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.
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: 1. Assess the feasibility and safety of administering SL Dex within a controlled in-laboratory sleep and circadian protocol with ambulatory follow-up. 2. Quantify the acute effects of SL Dex on sleep architecture, circadian physiology, and tau dynamics under controlled experimental conditions. 3. Characterize the duration and trajectory of SL Dex-associated effects on sleep and circadian physiology during ambulatory follow-up.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
TRIPLE
Enrollment
12
Participants receive a single 120 mcg dose of sublingual dexmedetomidine (IGALMI®) administered approximately 15-20 minutes before the scheduled sleep opportunity during the in-laboratory protocol.
Participants receive a matched placebo sublingual film identical in appearance, packaging, and administration method to the active dexmedetomidine formulation but containing no active medication.
Brigham and Women's Hospital
Boston, Massachusetts, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Number of Participants With Adverse Events
Number of participants experiencing one or more adverse events during the study, including hypotension, bradycardia, and excessive sedation.
Time frame: From first study intervention through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Participants Completing the Study
Proportion of enrolled participants who complete both study periods, including the in-laboratory protocols and post-laboratory ambulatory follow-up.
Time frame: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Consented Participants Who Are Randomized
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.
Time frame: At randomization, prior to the first study intervention
Proportion of Participants Completing the In-Laboratory Protocol
Proportion of enrolled participants who complete the 3-night in-laboratory protocol during both study periods.
Time frame: Through completion of the second 3-night in-laboratory study period
Proportion of Participants Completing Ambulatory Follow-Up
Proportion of enrolled participants who complete the 10-day post-laboratory ambulatory monitoring period during both study periods.
Time frame: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Required Actigraphy Monitoring Completed
Proportion of required actigraphy monitoring completed by participants across the pre-laboratory and post-laboratory ambulatory monitoring periods.
Time frame: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Required Polysomnography Assessments Completed
Proportion of required in-laboratory polysomnography assessments completed by participants.
Time frame: Through completion of the second 3-night in-laboratory study period
Proportion of Required Wearable EEG Assessments Completed
Proportion of required ambulatory wearable EEG assessments completed by participants.
Time frame: Through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Required Sleep Diaries Completed
Proportion of required sleep diary assessments completed by participants during ambulatory monitoring.
Time frame: Through completion of the 10-day ambulatory follow-up following the second study period
Number of Participants Withdrawing Due to Adverse Effects
Number of participants who withdraw from the study or discontinue study procedures because of adverse effects.
Time frame: From first study intervention through completion of the 10-day ambulatory follow-up following the second study period
Heart Rate Before and After Study Drug Administration
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.
Time frame: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Systolic Blood Pressure Before and After Study Drug Administration
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.
Time frame: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Diastolic Blood Pressure Before and After Study Drug Administration
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.
Time frame: Pre-dose and post-dose on Day 2 of each 3-day in-laboratory study period
Proportion of Required Blood Samples Collected
Proportion of protocol-specified blood samples successfully collected during the in-laboratory study periods.
Time frame: Through completion of the second 3-night in-laboratory study period
Number of Participants Unable to Complete a Study Procedure Due to Intolerance
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.
Time frame: From enrollment through completion of the 10-day ambulatory follow-up following the second study period
Proportion of Required Core Body Temperature Capsule Assessments Completed
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.
Time frame: 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 Participants Adherent to Required Caffeine Restrictions
Proportion of participants who adhere to protocol-specified caffeine restrictions during required study monitoring periods.
Time frame: From 72 hours before admission through completion of the 3-night in-laboratory protocol during each study period
Proportion of Participants Adherent to Required Alcohol Restrictions
Proportion of participants who adhere to protocol-specified alcohol restrictions during required study monitoring periods.
Time frame: From 24 hours before admission through completion of the 3-night in-laboratory protocol during each study period
Dim Light Melatonin Onset (DLMO) timing
Circadian phase assessed using dim light melatonin onset derived from serial plasma melatonin sampling during controlled dim-light conditions.
Time frame: During the 3-hour dim-light period preceding habitual bedtime on each in-laboratory study day
Sleep Latency Measured by Polysomnography
Sleep latency, defined as the time from lights out to sleep onset, measured by overnight polysomnography.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Total Sleep Time Measured by Polysomnography
Total time spent asleep during the overnight sleep period, measured by polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Sleep Efficiency Measured by Polysomnography
Sleep efficiency measured by polysomnography, calculated as total sleep time divided by time in bed multiplied by 100 and reported as a percentage.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Wake After Sleep Onset Measured by Polysomnography
Total time spent awake after initial sleep onset and before final awakening, measured by polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
REM Sleep Latency Measured by Polysomnography
Time from sleep onset to the first epoch of rapid eye movement (REM) sleep, measured by polysomnography and reported in minutes.
Time frame: 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
Percentage of total sleep time classified as stage N2 sleep based on polysomnography.
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Time frame: 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
Percentage of total sleep time classified as stage N3 sleep based on polysomnography.
Time frame: 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
Percentage of total sleep time classified as rapid eye movement (REM) sleep based on polysomnography.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Phase of the Core Body Temperature Circadian Rhythm
Circadian phase of the core body temperature rhythm derived from continuous core body temperature monitoring using a rectal thermistor
Time frame: Continuously across the 3-day in-laboratory protocol during each study period
Amplitude of the Core Body Temperature Circadian Rhythm
Amplitude of the core body temperature rhythm derived from continuous core body temperature monitoring using a rectal thermistor.
Time frame: Continuously across the 3-day in-laboratory protocol during each study period
Amplitude of the Melatonin Rhythm
Amplitude of the melatonin rhythm derived from serial plasma melatonin concentrations collected under controlled in-laboratory conditions.
Time frame: Across the 3-day in-laboratory protocol during each study period
EEG Delta Oscillation Power
Delta-band EEG power derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Delta Oscillation Power Density
Delta-band EEG power spectral density derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts per hertz (µV²/Hz).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Slow Oscillation Power
Slow-oscillation EEG power derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Theta Oscillation Power
Theta-band EEG power derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Alpha Oscillation Power
Alpha-band EEG power derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Beta Oscillation Power
Beta-band EEG power derived from quantitative EEG spectral analysis during overnight polysomnography and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Sigma Oscillation Power During NREM Sleep
Sigma-band EEG power derived from quantitative EEG spectral analysis during non-rapid eye movement (NREM) sleep stages and reported in squared microvolts (µV²).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Slow-Wave Amplitude
Mean amplitude of detected EEG slow waves derived from quantitative EEG analysis during overnight polysomnography and reported in microvolts (µV).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Slow-Wave Slope
Mean slope of detected EEG slow waves derived from quantitative EEG analysis during overnight polysomnography and reported in microvolts per second (µV/s).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Sleep Spindle Density During NREM Sleep
Density of detected sleep spindles derived from quantitative EEG analysis during non-rapid eye movement (NREM) sleep stages and reported as the number of spindles per minute.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Sleep Spindle Frequency During NREM Sleep
Mean frequency of detected sleep spindles derived from quantitative EEG analysis during non-rapid eye movement (NREM) sleep stages and reported in hertz (Hz).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Sleep Spindle Duration During NREM Sleep
Mean duration of detected sleep spindles derived from quantitative EEG analysis during non-rapid eye movement (NREM) sleep stages and reported in seconds.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Sleep Spindle Amplitude During NREM Sleep
Mean amplitude of detected sleep spindles derived from quantitative EEG analysis during non-rapid eye movement (NREM) sleep stages and reported in microvolts (µV).
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Time Spent in N1 Sleep Measured by Polysomnography
Total time classified as stage N1 sleep based on polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Time Spent in N2 Sleep Measured by Polysomnography
Total time classified as stage N2 sleep based on polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Time Spent in N3 Sleep Measured by Polysomnography
Total time classified as stage N3 (slow-wave) sleep based on polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
Time Spent in REM Sleep Measured by Polysomnography
Total time classified as rapid eye movement (REM) sleep based on polysomnography and reported in minutes.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period
EEG Slow-Wave Density
Density of detected EEG slow waves derived from quantitative EEG analysis during overnight polysomnography and reported as the number of slow waves per minute.
Time frame: 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
Percentage of total sleep time classified as stage N1 sleep based on polysomnography.
Time frame: Each night (Nights 1, 2, and 3) of each 3-night in-laboratory study period