COBENFY or trospium chloride (angioedema risks).
• Untreated narrow-angle glaucoma.
• Biliary Disease (symptomatic gallstones, gallbladder disorders, pancreatitis).
• Strong Inhibitors of CYP2D6 such as fluoxetine, paroxetine, bupropion, terbinafine.
• Sensitive Substrates of CYP3A4 such as buspirone, eletriptan.
• Narrow Therapeutic Index Substrates of P-glycoprotein such as digoxin, colchicine, apixaban.
• Drugs Eliminated by Active Tubular Secretion.
• Antimuscarinic Drugs such as diphenhydramine, benztropine, oxybutynin.

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Epilepsy; Seizures; Cognitive Dysfunction; Memory Disorders

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Neurobehavioral Manifestations

Study Officials

• Bradley C Lega, MD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bradley C Lega, MD

CONTACT

214-648-7816; Bradley.Lega@UTSouthwestern.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor - Neurological Surgery

Model Details: Patients are randomized to COBENFY or placebo by the pharmacy. Both researchers and patients are blinded to which session receives pharmaceutical versus placebo administration. Each of the patients receive COBENFY or placebo on Day 1 and Day 2 before completing tasks at to evaluate effects on episodic memory processes.

Study Record Dates

• First Submitted: November 12, 2025
• First Posted: November 14, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2031
• Study Completion (Estimated): October 1, 2031
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)