Conditions: Sleep Insomnia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: yes

Brief summary:
The broad objective of this investigation is to assess the safety and efficacy of oral therapy with dexmedetomidine for the induction and maintenance of restful sleep.

Detailed description:
Sleep is a basic human function that occupies approximately one-third of our lives. Much of what is known about the benefits of sleep in humans has been obtained from studies of patients with insomnia, the most common sleep disorder with a reported prevalence of 10 to 15%. Unfortunately, insomnia is an independent risk factor for acute myocardial infarction, coronary heart disease, heart failure, hypertension, diabetes, and death. More so, sleep disturbances lead to neurocognitive deficits such as delirium and psychosis. However, the principal medications (i.e. benzodiazepines, zolpidem) currently used to treat insomnia are associated with side effects such as daytime sedation, delirium, anterograde memory disturbance, and complex sleep-related behaviors. We recently found that a nighttime intravenous bolus administration of dexmedetomidine was associated with normal sleep architecture comprising of rapid eye movement (REM) and non-REM (N1, N2, N3) sleep, with improved next-day psychomotor vigilance performance compared to zolpidem. Presently, dexmedetomidine is only available in an intravenous formulation. The goal of this project is to develop dexmedetomidine, an alpha-2 receptor agonist, into an oral sleep therapeutic with a neurocognitive sparing profile.

Arms:
arm 1: This arm will enroll healthy control subjects, who will have an acclimation night followed by a night's sleep with oral dexmedetomidine and then a night's sleep with a placebo comparator. arm 2: This arm will enroll healthy control subjects, who will have an acclimation night followed by a night's sleep with a placebo comparator and then a night's sleep with oral dexmedetomidine .

Interventions: intervention 1: Dexmedetomidine intervention 2: Saline Placebo
Intervention descriptions: intervention 1: Oral form intervention 2: Saline Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
Protocol Version 07/12/2017 
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Repurposing Dexmedetomidine as an Orally Administered Sleep Therapeutic 
 
NCT02818569 
7/12/2017 


 
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Repurposing Dexmedetomidine as an Orally Administered Sleep Therapeutic 
Principal Investigator: Oluwaseun Johnson-Akeju, M.D., M.M.Sc. 
I. Background and Significance         
 
Challenges in Drug Discovery 
Basic science discoveries of the molecular basis of disease have the potential to provide immeasurable 
opportunities to translate discoveries into targeted therapeutics (Collins 2011). However, translation of these 
basic science discoveries to targeted therapeutics is often met with failure (Collins 2011). A paradigm shifting 
approach (complementing current approaches) to reposition drug discovery efforts from an era of ‘me-too’ or 
‘slightly me-better’ drugs to one of highly innovative medicines is necessary (Paul, Mytelka et al. 2010). 
Presently, we know the molecular basis of approximately 4,000 disorders, however targeted therapies for only 
250 exist (Collins 2012). This mismatch is present because the traditional approach to drug discovery involves 
de novo identification and validation of new molecular entities, which is a time-consuming and costly process 
(Paul, Mytelka et al. 2010). Despite huge investments in drug discovery and development, the number of new 
drugs introduced into clinical practice has not increased significantly. For example, while the total research and 
development expenditure for drug discovery worldwide increased 10 times from 1975 ($4 billion) to 2009 ($40 
billion), the number of new molecular entities approved has remained stagnant (Paul, Mytelka et al. 2010). 
Drug discovery failure rates can be as high as 95% and the average time from target selection to approval is 
approximately 13-14 years (Paul, Mytelka et al. 2010). When failures are accounted for, the cost of bringing a 
new drug to the market is approximately $2 billion (Paul, Mytelka et al. 2010). Therefore, strategies to reduce 
the average time for drug approval, decrease costs, and improve success rates are urgently needed. Drug 
rescue and repurposing can be one of those strategies, as it offers the key advantage of harnessing previous 
research and development efforts (Paul, Mytelka et al. 2010, Collins 2011). Approved drugs and many 
abandoned compounds have already been tested in humans, and detailed information is available on their 
pharmacodynamics, pharmacokinetics, formulation, dosing, and potential toxicity (Paul, Mytelka et al. 2010, 
Collins 2011). Since drug repurposing is built upon previous research and development efforts, new candidate 
therapies are ready for clinical trials in a very timely fashion, speeding their review by the Food and Drug 
Administration and their integration into clinical practice (Paul, Mytelka et al. 2010, Collins 2011). 
Neurophysiological Principled Approach to Drug Discovery and Repurposing 
Neural oscillations form well-orchestrated structure for communication or miscommunication within and across 
neural circuits at multiple time scales (Buzsaki and Freeman 2015). It has been postulated that in the next 
decade, studies of neural oscillations are expected to spearhead insights on brain function and provide a much 
needed alternative approach to the development of novel therapies (Buzsaki and Freeman 2015). Today, 
studies of neural oscillations are a significant component of systems neuroscience research. In humans, 
valuable insights into neural oscillations and neural circuit mechanisms of altered arousal come from our 
clinical and research experiences in anesthesiology. In our systems neuroscience studies of anesthesia, we 
have found that neural oscillations observed during altered states of arousal possess structured phenotypes 
that are appropriate for obtaining mechanistic insights into mechanisms such as sleep (Ching, Cimenser et al. 
2010, Purdon, Pierce et al. 2013, Vijayan, Ching et al. 2013, Akeju, Pavone et al. 2014). In my research 
laboratory, we are studying the functional characteristics and neuroanatomical basis of these oscillations, and 
relating them to normal and pathological brain functioning. We expect that the techniques and insights 
emanating from this neural oscillation focused approach will serve important areas in basic and clinical 
neuroscience especially sleep medicine. 
Mechanisms of Natural Sleep 
Sleep is a basic human function that occupies approximately one-third of our lives, yet science is not entirely 
clear on its purpose (Brown, Basheer et al. 2012). Although the purpose of sleep is not entirely clear, great 
progress has been made in understanding the neural oscillations and circuitry that control sleep (Brown, 
Basheer et al. 2012). During natural sleep, humans switch at approximately 90-minute intervals between two 
states: rapid eye movement sleep (REM) and non-REM sleep. This oscillatory dynamic is postulated to be 
fundamental for achieving the restorative benefits of natural sleep. Non-REM sleep is initiated when the 
preoptic area (POA) activates and thereby, blocks the arousal inputs of these centers to the thalamus and the 
cortex (Saper, Fuller et al. 2010). With the initiation of this inhibition, the EEG shows intermittent sigma/spindle 
activity (9–16 Hz oscillations) followed shortly thereafter, by slow-wave (< 1 Hz) and delta (1-4 Hz) oscillations 


 
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(Saper, Fuller et al. 2010). Non-REM II sleep is defined by the presence of spindles with slow waves and K-
complexes (Saper, Fuller et al. 2010). Spindling is believed to be intermittent rhythmic activity between the 
cortex and the thalamus that results from this inhibitory state (Saper, Fuller et al. 2010). Non-REM stage III 
sleep is characterized by a predominance of slow-delta EEG oscillations (Saper, Fuller et al. 2010). The slow-
delta oscillations likely result from cortical hyperpolarization due to decreased excitation from the arousal 
centers and the thalamus. The transition from non-REM sleep to REM sleep is initiated when the cholinergic 
centers in the pedunculopontine tegmentum (PPT) and the laterodorsal tegmentum (LDT) activate. Activity of 
the monoaminergic dorsal raphé and locus coeruleus (LC) during non-REM sleep inhibits the PPT and LDT 
suppressing REM sleep (Saper, Fuller et al. 2010). The dorsal raphé and LC cease firing at REM onset. 
Activation of the PPT and the LDT, which project to the thalamus, basal forebrain and to the cortex, results in 
the switch of the EEG from slow-wave-delta oscillations to the awake-like EEG patterns characteristic of REM 
sleep. Non-REM sleep represents periods of cortical quiescence that likely allow the brain to restore its energy 
levels and has been strongly linked to improved memory function (Stickgold 2005). REM sleep may play a 
critical role in memory consolidation (Stickgold 2005).  
Insomnia: A Clinical Problem With Healthcare Implications 
Much of what is known about the benefits of sleep in humans has been obtained from studies of patients with 
insomnia. Insomnia is defined as a repeated difficulty with sleep initiation, duration, consolidation, or quality 
that occurs despite adequate time and opportunity for sleep and results in some form of daytime impairment 
(American Psychiatric Association. 2013). Insomnia is the most common sleep disorder, with a reported 
prevalence of 10 to 15%, depending on the diagnostic criteria used (Winkelman 2015). Roughly 50% of 
patients with insomnia have a psychiatric disorder, most commonly a mood disorder (e.g., major depressive 
disorder) or an anxiety disorder (e.g., generalized anxiety disorder or post-traumatic stress disorder) 
(Winkelman 2015). Although roughly 80% of those with major depressive disorder have insomnia (insomnia 
doubles the risk factor for developing depression), in approximately half of those cases, insomnia predated the 
onset of the mood disorder (Winkelman 2015). This suggests that insomnia is an independent risk factor for 
major depressive disorder. Insomnia is also an independent risk factor for acute myocardial infarction and 
coronary heart disease, heart failure, hypertension, diabetes, and death (Winkelman 2015). Unfortunately, at 
present, the medicines currently used to treat insomnia are associated with side effects such as daytime 
sedation, delirium, ataxia, anterograde memory disturbance, and complex sleep-related behaviors (Wafford 
and Ebert 2008, Winkelman 2015). More so, sleep disturbances may also lead to delirium and other cognitive 
deficits such as psychosis (Maldonado 2013). Thus, an effective treatment for insomnia will have immense 
public health benefits. 
Current Sleep Therapeutics Do Not Approximate Natural Sleep  
In the United States, insomnia therapies, ranging from prescription to over-the-counter medications, are a 
multi-billion dollar market with numerous pharmacological targets for the treatment of insomnia. The principal 
sleep medications (i.e. benzodiazepines, eszopiclone, and zolpidem) are among the most widely sold 
pharmaceuticals (Wafford and Ebert 2008). These drugs target inhibitory gamma amino-butyric acid A 
(GABAA) receptors throughout the brain. The drug formulations are designed for immediate release or timed 
release based on whether the insomnia is due to difficulty falling asleep or difficulty staying asleep respectively. 
They cause changes in the normal sleep architecture, including increased non-REM II sleep and increased 
REM latency. Importantly, these medications do not approximate natural sleep or selectively activate the brain 
circuits in a precisely timed manner to drive the 90-minute non-REM-REM cycling of natural sleep required for 
its restorative benefits. Instead, these medications globally inhibit brain activity, and at best, produce only 
sedation. Sedation with these sleep medications is associated with beta (13-25 Hz) oscillations (van Lier, 
Drinkenburg et al. 2004), an oscillatory dynamic that is distinct from non-REM and REM sleep, and is 
responsible for the amnesic effects of GABAergic drugs (Feshchenko, Veselis et al. 1997). Thus it is not 
surprising that principal sleep medications possess adverse side effects such as memory and cognitive 
impairment (Wafford and Ebert 2008, Winkelman 2015).  
Other agents: Ramelteon selectively targets hypothalamic melatonin receptors involved in the sleep–wake 
cycle. Studies suggest it significantly shortens sleep onset and increases sleep time without evidence of 
rebound insomnia, but it is associated with somnolence, fatigue, and dizziness (Wafford and Ebert 2008). 
Melatonin is also used as an insomnia therapy but there is minimal data supporting its efficacy (Wafford and 
Ebert 2008). Other medications such as antidepressants are often used off-label when treating insomnia. 
Nonprescription sleeping aids include antihistamines, though much of the existing data does not support their 


 
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benefit for insomnia, and subjects quickly develop tolerance to sedative effects or rebound insomnia upon 
discontinuation (Wafford and Ebert 2008). The hypocretin/orexin system involved in narcolepsy was recently 
identified as a possible target (Wafford and Ebert 2008), and led to the development of the newest sleep 
therapeutic suvorexant. However, this drug has also been associated with adverse side effects such as 
memory and cognitive impairment, and suicidal thoughts (Jacobson, Callander et al. 2014). Thus, there is a 
great clinical need to develop more efficacious agents that closely approximates natural sleep with better side 
effect profiles. Given the high prevalence of insomnia and known diseases that are precipitated and/or 
aggravated by sleep disturbances such as depression, cardiovascular disease, diabetes, and cognitive 
impairments, a novel and effective medication for sleep will have immediate and immense public health 
benefit. 
Evidence For Repurposing Dexmedetomidine as a Sleep Therapeutic 
Dexmedetomidine is an alpha-2 adrenergic agonist that is typically administered as an anesthetic adjunct. 
Patients who are sedated with dexmedetomidine are arousable and responsive in a manner that is very similar 
to that seen in people who are sleeping (Cortinez, Hsu et al. 2004, Akeju, Pavone et al. 2014). 
Dexmedetomidine is thought to alter arousal primarily through its actions on pre-synaptic alpha-2A adrenergic 
receptors on neurons projecting from the LC (Correa-Sales, Rabin et al. 1992, Chiu, Chen et al. 1995). 
Dexmedetomidine binding hyperpolarizes LC neurons, decreasing norepinephrine release (Jorm and Stamford 
1993, Nacif-Coelho, Correa-Sales et al. 1994, Nelson, Lu et al. 2003). Hyperpolarization of LC neurons results 
in loss of inhibitory inputs to the pre-optic area of the hypothalamus and excitatory inputs to the cortex, basal 
forebrain and the central thalamus. The pre-optic area sends GABAergic and galanergic inhibitory projections 
to the major arousals centers in the midbrain, pons and hypothalamus (Saper, Fuller et al. 2010). Hence, loss 
of inputs from the LC is thought to result in sleep-like state (Carter, Yizhar et al. 2010), due to activation of 
inhibitory pathways from the pre-optic area to the arousal centers along with loss of excitatory inputs to the 
cortex, basal forebrain and the central thalamus. Not surprisingly, as in non-REM II sleep, spindles and slow 
oscillations are associated with the altered state of arousal that is induced by dexmedetomidine (Akeju, 
Pavone et al. 2014). It is important to note the behavioral and neurophysiologic similarities between 
dexmedetomidine-induced altered arousal and sleep occurs because activation of inhibitory inputs from the 
pre-optic area is an essential component of how non-REM sleep is initiated (Sherin, Elmquist et al. 1998, 
Morairty, Rainnie et al. 2004, Saper, Fuller et al. 2010).  
 
We recently conducted a clinical trial (NCT01485380) that utilized a combination of high-density EEG and 
Fludeoxyglucose Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging to study the brain 
states induced by dexmedetomidine. Results from this clinical trial of dexmedetomidine suggests that this drug 
may be used to induce and maintain a brain state that closely approximates non-REM II sleep state 
characterized by sleep spindles, and slow-delta oscillations (Akeju, Pavone et al. 2014). Similar to non-REM 
sleep, we also found that dexmedetomidine decreased cerebral blood flow and cerebral metabolism, but 
maintained cortico-cortical functional connectivity patterns (Akeju, Loggia et al. 2014). These results lend to a 
very specific rhythms based hypothesis of the mechanisms necessary to engage sleep. Can successful sleep 
state switching be accomplished in humans by inducing a non-REM II state and then allowing indigenous sleep 
mechanism to engage normal sleep cycling. Until now, it has been unclear whether any pharmacological agent 
can induce a state that closely approximates natural sleep or sleep state switching. The possibility that 
dexmedetomidine could be used as a sleep therapy has not been readily apparent because it is currently 
marketed as an intravenous drug. Furthermore, a systems neuroscience approach to studying the 
dexmedetomidine-induced brain state had previously not been accomplished. A key strength of this proposal is 
that it is based upon compelling results obtained from our recently conducted Phase I/II proof-of-concept 
clinical study (NCT01485393) where we established the safety, efficacy, dosing paradigm, and dose for 
successfully using dexmedetomidine to induce sleep, which is characterized by non-REM I-III and REM sleep 
states. Therefore, we hypothesize that oral dexmedetomidine will shorten sleep latency by inducing a non-
REM II state that will allow indigenous sleep mechanisms to engage successful sleep state switching into non-
REM III and REM sleep states, conferring the restorative benefits of sleep. 
 
Currently dexmedetomidine is not available in an oral or sub-lingual preparation. However, the intravenous 
form of dexmedetomidine has a buccal bioavailability of approximately 86% and an oral bioavailability of 
approximately 16% (Anttila, Penttila et al. 2003). In our clinical practice of anesthesiology, the oral solution of 
dexmedetomidine, which is the intravenous formulation administered at up to 5 times the typical intravenous 


 
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bolus dose of 1mcg/kg has been used off-label and shown to be effective as a sedative (Ray and Tobias 2008, 
Mountain, Smithson et al. 2011). Thus, we expect that the oral reformulations of dexmedetomidine will be 
bioavailable and efficacious. Importantly, the oral administration of dexmedetomidine solution at up to 5 times 
of the recommended bolus dose does not appear to result in either of the two commonly reported side effects 
of hypotension and bradycardia that are associated with intravenous administration of dexmedetomidine (Ray 
and Tobias 2008, Mountain, Smithson et al. 2011). Therefore, we expect oral dexmedetomidine to be 
efficacious and safe for administration in humans.  
In summary, existing sleep medications are non-specific sedatives with significant cognitive side effects. 
However, our systems neuroscience based studies and proof-of-concept studies strongly suggest that 
dexmedetomidine is biochemically and neurophysiologically well suited to engage the natural mechanisms that 
drive sleep. Thus, this study will demonstrate a putative new class of sleep therapeutics to treat insomnia. If 
this research is successful, we will see a resolution to the problem of morbidity caused by insomnia and side 
effects of current sleep therapeutics. 
 
II. Specific Aims: 
The broad objective of this investigation is to assess the safety and efficacy of oral therapy with 
dexmedetomidine for the induction and maintenance of restful sleep.  
Specific Aim 1: Investigate the safety profile of dexmedetomidine in a phase I dose finding study. 
Hypothesis 1.1. Oral dexmedetomidine will maintain cardiovascular stability 
Hypothesis 1.2. Oral dexmedetomidine will result in electroencephalographic evidence of spindle and 
slow/delta oscillation. 
Specific Aim 2: Investigate the efficacy of dexmedetomidine for inducing sleep in a Phase II randomized 
double-blind placebo-controlled study. 
 
                                                                     
Hypothesis 2.1. Oral dexmedetomidine will reduce sleep latency 
Hypothesis 2.2. Oral dexmedetomidine will improve sleep efficiency 
III. Volunteer Selection and Enrollment 
Only those subjects capable of giving their own consent will be considered for this study.  
Phase 1: We will select 15 male and female healthy controls for this study between the ages of 18 and 50. 
Phase 2: We will select 15 male and female healthy controls for this study between the ages of 18 and 50. 
The volunteers will be recruited using an announcement of the study distributed through the Partners Public 
Affairs distribution list. All volunteers will be fit and healthy, meeting the American Society of Anesthesiologists 
(ASA) physical status classification P1 (normal healthy subjects) and P2 (stable chronic condition) and of 
normal body habitus. Prior to the study enrollment, each volunteer will sign informed consent. A complete 
medical history will be taken in addition to performing a complete physical examination in order to rule out 
active and chronic medical problems.  
Medical History 
Chronic health conditions that will exclude volunteers from the study include but are not limited to:  
Cardiovascular:  
Poorly controlled hypertension, myocardial infarction, coronary artery disease, peripheral 
vascular disease, arrhythmia, congestive heart failure, valvular disease, cardiac 
electrophysiological abnormalities ascertained from the screening ECG (i.e. but not limited 
to second and third degree heart block in the absence of a pace maker, supraventricular 
tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, junctional heart rhythms) 
Respiratory:  
Bronchitis, chronic obstructive pulmonary disease, smoking, shortness of breath, history of 
obstructive sleep apnea 
Hepatic:  
Hepatitis, jaundice, Child-Pugh Class C liver disease, generalized anasarca, ascites, 
encephalopathy and caput medusa 
Neurologic:  
Seizure, stroke, positive neurologic findings on neurologic examination, multiple sclerosis, 
Meniere’s disease, Parkinson’s disease 


 
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Gastrointestinal:  
Esophageal reflux, hiatal hernia, ulcer, oral ulcers, or other oral pathology 
 
Endocrine:  
Diabetes, thyroid disease 
Hematologic:  
Blood dyscrasias, anemia, coagulopathies 
Musculoskeletal:  
Prior surgery or trauma to head neck or face, arthritis, personal or family history of 
malignant hyperthermia 
Psychiatric:  
History or treatment for an active psychiatric problem, including, but not limited to: 
attention deficit hyperactivity disorder, depression, bipolar disorder, and schizophrenia 
Reproductive: 
Pregnancy, breast-feeding 
Medications:  
Regular use of prescription and non-prescription medications expected to affect central 
nervous system function or sleep 
Allergies:  
Dexmedetomidine, glycopyrrolate, phenylephrine, ephedrine, labetolol  
 
Physical Examination 
The volunteer will be given a standard pre-anesthetic physical examination. Abnormal findings on physical 
examination will provide reason for exclusion from the study. Abnormal finding(s) will be reported to the 
affected volunteer and recommendation(s) for medical follow-up will be given as needed. 
Screening Tests 
A complete blood count, blood glucose level, liver function test (LFT), blood urea nitrogen (BUN), and 
creatinine (Cr) level will be obtained at the initial screening visit. For inclusion into the study protocol, each 
volunteer will be required to have a platelet count, blood glucose, BUN, Cr and LFT's levels be within 1.5 times 
the upper limit of normal. Each volunteer will provide a urine specimen for a toxic substance screen both at the 
initial examination and on each active study day. Each female volunteer will be administered a pregnancy test 
at the initial examination and each active study day. Positive toxicity screening and/or positive results on the 
pregnancy test will prompt exclusion from the study. A 12-lead electrocardiogram will be performed on all study 
volunteers at the initial screening visit to identify any pre-existing cardiac issues.  
Primary Inclusion Criteria for “Healthy” control volunteers 
• 
Age between 18-50  
• 
Native English speaking 
• 
ASA physical status classification P1 and P2 (stable chronic condition) 
• 
Normal body habitus. 
Primary Exclusion Criteria for “Healthy” control volunteers 
• 
Abnormal sleep habits                                                                                                                                              
o Sleeping less than 5 hours each night  
o Going to sleep before 9:00 PM or after 2:00 AM on a regular basis  
o Waking up before 5:00 AM or after 10:00 AM on a regular basis.  
• 
Takes medication that alters sleep, cognitive function, or both.                                                                          
• 
Has a history of a known neurological or psychiatric problem.                                                                   
• 
Younger than 18 or older than 50 years of age.                                                                                                       
• 
Known or suspected sleep disorder(s). 
Remuneration 
For successful completion of Phase I of this protocol volunteer remuneration will be $500. If the study volunteer 
is unable to complete the entire protocol, the proration will be as follows: 
 


 
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• 
Study volunteers who complete the medical evaluation (screening visit) but do not begin the active 
portion of the study will receive no remuneration. 
• 
If the study must be stopped due to concerns for the study volunteer’s medical safety, volunteers will 
receive $500. 
 
For successful completion of Phase II of this protocol volunteer remuneration will be $750. If the study 
volunteer is unable to complete the entire protocol, the proration will be as follows: 
• 
Study volunteers who complete the medical evaluation (screening visit) but do not begin the active 
portion of the study will receive no remuneration. 
• 
Study volunteers who complete only one sleep study night will receive $100.  
• 
Study volunteers who complete two sleep study nights will receive $300.  
• 
Study volunteer who complete all sleep visits will receive $750.  
• 
If the study must be stopped due to concerns for the study volunteer’s medical safety, volunteers will 
receive remuneration commensurate with their time given to the study as listed above. 
• 
Participants will also be paid a bonus of $0.05 for every correct sequence on the MST task on the three 
overnight visits. 
IV. Study Procedures 
An Investigational New Drug (IND) application has been submitted to the Federal Drug Administration (FDA) 
and study initiation will be contingent upon IRB and FDA approval. Also, we will meet with Emily Ouellette, QI 
Program Assistant Director, FDA and Regulatory Support to make certain that this protocol is in compliance 
with all FDA regulations.  
All study visits will take place at the White 13 Clinical Research Center, except Phase 1, Visit 2, which will take 
place at the White 5 at the Carl Rosow Center for Clinical Research. This facility was constructed specifically 
for the performance of research on human volunteers receiving medications used in anesthesia. The research 
area is built to the same standard as a typical surgical procedure room at MGH with respect to ventilation, 
temperature control, plumbing and electrical facilities, as well as storage for sterile supplies and linens. There 
is piped oxygen and air, wall suction and waste anesthetic gas removal. The hospital’s backup generator 
supports electrical the outlets in clinical research center. There is a fully equipped anesthesia machine 
(ventilator) with an automated record keeper and standard anesthesia monitors. A fully equipped code cart is 
also available, and an emergency call system is connected to the Post Anesthesia Recovery Unit. Personnel 
from the Operating Room pharmacy check the code cart and medications at intervals, and the anesthesia 
equipment is checked and maintained by the bioengineering department. In summary, the level of 
physiological monitoring and clinical care that can be delivered in this facility is comparable to an Intensive 
Care Unit at MGH and far exceeds what is available in the White 13 Clinical Research Center. We deem this 
high level of care essential for our dose finding Phase I study. 
 
The initial starting doses selected for this Phase I clinical trial are based on clinical and research experience 
with intravenous dexmedetomidine, our synthesis of the literature on the pharmacodynamics/pharmacokinetics 
of oral dexmedetomidine, and clinical experience documented in the literature of the intravenous form of 
dexmedetomidine when it is administered orally. The starting doses are in accordance Food and Drug 
Administration’s guidelines for Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers which states that toxicity should be avoided at the initial clinical dose.  
However, doses should be chosen that allow reasonably rapid attainment of the Phase I trial objectives (e.g. 
Assessment of the therapeutics tolerability, pharmacodynamic or pharmacokinetic profile).   
Phase 1a – Oral, will follow an open-label, and dose escalation design. The first 5 subjects enrolled in this 
phase will receive 300 mcg (dose A) of dexmedetomidine in an unblinded fashion, and will be closely 
monitored for hemodynamic stability.  Assuming that dose A does not cause any adverse hemodynamic 
events, the next 5 subjects enrolled in the study will receive 500 mcg (dose B). Assuming that dose B does not 
cause any adverse hemodynamic events, the next 5 subjects enrolled in the study will receive 700 mcg (dose 
C).  
 
 


 
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Study Design Schematic Phase I  
 
Phase 1: Dose Escalation Study 
Visit 1 (Initial Screening) 
Prior to the beginning of the study, the study volunteer will sign informed consent. Next, the volunteer will 
undergo an initial pre-anesthetic exam and toxicology screening to assess exclusionary criteria. A pregnancy 
test will be administered to female volunteers. An electrocardiogram will be performed on all study volunteers 
at the initial screening visit to identify any pre-existing cardiac issues. A complete blood count, blood glucose 
level, LFT, BUN, and Cr level will be obtained. Volunteers will also complete a questionnaire concerning 
his/her sleep habits. This questionnaire is in clinical use by the Massachusetts General Hospital sleep 
laboratory. 
Visit 2 (Active Study Day) 
The study volunteer will arrive at the study site and a toxicology screen will be administered to exclude the use 
of prohibited substances, and female volunteers will again be required to undergo a pregnancy test. 
Physiological measures will include up to 256 channels of EEG, a 5 lead electrocardiogram, pulse oximetry, 
heart rate, end-tidal CO2, and audio/video data. All of the leads and sensors used are removed easily. 
Furthermore, blood samples will be obtained for pharmacokinetic/pharmacodynamic modeling of 
dexmedetomidine at T = 0 (baseline) and at T = 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 
hours, 3 hours, 4 hours, 5 hours, 6 hours and 7 hours after administration. 
 
An intravenous line will be placed and saline locked for the administration of rescue vasoactive medications if 
necessary. We will also place an arterial-line to enable real time assessment of beat-to-beat variability in the 
blood pressure. In contrast to a blood pressure cuff, the arterial line will provide for timely notification and 
intervention of any untoward events. Dexmedetomidine will be administered according to the predetermined 
dose escalation above. A board certified anesthesiologist will monitor the subject for up to 8 hours after the 
administration of the medication to ensure normal physiology is maintained. Upon the conclusion of testing a 
member of the study staff will remove the physiological monitors. Prior to leaving the study site, each volunteer 
will complete a brief questionnaire. Discharge home will be based on criteria established by the MGH 
Department of Anesthesia practices for discharge from the hospital following ambulatory surgery. The 
volunteer must have stable vital signs, i.e., within 20% of pre-study values, be able to respond appropriately to 
normal commands, be pain free, be free from any nausea and vomiting. Volunteers will be advised not to drive 
or operate heavy equipment for 24 hours.  
The primary endpoint for the Phase I studies will be hemodynamic stability defined as (1) hypotension: systolic 
blood pressure (SBP) < 60 mmHg, diastolic blood pressure (DBP) < 40 mmHg or decrease of SBP by ≥ 50 % 
from the baseline which is sustained over two consecutive minutes, (2) hypertension: SBP > 180 mmHg, 
DBP > 100 mmHg, or increase of SBP by ≥ 50 % from the baseline which is sustained over two minutes and, 
(3) bradycardia: heart rate (HR) < 40 bpm or decrease by ≥ 50 % from the baseline sustained over two 
consecutive minutes. Intravenous ephedrine, phenylephrine, glycopyrrolate and/or fluid bolus (500 ml of 0.9% 
normal saline) may be administered for the treatment of hypotension. Intravenous labetolol may be 
administered for the treatment of hypertension. The anesthesiologist based on his/her clinical judgment will 
administer all medications. Standard department guidelines will guide the administration of all ancillary 
medications. Secondary endpoints include the occurrence of dexmedetomidine-spindle, slow, and delta 
oscillations on the electroencephalogram. If no adverse events occur during the Phase I trial, we will then 
request the DSMB to review our results before proceeding with the Phase II trial. 
 
Visit 1 
Visit 2 
Consent, Physical Examination, Blood Work etc 
Location: White 13 Clinical Research Center 
Dexmedetomidine (doses A, B, and C) 
Location: White 5 Carl Rosow Center for Clinical 
Research. 


 
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Study Design Schematic Phase 2: Crossover Study 
 
Next, in a Phase II randomized double-blind placebo-controlled crossover study, 15 healthy volunteers will 
undergo one night of polysomnography acclimation, and two active polysomnography night visits. During the 
active visits, each volunteer will be randomized in a double-blinded fashion to receive either dexmedetomidine 
or placebo followed by polysomnography recording of 8 hours. The Phase II dose of dexmedetomidine will be 
700mcg oral, as determined by our Data Safety and Monitoring Board. We have concluded from our review of 
the literature and our proof-of-concept study that the aforementioned doses should be efficacious while 
maintaining cardiovascular stability. A requirement for this safe dose will be the maintenance of systolic blood 
pressure and the heart rate within 25% of baseline values without the administration of vasoactive medication. 
The MGH Research Pharmacy will consult the randomization assignment and will prepare the appropriate 
treatment for the volunteer. The primary endpoints for the Phase II study are polysomnography measures of 
sleep latency and efficiency. Secondary endpoints include subjective and objective measures of sleep, 
memory consolidation and learning. 
Phase II 
Visit 1 (Initial Screening) 
Prior to the beginning of the study, the study volunteer will sign informed consent. Next, the volunteer will 
undergo an initial pre-anesthetic exam and toxicology screening to assess exclusionary criteria. A pregnancy 
test will be administered to female volunteers. An electrocardiogram will be performed on all study volunteers 
at the initial screening visit to identify any pre-existing cardiac issues. A complete blood count, blood glucose 
level, LFT, BUN, and Cr level will be obtained. Volunteers will also complete a questionnaire concerning 
his/her sleep habits. This questionnaire is in clinical use by the Massachusetts General Hospital sleep 
laboratory. 
Visit 2 (Acclimation Night) 
In this crossover study, the study volunteer will arrive at the study site and a toxicology screen will be 
administered to exclude the use of prohibited substances, and female volunteers will again be required to 
undergo a pregnancy test. Physiological measures will include; up to 256 channels of EEG, 2 EOG channels, 2 
chin EMG channels, a 5 lead ECG, saturated oxygen levels, heart rate, end-tidal CO2, and audio/video data. 
All of the leads and sensors used are removed easily. The EEG cap will be placed on the volunteer to enable 
acclimation to the device. ECG, EOG and EMG channels will be attached so that the volunteer can acclimate 
to the sensation of contact at these points. The purpose of the first study night is for the volunteer to become 
acclimated to the study site and recording equipment, as well as to obtain a baseline reading of their brain 
activity during sleep. The volunteer will then be instructed to try to sleep for 8-hours. If he/she wakes up before 
the designated time, he/she will be instructed to stay in bed and try to go back to sleep. A registered nurse will 
monitor the volunteer all night. An on-call physician is available, at all times, in the event of an unforeseen 
problem. Prior to leaving the study site, each volunteer will complete a brief post-sleep questionnaire. Upon 
conclusion of testing, a member of the study staff will remove the physiological monitors and the volunteer will 
be permitted to resume his/her day as normal. The volunteer must have stable vital signs, i.e., within 20% of 
pre-study values and be able to respond appropriately to normal commands prior to discharge home. 
Volunteers will be advised not to drive or operate heavy equipment for 24 hours. 
Visit 3 and 4 (Active Study Night) 
Due to the crossover nature of this Phase II study, the volunteer will return to the study site on two separate 
nights to complete study procedures. A toxicology screen will be administered to exclude the use of prohibited 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Consent, Physical 
Examination, Blood Work 
etc 
Location: White 12 
Clinical Research Center 
Acclimation Night 
 
 
Location: White 12 
Clinical Research Center 
Dexmedetomidine or 
Placebo 
 
Location: White 12 
Clinical Research Center 
Dexmedetomidine or 
Placebo 
 
Location: White 12 
Clinical Research Center 


 
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substances. The electrodes on the EEG cap and the ECG, EOG and EMG channels will be attached per 
standard procedure. Saturated oxygen levels, heart rate, and end-tidal CO2, will be monitored. No arterial line 
will be placed in these volunteers. On each of the study nights, dexmedetomidine or placebo will be 
administered according to the predetermined randomization list by the MGH research pharmacy. However, 
both dexmedetomidine and placebo will not be administered on the same night. All volunteers will receive both 
dexmedetomidine and placebo either on Visit 3 or 4. A board certified anesthesiologist will monitor the subject 
for 1 hour after the administration of the medication to ensure normal physiology is maintained. A registered 
nurse will monitor the volunteer all night. An on-call physician is available, at all times, in the event of an 
unforeseen problem. The volunteer will then be instructed to try to sleep for 8-hours. If he/she wakes up before 
the designated time, he/she will be instructed to stay in bed and try to go back to sleep. Reflecting standard of 
post procedure monitoring, the study anesthesiologist will monitor the subject for one hour after the 
administration of the medication to ensure normal physiology. Prior to leaving the study site, each volunteer will 
complete a brief post-sleep questionnaire. Upon conclusion of testing, a member of the study staff will remove 
the physiological monitors and the volunteer will be permitted to resume his/her day as normal. The volunteer 
must have stable vital signs, i.e., within 20% of pre-study values and be able to respond appropriately to 
normal commands prior to discharge home. Volunteers will be advised not to drive or operate heavy equipment 
for 24 hours. 
Cognitive Testing 
Motor Sequence Task: Participants will be trained on a motor sequence task (MST), a well-established probe 
of sleep-dependent memory consolidation, on a laptop prior to the onset of sleep and then tested 8 hours later. 
The MST involves pressing four keys with the fingers of the left hand, repeating a five digit sequence (e.g., 4-1-
3-2-4) "as quickly and accurately as possible" for 30 seconds. During both the training (night time) and test 
sessions (morning), participants will perform twelve 30-second tapping trials each of which is followed by a 30 
second break. During tapping trials, the computer screen will be green with the numeric sequence displayed at 
the top, and dots appearing from left to right beneath the sequence with each keystroke. During the breaks, the 
display will be red, and instead of showing the sequence, numbers (displayed as words) counted down the 
seconds until the next trial. Three seconds before the display turns green, the words will be replaced by 
flashing dots to alert the participant. We will measure the number of correct sequences per 30 second tapping 
trial, which reflects the speed and accuracy of performance. Any unfinished sequence at the end of a trial will 
be added to the total, as a fraction of a correct sequence. Next-day improvement will be calculated as the 
percent increase in correct sequences from the last three training trials to the first three test trials. Learning 
during training will be calculated as the percent increase in correct sequences from the first training trial to the 
average of the last three training trials. Participants will be paid a bonus of $0.05 for every correct sequence.  
Psychomotor Vigilance Task (PVT): is a highly sensitive assay of vigilant attention used commonly in the study 
of sleep disruption after each night of sleep. 
 
While seated at a laptop computer, the subject will be asked to attend to an area enclosed by a small green 
rectangle against a black screen. After a variable delay (chosen randomly to last between 2 to 10 seconds) a 
digital millisecond counter will begin inside the rectangle.  
The subject will be asked to stop the timer as quickly as they can by pressing the space bar. At this time, the 
subject can view his/her reaction time, which serves as feedback for that trial.  
 
Instruction is given to avoid premature button presses during the variable inter-stimulus interval. If such a false 
start occurs, the subject will be asked to wait for the timer to begin before pressing the space bar and a new 
trial will commence. Trials of this nature repeat throughout a 10 minute session.  
 
The following instructions will be presented to the subject: 
 
Welcome. In this task, a rectangle will appear in the center of the screen. After a delay of variable 
duration, a counter will begin inside this rectangle. Your job is to press the SPACEBAR as rapidly as 
possible once this timer begins. Hitting the spacebar will stop the timer; you will then have a chance to 
view your speed. Aim for low numbers, but be sure not to press the spacebar before the timer starts! 
The task will continue for 10 minutes, and the computer will let you know when you have finished.       
 


 
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From this task we will analyze outcome measures such as the median reaction time, the variability of these 
reaction times, the occurrence of "lapses," (response times over 500 ms) errors of commission ("false-starts"), 
and a measure of performance degradation through time. The subject will perform this test before and after 
sleep on each study day. 
 
V. Biostatistical analysis 
Using an endpoint of sleep latency to guide sample size calculations. Our null hypothesis is the average within 
volunteer difference in sleep latency for oral dexmedetomidine compared with placebo is zero. Alternative 
hypothesis is the average within volunteer difference in total sleep time for dexmedetomidine compared with 
zolpidem is 30 minutes.  Assuming a standard deviation of 10 minutes in the dexmedetomidine groups and 15 
minutes in the placebo group, a type I error of 0.05 and minimum power of 0.80, the sample size 
determinations for our Phase II study is 4. Therefore, we should detect a clinically relevant improvement in 
sleep latency if we successfully enroll only 5 volunteers for the each of the dexmedetomidine groups. 
VI. Risk and Discomfort 
Dexmedetomidine: The risks involved in the administration of dexmedetomidine include nausea, xerostomia, 
atrial fibrillation, and transient hypertension during drug loading. The significant risks involved are directly 
related to a drug induced reduction in sympathetic activity, resulting in hypotension and bradycardia. Rare case 
reports of sinus arrest in instances of rapid drug administration and in subjects with a high resting vagal tone 
have also been described. Drug discontinuation, dose reduction, or the use of vasoactive substances causes a 
return of these hemodynamic parameters to baseline. As such, study volunteer hemodynamic parameters will 
be continuously monitored to ensure that appropriate medical intervention will be instituted for any clinically 
significant hypotensive or bradycardic episodes.   
Polysomnography risks: Electrodes placed on the scalp may cause temporary redness. 
Intravenous line risks: Pain at the needle insertion site, infection, and bleeding. 
Arterial Line risks: The most concerning risk is a <0.01% of permanent ischemic injury with placement of an 
arterial catheter in the radial artery. The risk factors that have been identified in the medical literature include 
high severity of illness (American Society of Anesthesiologists IV and greater), low cardiac output, use of 
vasopressor therapy, prolonged duration of catheter placement (greater than 4 days), large catheter size, 
multiple punctures for catheter insertion, predisposing comorbidities (i.e. peripheral vascular disease), 
diabetes. The study volunteers we will enroll are healthy ASA I/II and by definition are without any of these 
comorbid conditions.  Our research group has successfully executed three research protocols (2005P001549, 
1999P010748, and 2011P002333) that incorporate the use of arterial lines to monitor subjects being studied 
under general anesthetics. Under the aegis of these protocols, arterial lines have been placed without any 
ischemia related tissue injury. Other risks include pain at the needle insertion site, infection, bleeding, AND 
arterial thrombosis (blood clots). 
VII. Potential Benefits 
There are no direct benefits to the individual volunteers involved in this study. The potential benefits of this 
study to society are a clearer understanding of the potential benefit of dexmedetomidine as a therapy for 
insomnia compared with the established therapy zolpidem. We hope to also gain insight into the extent of 
which dexmedetomidine affects the sleep architecture of healthy volunteers. If successful, this study may lead 
to the identification of a new class of medications for sleep therapy.  
VIII. Monitoring and Quality Assurance 
All EEG, blood pressure, heart rate, electrocardiography, and capnography data will be visualized in real time 
for safe monitoring. These data will also be stored for later off-line analysis. Unanticipated problems involving 
risks to volunteers or others, including adverse events will be reported to the PHRC in accordance with PHRC 
unanticipated problems including adverse events reporting guidelines. 
Data and Safety Monitoring Board (DSMB) 
A Data and Safety Monitoring Board (DSMB) has been created as an independent body charged with ensuring 
that the safety of study volunteers is protected and that the scientific goals of the study are being met. To 


 
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support those purposes, the DSMB will perform expedited monitoring of all serious adverse events, perform 
ongoing monitoring of drop-outs and non-serious adverse events, determine whether study procedures should 
be changed or the study should be halted for reasons related to the safety of study volunteers, and perform 
periodic review of the completeness and validity of data to be used for analysis of safety and efficacy. The 
DSMB will also ensure volunteer privacy and research data confidentiality.   
Serious Adverse Events 
Expedited review will occur for all events meeting the FDA definition of SAEs – i.e., any fatal event, 
immediately life-threatening event, permanently or substantially disabling event, event requiring or prolonging 
inpatient hospitalization. This also includes any event that a study investigator or the DSMB judges to impose a 
significant hazard, contraindication, side effect, or precaution. For purposes of this study, all SAEs are required 
to be reported to the DSMB, regardless of any judgment of their relatedness to the study drug. All relevant 
information will be reported to the DSMB for each SAE including information about the event and its outcome, 
dosing history of all study drugs, concomitant medications, the volunteer’s medical history and current 
conditions, and all relevant laboratory data.  Notification by e-mail of all related study forms shall be made to 
the DSMB within 2 days of the occurrence of any SAE.  Information will be reviewed and a determination made 
of whether there was any possible relevance to the study drug.  Additional reporting to the IRB will be done 
within 24 hours of the SAE. 
Other Safety-Related Reports 
At twelve-month intervals throughout the course of the study, the DSMB will also receive unblinded summary 
reports of treatment retention and reasons for dropout, by treatment arm and study phase.    
Study Stopping Rules 
If at any time during the course of the study, the DSMB judges that risk to volunteers outweighs the potential 
benefits, the DSMB shall have the discretion and responsibility to recommend that the study be terminated.  
Monitoring of Data Quality by the DSMB 
At least on a yearly basis during the course of the study, the DSMB will receive a report on data quality and 
completeness. The Charter and Membership has been submitted to the IRB. 
 
 
 


 
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