Dexmedetomidine Trial for Effects on Rhythms, Sleep Architecture, and Biomarker Dynamics - A Pilot Study (DEXTER)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Number of Participants With Adverse Events
研究概览
简要总结
The DEXTER study is a cross-over, double-blind, placebo-controlled pilot research study led by Dr. Peng Li. The goal of this project is to evaluate the safety, feasibility, and biological effects of a single dose of sublingual (under-the-tongue) dexmedetomidine (SL Dex) in older adults. Specifically, researchers want to see how this medication affects sleep patterns, internal 24-hour circadian rhythms, and the daily cycles of certain neurological proteins (specifically plasma p-tau217) associated with brain aging.
详细描述
Circadian rhythms are fundamental regulators of human physiology, coordinating sleep-wake timing, neural activity, metabolic processes, and hormonal signaling across the 24-hour day. These endogenous rhythms are coordinated by the suprachiasmatic nucleus (SCN), the central circadian pacemaker in the hypothalamus that integrates environmental cues such as light to synchronize peripheral and central biological processes. In older adults, circadian rhythms often degrade, exhibiting reduced robustness and impaired alignment with behavioral cycles. Such alterations are closely linked to disrupted sleep architecture, particularly sleep fragmentation and loss of restorative non-rapid eye movement (NREM) sleep. Crucially, sleep and circadian dysfunction is increasingly recognized as a critical modulator of neurodegenerative biomarker dynamics. Experimental evidence suggests that fragmented sleep and reduced slow-wave sleep directly alter the production, release, and clearance of neurotoxic proteins, leading to elevated tau levels. These observations highlight a potential mechanistic pathway linking sleep-circadian dysfunction to neurodegeneration and underscore the need to understand how interventions that stabilize these systems influence the temporal profile of tau-related biomarkers. Dexmedetomidine, a highly selective alpha2-adrenergic receptor agonist, represents a unique pharmacologic probe for investigating the links between sleep architecture, circadian physiology, and tau biomarker dynamics. Unlike traditional sedatives, dexmedetomidine engages endogenous sleep-promoting pathways and produces a NREM-like state characterized by electrophysiologic features resembling natural sleep. Beyond its sleep-modulating properties, emerging preclinical evidence suggests that dexmedetomidine exerts potent chronobiotic effects (i.e., the ability to stabilize or entrain circadian rhythms). For instance, preclinical models indicate it activates vasoactive intestinal peptide (VIP) neurons within the SCN and modulates circadian entrainment processes. Clinical studies of thoracic surgery patients further suggest that dexmedetomidine may preserve endogenous circadian signaling, such as melatonin secretion, during the early postoperative period. The recent development of sublingual dexmedetomidine (SL Dex) provides a transformative, noninvasive formulation that enables controlled administration outside of intensive care settings, distinguishing it from traditional intravenous (IV) dexmedetomidine, which is typically limited to monitored environments. Preliminary studies have suggested that SL Dex produces measurable changes in sleep architecture, including increased slow-wave activity, shortened sleep latency, and prolonged REM sleep latency. However, the extent to which SL Dex influences circadian regulation, sleep architecture, and the temporal profile of tau biomarkers across the 24-hour sleep-wake cycle in humans has not been systematically characterized. Addressing this gap requires a rigorously controlled experimental approach capable of isolating the physiologic effects of SL Dex from environmental and behavioral confounders. Prior clinical studies have largely occurred in perioperative or other medically complex settings in which surgery, pain, inflammation, environmental disruption, concomitant medications, and irregular behaviors may confound interpretation of sleep and circadian outcomes. An in-laboratory protocol that standardizes light exposure, posture, feeding, activity, and sampling timing provides a necessary platform to isolate these effects. Determining whether SL Dex produces not only sleep-like sedation, but also measurable sleep/circadian effects and tau dynamics would provide important insights into the relationship between pharmacologic modulation of sleep-circadian biology and inform future translational studies in aging and neurobiology.
Specific Aims and Objectives: This study aims to evaluate the feasibility, safety, and physiologic effects of sublingual dexmedetomidine (SL Dex) on sleep architecture, circadian physiology, and tau biomarker dynamics in older adults under controlled laboratory conditions. SL Dex represents a novel, noninvasive approach to modulating sleep and circadian biology and provides a unique opportunity to examine downstream effects on neurodegenerative biomarkers. Specifically, this study aims to:
- Assess the feasibility and safety of administering SL Dex within a controlled in-laboratory sleep and circadian protocol with ambulatory follow-up.
- Quantify the acute effects of SL Dex on sleep architecture, circadian physiology, and tau dynamics under controlled experimental conditions.
- Characterize the duration and trajectory of SL Dex-associated effects on sleep and circadian physiology during ambulatory follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Supportive Care
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
All personnel interacting with the participants, administering the sublingual films, drawing the serial blood samples, and analyzing the physiological or biomarker data are kept fully unaware of the treatment sequence (whether the participant received 120 mcg of sublingual dexmedetomidine or the matched identical placebo film on Day 2 of a given study period). The randomization sequence is maintained securely by the MGH/BWH research pharmacy infrastructure and a trial statistician who is completely isolated from data collection and participant interaction.
入排标准
- 年龄范围
- 65 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 65 years or older
- •Able to provide informed consent
- •Willing and able to comply with all study procedures, including in-laboratory and ambulatory monitoring
- •Able to provide informed consent using an IRB-approved translated consent document (when available) and complete study procedures with translated materials and/or qualified interpreter services, if needed- Stable residence and sleep schedule sufficient to complete study monitoring periods
- •Able to safely discontinue or adjust medications that may interfere with study procedures or outcomes, as determined by the study investigator
排除标准
- •Clinically significant sleep disorders including narcolepsy, severe obstructive sleep apnea, REM sleep behavior disorder, or periodic limb movement disorder
- •Clinically significant cardiovascular disease including bradyarrhythmia, conduction abnormalities, heart failure, cardiomyopathy, ischemic heart disease, or conditions increasing risk with dexmedetomidine
- •Known QT prolongation, clinically significant arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, or concurrent use of QT-prolonging medications
- •Contraindication or allergy to dexmedetomidine or study medications
- •Severe hepatic impairment
- •Neurologic, psychiatric, or substance use disorders that may interfere with participation or data interpretation
- •Use of medications significantly affecting sleep, circadian rhythms, or cardiovascular function
- •Gastrointestinal conditions increasing risk of capsule retention or bowel obstruction
- •Swallowing disorders or aspiration risk
- •Presence of implantable electronic medical devices
- •Use of anticoagulant or antiplatelet medications increasing bleeding risk
- •Pregnancy or breastfeeding
- •Shift work or frequent travel across more than two time zones
- •Participation in another interventional study that may interfere with study participation or interpretation of results
- •Anticipated need for MRI during the period in which the ingestible telemetry capsule may remain in the body
- •Inability to tolerate study procedures (blood draws, PSG, wearable devices, ingestible capsule)
- •Unable to provide informed consent even with translated materials/interpreter support
- •Previous participation in this trial
- •Concurrent interventional studies that may interfere with participation
研究组 & 干预措施
Sublingual Dexmedetomidine First
Participants receive a single 120 mcg dose of sublingual dexmedetomidine (IGALMI®) during the first in-laboratory study period and matched placebo during the second study period after a washout interval of at least 3 weeks. The study evaluates effects on sleep architecture, circadian physiology, and plasma tau biomarker dynamics under controlled laboratory conditions.
干预措施: Placebo Sublingual Film (Drug)
Placebo First
Participants receive matched placebo during the first in-laboratory study period and a single 120 mcg dose of sublingual dexmedetomidine (IGALMI®) during the second study period after a washout interval of at least 3 weeks. The study evaluates effects on sleep architecture, circadian physiology, and plasma tau biomarker dynamics under controlled laboratory conditions.
干预措施: Placebo Sublingual Film (Drug)
Sublingual Dexmedetomidine First
Participants receive a single 120 mcg dose of sublingual dexmedetomidine (IGALMI®) during the first in-laboratory study period and matched placebo during the second study period after a washout interval of at least 3 weeks. The study evaluates effects on sleep architecture, circadian physiology, and plasma tau biomarker dynamics under controlled laboratory conditions.
干预措施: Dexmedetomidine sublingual film (Drug)
Placebo First
Participants receive matched placebo during the first in-laboratory study period and a single 120 mcg dose of sublingual dexmedetomidine (IGALMI®) during the second study period after a washout interval of at least 3 weeks. The study evaluates effects on sleep architecture, circadian physiology, and plasma tau biomarker dynamics under controlled laboratory conditions.
干预措施: Dexmedetomidine sublingual film (Drug)
结局指标
主要结局
Number of Participants With Adverse Events
时间窗: From first study intervention through completion of the 10-day ambulatory follow-up following the second study period
Number of participants experiencing one or more adverse events during the study, including hypotension, bradycardia, and excessive sedation.
Number of Participants Unable to Complete a Study Procedure Due to Intolerance
时间窗: From enrollment through completion of the 10-day ambulatory follow-up following the second study period
Number of participants who are unable to complete one or more protocol-specified study procedures because of intolerance, including blood draws or physiologic monitoring procedures.
Proportion of Required Core Body Temperature Capsule Assessments Completed
时间窗: Pre-laboratory Day 6, continuously during the 3-day in-laboratory protocol, and post-laboratory Days 4 and 6 during each study period
Proportion of required core body temperature assessments using the ingestible telemetry capsule that are completed by participants across the pre-laboratory, in-laboratory, and post-laboratory monitoring periods.
Proportion of Participants Completing the Study
时间窗: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of enrolled participants who complete both study periods, including the in-laboratory protocols and post-laboratory ambulatory follow-up.
Proportion of Consented Participants Who Are Randomized
时间窗: At randomization, prior to the first study intervention
Proportion of participants who provide informed consent and are subsequently randomized to a study intervention sequence, calculated as the number of randomized participants divided by the total number of participants who provide informed consent.
Proportion of Participants Completing the In-Laboratory Protocol
时间窗: Through completion of the second 3-night in-laboratory study period
Proportion of enrolled participants who complete the 3-night in-laboratory protocol during both study periods.
Proportion of Participants Completing Ambulatory Follow-Up
时间窗: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of enrolled participants who complete the 10-day post-laboratory ambulatory monitoring period during both study periods.
Proportion of Required Actigraphy Monitoring Completed
时间窗: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of required actigraphy monitoring completed by participants across the pre-laboratory and post-laboratory ambulatory monitoring periods.
Proportion of Required Polysomnography Assessments Completed
时间窗: Through completion of the second 3-night in-laboratory study period
Proportion of required in-laboratory polysomnography assessments completed by participants.
Proportion of Required Wearable EEG Assessments Completed
时间窗: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of required ambulatory wearable EEG assessments completed by participants.
Proportion of Required Sleep Diaries Completed
时间窗: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of required sleep diary assessments completed by participants during ambulatory monitoring.
Number of Participants Withdrawing Due to Adverse Effects
时间窗: From first study intervention through completion of the 10-day ambulatory follow-up following the second study period
Number of participants who withdraw from the study or discontinue study procedures because of adverse effects.
Heart Rate Before and After Study Drug Administration
时间窗: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Heart rate measured before and after administration of sublingual dexmedetomidine or placebo to assess hemodynamic safety and tolerability. Heart rate will be reported in beats per minute.
Systolic Blood Pressure Before and After Study Drug Administration
时间窗: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Systolic blood pressure measured before and after administration of sublingual dexmedetomidine or placebo to assess hemodynamic safety and tolerability. Systolic blood pressure will be reported in mm Hg.
Diastolic Blood Pressure Before and After Study Drug Administration
时间窗: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Diastolic blood pressure measured before and after administration of sublingual dexmedetomidine or placebo to assess hemodynamic safety and tolerability. Diastolic blood pressure will be reported in mm Hg.
Proportion of Required Blood Samples Collected
时间窗: Through completion of the second 3-night in-laboratory study period
Proportion of protocol-specified blood samples successfully collected during the in-laboratory study periods.
Proportion of Participants Adherent to Required Caffeine Restrictions
时间窗: From 72 hours before admission through completion of the 3-night in-laboratory protocol during each study period
Proportion of participants who adhere to protocol-specified caffeine restrictions during required study monitoring periods.
Proportion of Participants Adherent to Required Alcohol Restrictions
时间窗: From 24 hours before admission through completion of the 3-night in-laboratory protocol during each study period
Proportion of participants who adhere to protocol-specified alcohol restrictions during required study monitoring periods.
次要结局
- Dim Light Melatonin Onset (DLMO) timing(During the 3-hour dim-light period preceding habitual bedtime on each in-laboratory study day)
- Sleep Latency Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Total Sleep Time Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Sleep Efficiency Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Wake After Sleep Onset Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- REM Sleep Latency Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Percentage of Total Sleep Time Spent in N2 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Percentage of Total Sleep Time Spent in N3 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Percentage of Total Sleep Time Spent in REM Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Phase of the Core Body Temperature Circadian Rhythm(Continuously across the 3-day in-laboratory protocol during each study period)
- Amplitude of the Core Body Temperature Circadian Rhythm(Continuously across the 3-day in-laboratory protocol during each study period)
- Amplitude of the Melatonin Rhythm(Across the 3-day in-laboratory protocol during each study period)
- EEG Delta Oscillation Power(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Delta Oscillation Power Density(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Slow Oscillation Power(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Theta Oscillation Power(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Alpha Oscillation Power(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Beta Oscillation Power(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Sigma Oscillation Power During NREM Sleep(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Slow-Wave Amplitude(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Slow-Wave Slope(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Sleep Spindle Density During NREM Sleep(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Sleep Spindle Frequency During NREM Sleep(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Sleep Spindle Duration During NREM Sleep(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Sleep Spindle Amplitude During NREM Sleep(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Time Spent in N1 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Time Spent in N2 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Time Spent in N3 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Time Spent in REM Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- EEG Slow-Wave Density(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
- Percentage of Total Sleep Time Spent in N1 Sleep Measured by Polysomnography(Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period)
研究者
Peng Li
Assistant Professor
Massachusetts General Hospital