Clinical trial NCT01485393
Conditions: Insomnia
Sponsor: Massachusetts General Hospital
Start date: 2015-01-01; Completion date: 2018-06-29
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine whether dexmedetomidine can be used to induce normal physiological sleep in humans.

Detailed description:

Arms: arm 1: This arm will enroll healthy control subjects, who will receive a regular nights sleep followed by a night of Zolpidem induced-sleep and then a night of Dexmedetomidine induced-sleep. arm 2: This arm will enroll healthy control subjects, who will receive a regular nights sleep followed by a night of Dexmedetomidine induced-sleep and then a night of Zolpidem induced-sleep.
Interventions: intervention 1: Dexmedetomidine intervention 2: Zolpidem
Intervention descriptions: intervention 1: A dose of dexmedetomidine will be administered at 1mcg/kg over 10 minutes. Subjects will never receive active drugs (Zolpidem or dexmedetomidine concurrently). intervention 2: 12.5 mg of oral Ambien CR. Subjects will never receive active drugs (Zolpidem/Ambien or dexmedetomidine concurrently).

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol Version 11/09/2017 
Page 1 of 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
Polysomnographic Study Comparing the Use of Dexmedetomidine and Zolpidem to 
Induce Natural Sleep 
 
NCT01485393 
11/09/2017 


 
Protocol Version 11/09/2017 
Page 2 of 13 
Polysomnographic Study Comparing the Use of Dexmedetomidine and Zolpidem to 
Induce Natural Sleep 
 
Principal Investigator: Oluwaseun Johnson-Akeju, M.D. 
BACKGROUND AND SIGNIFICANCE          
 
Sleep is a natural human behavioral state of decreased arousal, crucial for survival, 
maintenance of health and consolidation of newly learned information.1,2,3,4 Population-based 
studies estimate that 25 to 35% of American adults suffer from transient insomnia, 10% to 15% 
from chronic insomnia, with 2 to 6% of the population taking medications to promote sleep.5,6 
Sleep disturbance directly results in poor memory, impaired work performance, reduced 
concentration, and increased risk of accidents.7,8,9 Symptoms of insomnia that lead to these 
clinically significant functional impairments include difficulty in initiating and maintaining sleep.  
 
Insomnia treatments have generally involved behavioral changes and pharmacotherapy with 
sedating antidepressants, antihistamines, anti-cholinergics, melatonin receptor agonists, 
benzodiazepines, and non-benzodiazepine hypnotics.10,11 The benzodiazepines and the newer 
sedative hypnotics zolpidem (Ambien CR), zaleplon (Sonata), zopiclone (Imovane), and 
eszopiclone (Lunesta) form the mainstay of current treatment.10,11 These drugs modulate the 
activity of the γ-Amino butyric acid A receptor causing a generalized state of sedation with 
alteration of normal sleep electrophysiology. Additionally, they pose the added risk of tolerance 
and dependence.10,11  
 
The architecture of natural sleep consists of regular cycling at approximately 90-minute intervals 
between non rapid eye movement (nREM) and rapid eye movement (REM) sleep. Since these 
drugs do not provide for natural non REM-REM cycling, they lead to disruption in awake-
performance and create what many patients report as a state of grogginess.11 Consequently, 
these medications do not provide the restorative benefits of natural sleep. Furthermore, 
consistency in sleep maintenance by these drugs has not been clearly demonstrated.10 Hence, 
the beneficial effects from effective sleep therapies that maximize the benefits of restorative 
sleep cannot be understated.  
 
With this in mind, we are proposing to uncover the benefits of the medication, 
dexmedetomidine, for inducing physiologically natural sleep in insomniacs. The FDA approved 
dexmedetomidine in 1999 for short-term sedation by intravenous administration in the intensive 
care unit.12 Its indication was recently expanded to include non-intubated patients requiring 
sedation for surgery or procedures.12 The neurophysiological and behavioral characteristics of 
the sedative state induced by dexmedetomidine closely resembles non REM sleep.13, 14, 15 This 
is because dexmedetomidine binds to alpha2 receptors on neurons in the locus ceruleus (LC),  
causing an inhibition of the LC with the downstream effect of VLPO activation via direct 
neuronal projections. The active VLPO facilitates GABAA and galanin mediated inhibition of the 
midbrain, hypothalamic, and pontine arousal nuclei, promoting non REM sleep. 16,17,18,19 
Damage to the VLPO bilaterally attenuates the sedative response to dexmedetomidine20. 
Additionally dexmedetomidine has been confirmed to decrease expression of c-Fos in the LC 
and tuberomammillary nucleus, with increased expression in the VLPO.26 In essence, 
dexmedetomidine converges on endogenous sleep pathways to exert its effect. Since this drug 
is an intravenous agent, it has not been immediately apparent that it might be useful as a 
therapeutic agent for sleep therapy. 
 
We propose to undertake a study to characterize the benefits of dexmedetomidine for inducing 
a natural, restful night's sleep in insomniacs. Intravenous dexmedetomidine will be administered 
to promote sleep in healthy volunteers and patients with insomnia, comparing its effects to the 


 
Protocol Version 11/09/2017 
Page 3 of 13 
FDA-approved medication zolpidem. The benefits of dexmedetomidine will be demonstrated 
electrophysiologically by characterizing the sedative state induced by dexmedetomidine and 
also by assessing the impact of treating insomnia with dexmedetomidine on sleep quality, 
awake performance and cognition relative to zolpidem. This project is based upon the 
mechanistic understanding of how dexmedetomidine works, clinical experience with the 
sedative state induced by dexmedetomidine, electroencephalogram (EEG) patterns that are 
consistent with natural sleep in recent medical literature and on the SEDLine™ Brain-Function 
Monitoring System utilized in the MGH operating rooms. 
 
In contrast to existing sleep medications, which are non-specific sedatives, we believe that 
dexmedetomidine is biochemically well suited to engage the natural mechanisms that drive 
sleep. This study would help demonstrate that dexmedetomidine can be used to induce normal 
physiological sleep in humans suffering from insomnia, providing a new approach to the 
treatment of this debilitating disorder by strongly suggesting a new class of medications to be 
developed as a sleeping aid.  In addition to this, a novel neurophysiological description of the 
state of the brain under this new and important drug will be accomplished.  
 
SPECIFIC AIMS: 
The specific aims of this research project will test our hypotheses that dexmedetomidine 
exhibits neurophysiological and behavioral characteristics that closely resemble normal sleep in 
humans.  
Hypothesis 1: Intravenous therapy with dexmedetomidine will induce a sedative state whose 
architecture closely resembles the architecture of natural sleep 
 
                                                           
Hypothesis 2: The architecture of the sedative state induced by dexmedetomidine will be 
closer in nature to the architecture of natural sleep than the sedative architecture induced by 
zolpidem                         
Hypothesis 3: Dexmedetomidine will have minimal to no effect on the sleep architecture of 
healthy subjects 
Hypothesis 4: Dexmedetomidine will be objectively and subjectively more restful than 
zolpidem.  
Hypothesis 5: Compared to zolpidem, next day cognitive and psychomotor function will be 
improved 
 
SUBJECT SELECTION AND ENROLLMENT 
We will select 30 male and female volunteers for this study, comprised of 15 healthy controls 
and 15 patients with insomnia between the ages of 18 and 35. 
 
The subjects will be recruited using:  
1. An announcement of the study distributed through the Partners Public Affairs distribution list. 
2. MGH Research Study Volunteer Program. 
3. Through the Division of Sleep Medicine at Massachusetts General Hospital where physicians 
will identify insomnia patients. Patients found suitable will be given information about the 
study. This will include a clear statement that decision to forego or participate in the study will 
have no impact on their ongoing medical treatment. 
All subjects will be fit and healthy, meeting the American Society of Anesthesiologists (ASA) 
physical status classification P1 (normal healthy patient) or P2 (stable chronic problem) and of 
normal body habitus. 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.  


 
Protocol Version 11/09/2017 
Page 4 of 13 
Medical History. Chronic health conditions that will exclude subjects from the study include but 
are not limited to:  
 
Cardiovascular: 
hypertension, myocardial infarction, coronary artery disease, peripheral 
vascular disease, arrhythmia, congestive heart failure, valvular disease, 
resting 
heart 
rate 
less 
than 
55 
beats 
per 
minute, 
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:  
asthma, sleep apnea, bronchitis, chronic obstructive pulmonary disease, 
smoking, shortness of breath 
 
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 
 
Gastrointestinal: 
esophageal reflux, hiatal hernia, ulcer 
 
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 or zolpidem 
 
Physical Examination. The subject 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 subject 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 subject will be required to have a platelet count, blood 
glucose, BUN and Cr levels in the normal range. LFT's for inclusion will be required to be within 
1.5 times the upper limit of normal. Additionally, white blood cell count, hemoglobin, and 
differential will be required to range within 15% normal values in order to be included in the 
study. Each subject will provide a urine specimen for a toxic substance screen both at the initial 


 
Protocol Version 11/09/2017 
Page 5 of 13 
examination and on each active study day. Each female subject 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 5-lead 
electrocardiogram will be performed on all study subjects at the initial screening visit to identify 
any pre-existing cardiac issues. On active study nights, a five lead electrocardiogram will be 
applied to continuously monitor cardiac electrophysiological status. 
 
If a subject in the insomnia group is already taking prescription medications for sleep, he/she 
will not be eligible for the study. We will only be recruiting insomnia subjects who are 
undergoing behavioral therapy or are not being pharmacologically treated for insomnia.  
 
Primary Exclusion Criteria for “Healthy” control subjects: 
1. Abnormal sleep habits (This will be objectively assessed by wrist actigraphy measured 
for one week prior to the first study night).                                                                                                   
a. Sleeping less than 5 hours each night  
b. Going to sleep before 9:00 PM or after 2:00 AM on a regular basis  
c. Waking up before 5:00 AM or after 10:00 AM on a regular basis.  
2. Sleep latency greater than 60 minutes, or greater than 3 awakenings per night. (This will 
also be objectively assessed by wrist actigraphy.)                                                                                       
3. A score greater than or equal to 10 on the Epworth Sleepiness Scale.                                                       
4. Takes medication that alters sleep, cognitive function, or both.                                                                   
5. Has a history of a known neurological or psychiatric problem.                                                                   
6. Younger than 18 or older than 35 years of age.                                                                                           
7. Known or suspected sleep disorder(s). 
 
Primary Inclusion Criteria for “Insomniac” subjects: 
Subjects will be deemed “Insomniacs” if they suffer from any of the following: 
1. Subject will be required to meet the criteria for insomnia, set by the International 
Classification of Sleep Disorders, which requires that a patient have difficulty initiating or 
maintaining sleep that is not accounted for by another sleep disorder, neurologic or 
psychiatric disorder or substance or medication.                                                                                         
2. Subjects are required not be on any current pharmacological sleep disorder treatment. 
3. Between the ages of 18 and 35.                                                                                                                  
4. Not taking any prescription medications that alter sleep, cognitive functions, or both. 
MRI Reasons for Exclusion 
High magnetic fields may pose a serious health hazard to subjects with implanted ferromagnetic 
objects. Every participant in this study will be screened for implanted ferromagnetic objects 
before they are enrolled and will provide written responses to a questionnaire to screen for 
implanted ferromagnetic objects before entering the high magnetic field shielded room. Subjects 
with the following conditions/diseases will be excluded from the study: 
a) History of head trauma  
b) Surgical aneurysm clips  
c) Cardiac pacemaker 
d) Prosthetic heart valve 


 
Protocol Version 11/09/2017 
Page 6 of 13 
e) Neurostimulator 
f) Implanted pumps 
g) Cochlear implants 
h) Metal rods, plates 
i) Screws 
j) Intrauterine device 
k) Hearing aid 
l) Dentures (which might create artifacts) 
m) Metal injury to eyes 
n) Metallic tattoos anywhere on the body or tattoos near the eye 
 
Remuneration 
Prior to the study, each subject will sign witnessed, informed consent for anesthesia, EEG, MRI, 
and other physiological measures. For successful completion of this protocol, subject 
remuneration will be $500.  If the study subject is unable to complete the entire protocol, the 
proration will be as follows: 
 
 
1. Study subjects who complete the medical evaluation will receive $25. 
 
2. Study subjects who complete only one sleep study night will receive $100.  
3. Study subjects who complete only two sleep study nights will receive $200.  
4. Study subjects who complete only three sleep study nights will receive $300. 
5. Study subjects who complete all four sleep study night will receive $400. 
6. Study subjects who complete the optional fifth day-time sleep visit will receive $150. 
7. Study subjects who complete the MRI visit will receive $100. 
8. Study subject who complete all 4 sleep visits and the MRI visit will receive $500.  
9. Study subjects who complete all 4 sleep visits, the optional day-time visit, and the MRI 
visit will receive $650 
10. If the study must be stopped due to concerns for the study subject’s medical safety, 
subjects will receive remuneration commensurate with their time given to the study as 
listed above. 
Parking vouchers will be provided.  
 
STUDY PROCEDURES 
This study will follow a 3 part randomized design. Upon study enrollment, each subject will be 
assigned to receive each treatment: intravenous dexmedetomidine, zolpidem, and regular sleep 
(X, Y, or Z) in a random order.  
 
Study Design Schematic 
 
Screening 
Visit 
Study Visit 1 
Study Visit 
2 
Study Visit 
3 
Study Visit 
4 
Study Visit 5 
(optional) 
fMRI 
Visit 
Consent, 
Labs, etc 
Acclimation 
Night 
X, Y, or Z 
X, Y, or Z 
X, Y, or Z 
Day time visit with 
Dexmedetomidine 
fMRI 
scan 
 
 


 
Protocol Version 11/09/2017 
Page 7 of 13 
Active study nights will not occur back-to-back ensuring that there are no residual effects or 
interactions with the drugs being studied (i.e., a 48 hour washout period,). Visit 1 is intended for 
the subject to acclimate to the recording equipment. The second, third and fourth nights will be 
designated as an active study night where the subject will receive dexmedetomidine, zolpidem 
or regular sleep. The subject will be aware of the treatment assignment.  
 
Since the order in which these treatments are given is randomized at study enrollment, the 
active pill day (zolpidem administration) will never coincide with the active intravenous day 
(dexmedetomidine administration). Each subject will only receive dexmedetomidine or zolpidem 
once.  
 
Initial Screening Visit: 
Prior to the beginning of the study, the study subject will sign informed consent. Next, the 
subject will undergo an initial pre-anesthetic exam and toxicology screening to assess 
exclusionary criteria. A pregnancy test will be administered to female subjects. A 
electrocardiogram will be performed on all study subjects at the initial screening visit to identify 
any pre-existing cardiac issues. Subject will also complete a questionnaire concerning his/her 
sleep habits. This questionnaire is in clinical use by the Massachusetts General Hospital sleep 
laboratory. Afterward, the subject may be outfitted with an Actiwatch actigraphy monitor, similar 
to a regular wrist watch, to track their activity levels prior to the first study day. Every subject will 
be required to maintain a sleep log from the week prior to the first study night, until the last study 
night. 
 
Study Visit 1: Subject will arrive at the study site. Actigraphy and the sleep log will be checked 
to ensure that the subject has kept a consistent schedule, in keeping with the screening criteria 
defined above. A toxicology screen will be administered to exclude the use of prohibited 
substances, and female subject will again be required to undergo a pregnancy test.  
 
High-density EEG will be collected using a flexible cap with embedded electrodes that fits over 
the subject's head and fastens beneath the chin. Physiological measures may also include 2 
electrooculogram (EOG) channels, 2 chin electromyogram (EMG) channels, a 5 lead 
electrocardiogram (ECG), saturated oxygen levels, heart rate, non-invasive blood pressure cuff, 
end-tidal CO2, and audio/video data. All of the leads and sensors used are removed easily and 
comfortably following the sleep study.  
 
The EEG cap will be placed on the subject to enable acclimation to the device. ECG, EOG and 
EMG channels will be attached, and a mock (non-invasive) intravenous line will be attached so 
that the subject can acclimate to the sensation of contact at these points. The purpose of the 
first study night is for the subject to become acclimated to the study site and recording 
equipment, as well as to obtain a baseline reading of their brain activity during sleep. 
 
Just before bed the subject will participate in a 10 minute Psychomotor Vigilance Test (PVT), as 
well as the Motor Sequence Task (MST) and 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. After the sleep period, has concluded the subject will then again participate in 
a 10 minute Psychomotor Vigilance Test (PVT) and the Motor Sequence Task (MST).  Upon 
conclusion of testing a member of the study staff will remove the physiological monitors and the 
subject will be permitted to shower and eat breakfast and will then be permitted to resume 
his/her day as normally would.  
 


 
Protocol Version 11/09/2017 
Page 8 of 13 
A trained technician will be with the subject all night, monitoring the subject's room with audio 
and video equipment. An on-call physician is available, at all times, in the event of an 
unforeseen problem. 
 
Study Visit 2: Subject will return to the study site. A toxicology screen will be administered to 
exclude the use of prohibited substances. Electrodes on the EEG cap will be fixed in place with 
conductive paste, and ECG, EOG and EMG channels will be attached per standard procedure. 
The subject will then participate in a 10 minute Psychomotor Vigilance Test (PVT) and complete 
the Motor Sequence Task (MST). If indicated according to the randomization schedule, a 
peripheral intravenous line will be placed for administration of dexmedetomidine. We will then 
follow the “DEXMEDETOMIDINE DOSING PROCEDURES” listed below. 
 
The subject will 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. After 8-
hours have elapsed the subject will then again participate in a 10 minute Psychomotor Vigilance 
Test (PVT) and the Motor Sequence Task (MST). Upon the conclusion of testing a member of 
the study staff will remove the physiological monitors, and the subject will be permitted to 
shower. Prior to leaving the study site, each subject will complete a brief post-sleep 
questionnaire. This will also include some questions about dreams. In addition, the subject will 
respond to a questionnaire regarding time estimation – not only of his/her sleep patterns from 
the prior night, but also of the time required to perform the various cognitive and other testing 
components described above.  The will help address the issue of sleep misperception which is 
common in the insomnia population (likely multi-factorial, and one of the potential contributors is 
misperception of elapsed time).  
 
Each subject may be fitted with an Actiwatch actigraphy monitor prior to leaving the study site to 
monitor his/her sleep cycle until the following study visit. Subjects will then resume his/her 
normal workday.  
 
Study Visit 3: The subject will repeat the protocol as specified in Study Visit 2. However, it will 
be the second of the randomized treatments; he/she will receive zolpidem, dexmedetomidine or 
regular sleep.  
 
Study Visit 4: The subject will repeat the protocol as specified in Study Visit 2. However, it will 
be the third of the randomized treatments; he/she will receive zolpidem, dexmedetomidine or 
regular sleep. 
 
Study Visit 5 (optional): The subject will repeat the protocol as specified in Study Visit 2. 
However, this study visit will not be randomized; he/she will receive dexmedetomidine during an 
active study day instead of night. This will enable us to study the effect of the human circadian 
rhythm on sleep induction with dexmedetomidine. 
 
Dexmedetomidine Dosing Procedures 
Dexmedetomidine will be administered by one of the study anesthesiologists through a 
peripheral 18 or 20 gauge intravenous line. The study anesthesiologist will initiate and terminate 
the dexmedetomidine infusion using the following dosing scheme: Subjects will be randomized 
by block design to receive dexmedetomidine at 1.0mcg/kg over 10 minutes or 0.5 mcg/kg over 
10 minutes. 1.0 mcg/kg is the standard specification for the loading dose for procedural 
sedation.12   
 
The study anesthesiologist will monitor the patient continuously for the duration of the infusion, a 
research technician will also be present to ensure that standard of care is maintained at an 


 
Protocol Version 11/09/2017 
Page 9 of 13 
optimum. At the conclusion of infusion, the infusion pump will be turned off and the syringe 
containing dexmedetomidine will be removed to prevent inadvertent drug administration. 
Reflecting standard of post procedure monitoring, the study anesthesiologist will monitor the 
patient for one hour after the infusion has been stopped to ensure normal physiology. All 
aspects of the sleep study will also be attended during the night by a technologist to assure that 
the subject’s safety and comfort needs are met.  
 
On the active dexmedetomidine study night, discharge home will be based on criteria 
established by the MGH Department of Anesthesia practices for discharge from the hospital 
following ambulatory surgery. The subject 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, and have no bleeding from the intravenous insertion site. Subjects 
will be advised not to drive or operate heavy equipment for 24 hours. 
 
Cognitive Testing 
The subject will undergo the Motor Sequence Task (MST) and the PVT before and after sleep of 
each visit.  
 
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. 21 
 
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: 


 
Protocol Version 11/09/2017 
Page 10 of 13 
 
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.       
 
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. 
 
fMRI Visit: This visit may occur at any time during the course of the study. Concomitant to the 
registration of the EEG, subjects will participate in an fMRI scan to aid in source localization for 
data analysis. The study subject will arrive at the Martinos Center for Biological Imaging and a 
urine sample will be obtained for a toxic substance screen and for female study subjects a urine 
pregnancy test. The subjects will undergo approximately 45-60 minutes of MR imaging. No 
drugs will be administered at this visit.  
 
The study subject will be able to verbally communicate with the investigators during the 
structural MRI portion.  MR images of the brain will be acquired using the Siemens 3 Tesla Tim 
Trio scanner or the Siemens 3 Tesla Biograph mMR scanner. Head motion will be minimized 
during the image acquisition by use of a foam head holder. When applicable, the study subjects 
will be instructed to lie still during the imaging protocol.  
 
Inter-modality coordinate system co-registration: The structural MRI will be registered with the 
locations of the EEG sensors using a Polhemus FASTRAK digitizing system.  Using this 
digitizing system fiducial landmarks (periauricular points, nasion), EEG electrode locations, and 
the head outline are digitized in 3D space, and then registered with the study subject’s structural 
MRI in order to construct an anatomically accurate EEG forward model (Hari and Lounasmaa, 
1989).  
 
BIOSTATISTICAL ANALYSIS 
Neurophysiological endpoint: Using an endpoint of total sleep time to guide sample size 
calculations. Our null hypothesis is the average within subject difference in total sleep time for 
dexmedetomidine compared with zolpidem is zero. Alternative hypothesis is the average within 
subject difference in total sleep time for dexmedetomidine compared with zolpidem is 1.5 hours.  
Assuming that the variance in total sleep time is 2.75 hours2, a type I error of 0.05 and minimum 
power of 0.80 and 0.90 for a one-sided z-test, the sample size determinations for our study are 
8 and 11 respectively. Therefore, we should detect a clinically relevant improvement in total 
sleep time if we successfully enroll only 8 insomnia patients. 
 
Behavioral endpoint: Using an endpoint of performance score on the word-pair task word-pair 
task (a cognitive exercise that tests the interaction of sleep and interference learning on long-
term memory consolidation) to guide sample size determination. Our null hypothesis is the 
average within subject difference in performance score for dexmedetomidine compared with 
zolpidem is zero. Our alternative hypothesis is the average within subject difference in 
performance score for dexmedetomidine compared with zolpidem is 3. If we assume that the 
variance in performance score is 9, a type I error of 0.05 and a minimum power of 0.80 or 0.90 
for a one-sided z-test, the sample size determinations for our study are 7 and 9 respectively. 


 
Protocol Version 11/09/2017 
Page 11 of 13 
Therefore, we should detect a clinically relevant improvement in performance score if we 
successfully enroll only 7 insomnia patients 
 
RISK AND DISCOMFORT 
Dexmedetomidine Risks: 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 patients 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 subject hemodynamic parameters 
will be continuously monitored to ensure that appropriate medical intervention will be instituted 
for any clinically significant hypotensive or bradycardic episodes.   
Zolpidem Risks: The most common side effects associated with the administration of zolpidem 
are dizziness, headache, and drowsiness. Actual frequency of these effects may be dosage 
form, dose, and/or age dependent. 
  
Polysomnography risks: Electrodes placed on the scalp may cause temporary redness. 
 
MRI risks: Risks already established for MRI include claustrophobia due to confinement of the 
patient in the system, malfunction of electromagnetic implants caused by interaction with the 
magnetic fields, projectiles and tissue burns caused by metallic tattoos or implants, risks to the 
fetus of a pregnant patient, surface burns due to interaction of metallic system components or 
surface adhesives with the patients skin, slight hearing impairment due to high acoustic noise 
levels generated by the system, and slight neuromuscular twitching (for the higher field strength 
systems).   However, system safeguards have been designed and operating guidelines have 
been provided to minimize any of the aforementioned risks.  
 
POTENTIAL BENEFITS 
There are no direct benefits to the individual subjects 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 subjects. If successful, this study may lead to the identification of a new 
class of medications for sleep therapy.  
 
MONITORING AND QUALITY ASSURANCE 
All EEG data will be stored for later off-line analysis. Unanticipated problems involving risks to 
subjects or others including adverse events will be reported to the PHRC in accordance with 
PHRC unanticipated problems including adverse events reporting guidelines. 
 
An anesthesiologist will monitor the study subject throughout the time he/she is receiving 
intravenous drug infusions (dexmedetomidine), and for one hour thereafter. This is in 
accordance with MGH Department of Anesthesia, Critical Care, and Pain Medicine (DACCPM) 
standards for monitoring during procedural sedation at an out-of-operating room location and 
the standards for monitoring in the post-anesthesia care unit. A DACCPM provided emergency 
airway bag and supplemental oxygen tanks will be made available on all active study nights, as 
well as an MGH pharmacy emergency medicine kit containing glycopyrrolate, atropine, and 
epinephrine. Study personnel will also be required to perform mock emergency drills on all study 
nights. 
 


 
Protocol Version 11/09/2017 
Page 12 of 13 
The Siemens system has a built in self-monitoring system that automatically shuts off if 
parameters exceed safe levels.  For backup protection, the study stuff will constantly be in 
contact with the subject during the scan. Subject monitoring will be performed using the 2-way 
intercom system between the scanner operator and subject and by visual monitoring of the 
subject through the window into the scan room or monitoring cameras (the subject is visible to 
the operator at all times).  Quality assurance of the scanner’s performance is obtained by a daily 
quality assurance protocol.  More extensive quality assurance protocols are performed monthly 
under the commercial service contract with Siemens Healthcare.  
 
 
REFERENCES: 
 
1. Walker, M. P., The role of sleep in cognition and emotion. Ann N Y Acad Sci 2009, 1156, 168-97. 
2. King, C. R.; Knutson, K. L.; Rathouz, P. J.; Sidney, S.; Liu, K.; Lauderdale, D. S., Short sleep duration 
and incident coronary artery calcification. Jama 2008, 300 (24), 2859-66.  
3. Gottlieb, D. J.; Punjabi, N. M.; Newman, A. B.; Resnick, H. E.; Redline, S.; Baldwin, C. M.; Nieto, F. 
J., Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med 
2005, 165 (8), 863-7.  
4. Neckelmann, D.; Mykletun, A.; Dahl, A. A., Chronic insomnia as a risk factor for developing anxiety 
and depression. Sleep 2007, 30 (7), 873-80. 
5. Ohayon, M. M., Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med 
Rev 2002, 6 (2), 97-111. 
6. Balter, M. B.; Uhlenhuth, E. H., New epidemiologic findings about insomnia and its treatment. J Clin 
Psychiatry 1992, 53 Suppl, 34-9; discussion 40-2. 
7. Ancoli-Israel, S.; Cooke, J. R., Prevalence and comorbidity of insomnia and effect on   functioning in 
elderly populations. J Am Geriatr Soc 2005, 53 (7 Suppl), S264-71. 
8. Van Dongen, H. P.; Maislin, G.; Mullington, J. M.; Dinges, D. F., The cumulative cost of additional 
wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic 
sleep restriction and total sleep deprivation. Sleep 2003, 26 (2), 117-26. 
9. Williamson, A. M.; Feyer, A. M., Moderate sleep deprivation produces impairments in cognitive and 
motor performance equivalent to legally prescribed levels of alcohol intoxication. Occup Environ Med 
2000, 57 (10), 649-55. 
10. Carson S, 
McDonagh 
M, Thakurta S, 
Yen 
P. Drug class review: Insomnia. 2008. 
http://www.ohsu.edu/drugeffectiveness/reports/final.cfm 
11. Rosenberg, R. P., Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic 
therapies. Ann Clin Psychiatry 2006, 18 (1), 49-56. 
12. Dexmedetomidine 
Package 
Insert. 
http://www.precedex.com/wpcontent/uploads/2010/11/Precedex_PI.pdf 
13. Huupponen, E.; Maksimow, A.; Lapinlampi, P.; Sarkela, M.; Saastamoinen, A.; Snapir, A.; Scheinin, 
H.; Scheinin, M.; Merilainen, P.; Himanen, S. L.; Jaaskelainen, S., Electroencephalogram spindle 
activity during dexmedetomidine sedation and physiological sleep. Acta Anaesthesiol Scand 2008, 52 
(2), 289-94. 
14. Mason, K. P.; O'Mahony, E.; Zurakowski, D.; Libenson, M. H., Effects of dexmedetomidine sedation 
on the EEG in children. Paediatr Anaesth 2009, 19 (12), 1175-83. 
15. Aksu, R.; Kumandas, S.; Akin, A.; Bicer, C.; Gumus, H.; Guler, G.; Per, H.; Bayram, A.; Boyaci, A., 
The 
comparison 
of 
the 
effects 
of 
dexmedetomidine 
and 
midazolam 
sedation 
on 
electroencephalography in pediatric patients with febrile convulsion. Paediatr Anaesth 2011, 21 (4), 
373-8. 
16. Correa-Sales, C.; Rabin, B. C.; Maze, M., A hypnotic response to dexmedetomidine, an alpha 2 
agonist, is mediated in the locus coeruleus in rats. Anesthesiology 1992, 76 (6), 948-52. 
17. Correa-Sales, C.; Nacif-Coelho, C.; Reid, K.; Maze, M., Inhibition of adenylate cyclase in the locus 
coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat. J Pharmacol Exp Ther 
1992, 263 (3), 1046-9. 
18. Jorm, C. M.; Stamford, J. A., Actions of the hypnotic anaesthetic, dexmedetomidine, on noradrenaline 
release and cell firing in rat locus coeruleus slices. Br J Anaesth 1993, 71 (3), 447-9. 


 
Protocol Version 11/09/2017 
Page 13 of 13 
19. Brown, E. N.; Lydic, R.; Schiff, N. D., General anesthesia, sleep, and coma. N Engl J Med 2010, 363 
(27), 2638-50. 
20. Nelson, L. E.; Lu, J.; Guo, T.; Saper, C. B.; Franks, N. P.; Maze, M., The alpha2-adrenoceptor agonist 
dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative 
effects. Anesthesiology 2003, 98 (2), 428-36. 
21. Lim, J.; Dinges, D. F., Sleep deprivation and vigilant attention. Ann N Y Acad Sci 2008, 1129, 305-22.