Muscarinic Agonist Modulation of Memory Processing Oscillatory Activity
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)
研究概览
简要总结
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.
详细描述
Patient Identification: The study team plans to recruit adult patients who are undergoing invasive electroencephalographic (EEG) monitoring as part of standard clinical procedure for the treatment of pharmacologically resistant epilepsy at UT Southwestern. Patients are identified from the pool of patients presented at the epilepsy management conference and approached when they present to the clinic for evaluation for seizure surgery. Patients are screened by a coordinator as well as anesthesiologist on the study team for contraindications which make them ineligible for receiving the drug.
Study procedures: Participation takes place only during the time that the electrodes are surgically in place. Active participation will end when the electrodes are removed. Tasks described below will be administered by key personnel on the study. The data will be de-identified and converted to signal data for processing and analysis. Study personnel, excluding the PI (aka 'experimenters') will perform analysis.
Once patients are in the epilepsy monitoring unit (EMU), subjects will be randomized to receive either a dose of 50 mg/20 mg orally BID of xanomeline and trospium chloride (COBENFY) or placebo pill. Approximately 2 hours after administration, the participant will complete an episodic memory task session. At least 24 hours following the first session (at least four half-lives after the first session), the participant will receive the alternative agent not given the first day. For example, if the patient received COBENFY the first day, they would receive the placebo the second day, and vice versa. They will then complete an additional episodic memory task session 2 hours after administration.
Day 1: Randomized to receive either COBENFY or placebo (sham); Complete episodic memory task session Day 2: Receives alternate agent from day 1; Completes episodic memory task session
Participant will not know whether Cobenfy KarXT is being administered, or if he/she receives the placebo. Researchers will be blind to this until after patient has completed both sessions. The randomization will be generated by the pharmacy using a psuedorandomizer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
COBENFY KarXT (50/20 mg)
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.
干预措施: COBENFY KarXT (50/20 mg) (Drug)
Placebo
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)
时间窗: 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.
Memory-related changes in brain electrical activity in participants from baseline at Day 2 post-intervention (approx. within 1-3 hrs)
时间窗: 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.
Memory-related changes in brain electrical activity in participants from baseline at Day 1 post-intervention (approx. within 1-3 hrs)
时间窗: 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.
Memory-related changes in brain electrical activity in participants from baseline at Day 2 post-intervention (approx. within 1-3 hrs)
时间窗: 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.
次要结局
未报告次要终点
研究者
Bradley Lega
Professor - Neurological Surgery
University of Texas Southwestern Medical Center