A Phase IV 3-Way Double-blind, Randomized, Crossover Study to Compare the Awakening Threshold Effects (Responsivity) of Belsomra 10 mg and 20 mg to Placebo in Non-elderly Insomniacs
Phase: PHASE4
Conditions: Insomnia
Sponsor: Henry Ford Health System

 
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Requirements for Submitting a Full Proposal 
 
 
Section #1 - MISP Protocol Identification 
 
Study Title: 
  
 
A Phase IV 3-Way Double-blind, Randomized, Crossover Study to 
Compare the Awakening Threshold Effects (responsivity) of Belsomra 
10 mg and 20 mg to Placebo in non-elderly Insomniacs 
 
Request Date: 
 
Revised – August 23, 2017 
Institution Name 
 
Henry Ford Hospital Sleep Disorders and Research Center 
Investigator Contact 
Information: 
- Full address  
- Phone No. 
- Fax  No. 
- e-mail address 
 
Christopher L. Drake, PhD 
Director, Sleep Research Laboratory 
Henry Ford Hospital 
Sleep Disorders and Research Center 
39450 W. 12 Mile Road 
Novi, Michigan 
Phone: (258) 344-6672 
FAX: (258) 344-8084 
 
258-344-6672 
258-344-8084 
Cdrake1@hfhs.org 
 
Co-investigators: Thomas Roth, PhD 
Meeta Singh, MD 
 
 
 
 

 
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Section #2- Core Protocol 
 
2.1 Objectives & 
Hypotheses  
 
 
 
 
Primary 
To determine the absolute and relative effects at Tmax of Belsomra 10 
mg; 20 mg; and placebo on responsivity in nonelderly insomniacs (< 65 
yrs). 
 
We hypothesize that: 
1) Belsomra 20 mg will have a similar awakening/arousal threshold compared 
to placebo  
2) Belsomra 10 mg will have a similar awakening/arousal threshold compared 
to placebo 
3) Belsomra 20 mg will have a similar awakening/arousal threshold to 
Belsomra 10 mg 
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data  
 
Insomnia is characterized by difficulty falling asleep, waking frequently 
during the night, waking too early in the morning and not being able to get 
back to sleep, and waking feeling unrefreshed. Insomnia can be transient 
(lasting for several days), intermittent (when transient insomnia recurs), or 
chronic (lasting for more than a month and has been reported in all age 
groups.  An estimated 30%-50% of the adult population is affected by 
insomnia and prevalence tends to increase with age.   
 
Hypnotic medications are utilized to improve sleep initiation and/or 
maintenance. The most commonly used hypnotics, Benzodiazepine Receptor 
Agonists (BzRAs), bind at the benzodiazepine receptor at the  GABA-A 
complex and demonstrate broad CNS depressant effects  which  been shown 
to  reduce responsivity to the environment, particularly at peak plasma 
concentrations (Frey, et al., 2011; Zammit et al., 2008). The ability to respond 
following a nocturnal stimuli is critical to safety (e.g., responding to fire 
alarms, infants, burglary, or other emergencies) (Johnson et al., 1983). 
Recently, the hypnotic suvorexant (dual orexin antagonist) has been shown to 
have no effects on the ability to wake to a novel auditory stimuli and thus 
may have a comparative benefit to BzRA hypnotics in terms of auditory 
awakening threshold (Tannenbuam et al., 2014; 2016). However, the previous 
study was not done in humans. The present study is designed to test arousal 
response (responsivity) at peak plasma levels following administration of 
Belsomra (10 and 20 mg) compared to placebo. Specifically, responsivity will 
be assessed using standardized measures as in a previous study of auditory 
awakening threshold (Drake et al., 2017). The doses proposed are Belsomra 
10 mg and 20 mg as these represent the clinically recommended and utilized 
doses. 
The Primary objective is to determine the absolute and relative effects of 
Belsomra 10 mg and 20 mg on responsivity during sleep in patients with 
insomnia at estimated Tmax versus placebo (~2.5 hrs post-dosing). 
 

 
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Our Sleep Research Center has considerable experience in the design and 
execution of responsivity studies. In a recent trial published in 2017 we 
compared the effects of a 10 mg dose of zolpidem to placebo in men to 
determine the level of responsivity and balance/Ataxia effects at T-max (~2.5 
hrs.). Results of this trial showed a significantly higher auditory awakening 
threshold for zolpidem compared to placebo (p< .001). In addition, the effects 
of zolpidem on middle of the night balance were also significantly greater 
than placebo (p<.005). We expect a similar effect size in the present study as 
compared to what was found for placebo in our previous trial. 
2.3 Study Design 
 
The proposal is for an interventional single site study using a double blind, 
randomized 3-way crossover design with Belsomra 10 mg and 20 mg compared 
to a placebo. The total number of enrolled patients proposed is 12 providing 
reasonable power (>70%) to detect differences of 15 db vs. placebo for 
Belsomra if present (although no differences are expected). Patients will be 
crossed over to experience all treatment conditions in a controlled order 
(Belsomra 10 mg, 20 mg and placebo). Both men and women with insomnia 
will be utilized as the study population to improve the generalizability of 
outcome data. However, we will enroll equal numbers of men and women in 
order to allow comparative analyses within both men and women, albeit with 
reduced power. In the overall analyses sex will be utilized as a covariate. 
Subjects with other sleep disorders or unstable medical/psychiatric disorders 
will be excluded from the trial. Inclusion criteria will be men and women >18 
and < 65 years of age. 
 
An initial standardized screening PSG will be used to rule out the presence of 
sleep disordered breathing and/or periodic limb movements during sleep (mean 
AHI/PLMAI <10/hr for both). The 3 study treatments include Belsomra 10 mg 
and 20 mg with a middle-of-the-night awakening at ~2.5 hours (BEL10; 
BEL20), and placebo with a middle-of-the-night awakening at 2.5 hours 
(PBO). Study drug will be administered under fasted conditions (at least 3 
hours) as a single dose at bedtime (approximately 2300 hours), and each subject 
will receive one dose of each active drug, and one dose of placebo during the 
treatment period for a total of 3 overnight testing sessions and 1 overnight PSG 
screening. 
 
Subjects will be randomly assigned to treatment sequences using a Latin square 
design. After a subject has qualified for the study, the next sequentially 
available randomization number will be assigned.  The subject will be 
administered study drug corresponding with this assigned number. 
 
Inclusion Criteria: 
 Meets DSM-5 diagnostic criteria for insomnia disorder 
 ISI > 10 
 Age >18 and < 65 
 Negative audiological screening exam 
Exclusion Criteria: 

 
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 BMI >35 kg/m2 
 Have symptoms consistent with the diagnosis of any sleep disorder 
other than insomnia (e.g., sleep apnea, narcolepsy, periodic leg 
movements, or restless leg syndrome). 
 Have a known or suspected diagnosis of Acquired Immune Deficiency 
Syndrome (AIDS), or have tested seropositive for human 
immunodeficiency virus (HIV) antibody or antigen previously. 
 Have any clinically significant abnormal finding in physical 
examination, neurological assessment, vital signs, elevated body 
temperature, or clinical laboratory tests, as determined by the 
Investigator. 
 Have a known or exaggerated pharmacological sensitivity, 
hypersensitivity, or intolerance to Belsomra. 
 Currently taking CYP3A inhibitors. 
 Positive breathalyzer test for alcohol at Screening, PSG Screening or 
any Treatment night, or a positive urine drug screen (for 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, or 
cannabinoids) at Screening; 
 History of hearing difficulty (e.g., use of a hearing aid). 
 Intends to use any medication including over-the-counter (OTC) 
medications that would interfere with normal sleep architecture (such 
as systemic steroids, beta-adrenergic blockers, amphetamines, 
modafinil, etc.); 
 Self-reports use of products containing nicotine of greater than 15 
cigarettes daily, or cannot avoid products containing nicotine during the 
normal sleep periods; 
 Self-report consumption of more than five alcoholic beverages on any 
one day or > 14 alcoholic beverages weekly over the past week; 
 Have a history of epilepsy or serious head injury 
 Average TIB < 6.5 hrs. 
 Have used prescribed or OTC medications within 7 days of screening 
(Day 0) or intend to use any prescription or OTC medication during the 
study that may interfere with the evaluation of the study drug. This 
restriction includes taking medications that affect the CNS.  Any 
chronic maintenance therapy should have been maintained at a stable 
dosing regimen for at least 30 days before screening and subjects must 
continue this regimen throughout the study.   
 Have used an investigational drug within 30 days or five half-lives 
(whichever is longer) before screening, or plans to use an 
investigational drug during the study or have used BEL/ZOL. 

 
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A study timeline is included below: 
 
 
Evaluation 
Screening Period 
Crossover Treatment Period 
Timing 
Days 
-14 to -1 
TX 1 
 
TX 2 
 
TX 3 
 
Final Study Day  
 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Breathalyzer Test 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Sleep Heart Health Survey 
X 
 
 
 
 
Epworth Sleepiness Scale 
X 
 
 
 
 
Restless Leg Questionnaire 
X 
 
 
 
 
Stop Bang Questionnaire 
X 
 
 
 
 
Laboratory (Routine) 
X 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
X 
Randomization 
X 
 
 
 
 
Height, Weight, BMI 
X 
 
 
 
 
Prior & Concomitant Medications 
X 
X 
X 
X 
X 
Study Drug  Administration  
 
X 
X 
X 
 
AAT 
 
X 
X 
X 
 
PSG 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 

 
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2.5 Study 
Procedures 
Subjects will be screened by clinical interview and full physical evaluation to 
establish health, and rule out medical disorders and sleep disorders other than 
insomnia. In addition, participants will complete medical history and be asked 
to complete a Sleep Health Survey and sleep disorders questionnaires to rule 
out restless leg syndrome and sleep disordered breathing (RLS screening 
questionnaire and STOP-BANG questionnaire). Participants will be screened 
using standard urine and blood chemistry laboratory tests (LabCorps) and be 
administered a breathalyzer to screen for alcohol and urine drug screen. AAT 
protocol will be reviewed and demonstrated with each participant on the 
morning of the screening PSG. 
 
During the night of each respective PSG assessment night, subjects will be 
awoken at the approximate T-max of the active drug (2.5 hrs), with a 
matching placebo condition at the same time point using an identical 
responsivity protocol for each condition. The rationale for this is that t-max 
represents the time of  greatest potential  risk for a hypnotic in terms of 
balance, responsivity, and memory. Responsivity will be assessed using the 
Auditory Awakening Threshold test (AAT) and will be measured at 2.5 hours 
post dose for the Belsomra 10 and 20 mg (BEL), and placebo (PBO) 
conditions.  Responsivity will be assessed at the approximate time above 
immediately after 5 minutes of consolidated (without arousals) NREM stage 2 
sleep has occurred. 
 
Responsivity Protocol: Responsivity will be measured in response to a series 
(20-sec intervals) of increasing 1.5-sec. tones at 520 Hz (fire alarm) with a 
range from 40 db to 110 db. The outcome measure will be the mean decibel 
level (db) at awakening (mean of 2 awakenings at ~T-max for each subject 
for each condition). 
 
Subjects will be discharged from the sleep center once all assessments have 
been completed.  A 6-12 day drug-free interval will separate each Treatment 
Period.  A final study visit will be performed for subjects either after they have 
completed all three Treatment Periods or they have prematurely discontinued 
the study.   
 
2.6 Study 
Duration 
The expected duration of study participation for a patient is ~30 days, 
including up to 14 days for medical screening, and 3 one-night treatments.  
All assessments will be separated by a 6-12 day drug free interval. A 
maximum of 3-4 patients will be enrolled in the study at a given time. Thus, 
the expected duration for study completion will be ~9 months. 
 
2.7 Statistical 
Analysis and 
Sample Size 
Justification  
The Sleep Disorders Center will be responsible for analyzing the study data 
(Investigator and expert statistical staff).  The blind will be maintained during 
the study and the data will be unblinded at the completion of the trial. For the 
purpose of the final analysis, the official clinical database will not be unblinded 
until medical/scientific review has been completed, protocol violations have 

 
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been identified and data has been declared complete in conjunction with the 
study Sponsor. 
Data analysis will compare the change from placebo in each active drug 
condition. The primary analysis will be based on the evaluable population, 
defined as subjects who have data from each of the three Treatment Periods 
with no major protocol violations. Safety analyses will be presented 
descriptively for the safety population; defined as all subjects who were 
randomized and received at least one dose of study medication. 
 
The primary endpoint will be the mean Auditory Arousal Threshold in 
decibels (AAT).  
 
All statistical analyses will be conducted using IBM SPSS Statistics for 
Windows – Version 23 (Armonk, NY). The primary outcome of the study 
include within-person differences between active medications and respective 
placebo on the AAT. Univariate within-group comparisons for these 
continuous endpoints will be accomplished via paired samples t-tests. 
Repeated-measures analysis of covariance (ANCOVA) analyses will be used 
for estimating more complex models involving multiple factors or covariates 
(e.g., age. Given the extensive array of variables, covariates will be selected for 
inclusion in omnibus models per recommendations outlined by Mickey and 
Greenland (1989). Specifically, only those variables are related to the 
dependent variable in univariate analyses at a significance level of P < 0.20 will 
be retained in the final model. Similar analyses will be used to examine all 
potential secondary/exploratory endpoints. 
 
Power analyses: Based on a previous study using zolpidem 10 mg in younger 
men, we estimate the power for this project to be 70% or greater for detecting 
a mean difference of ~15 db between belsomra and placebo given a sample of 
12 individuals. This assumes a variance of 15 db. In our previous study the 
variance was ~15 db indicating an effect size of d=1.0. We do not expect 
insomnia status to impact the arousal threshold effect size as shown in previous 
studies (Johnson et al., 1978). 
 
Safety and tolerability will be assessed by statistical and clinical review of the 
data on adverse clinical events, such as complex sleep-related behaviors, 
predefined limits of change for selected laboratory and vital sign values, as well 
as next-day residual effects. The primary approach for all safety analyses will 
be the All Patients as Treated (APaT) approach. All randomized patients who 
receive at least one dose of study medication will be included in the safety 
analyses.  
 
The results will be reported using summary tables, figures, and data listings. 
Continuous variables will be summarized using mean, standard deviation, 
median, minimum, and maximum values. Categorical variables will be 
summarized by presenting the number (frequency) and percentage in each 
category. 

 
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Demographics will be tabulated and summarized. Medical history data at 
Screening will be listed, as will Physical Examination data including height 
and weight.  Vital signs (resting heart rate, systolic/diastolic blood pressure, 
respiratory rate and temperature) will be tabulated and summarized.  
Treatment-emergent adverse events will be listed and summarized. Adverse 
events reported in this study will be coded using MedDRA (Medical 
Dictionary for Regulatory Activities).  
Clinical laboratory data will be summarized with descriptive statistics.  
Abnormal laboratory test results will be flagged in the subject data listings. 
 
2.8 Specific Drug 
Supply 
Requirements  
Suvorexant will be supplied by Merck. Due to the limited nature of study 
drug needed the HFHS pharmacy will not require bulk supplies (if necessary 
study drug can be purchased by HFHS pharmacy and over encapsulated for 
the study procedures in house). Study drug will be unknown to the patient and 
therefore will be labeled only with study night number. 
2.9 Adverse 
Experience 
Reporting 
Model Study Agreement will be used and all safety/adverse event reporting 
will occur in strict accordance with those guidelines.  
2.10 Itemized 
Study Budget  
Study budget for 12 completed participants = $299,435 (see attached detailed 
budget). In order to facilitate the MISP evaluation of the proposed study and 
budget we have chosen the most efficient study design, sample population, 
study duration, and subject numbers. However, we recognize that the present 
study parameters may have limitations. With this in mind we have provided an 
initial cost estimate, but adjustments to the proposed design could be 
effectively made to minimize such limitations (i.e., increase/decrease the 
number participants, add additional comparison doses, or additional study 
populations/measures).  
 
2.11 References 
Drake, C.L., Durrance, H., Chang, P., Roth, T., Pillai, V., Peterson, E. Singh, 
M., Tran, K.M. (2017). Arousability and fall-risk during forced awakenings 
from nocturnal sleep following administration of zolpidem 10 mg and doxepin 
6 mg in healthy men: A randomized, placebo-controlled, four-arm crossover 
trial. Sleep, In Press. 
 
Frey, D. J., Ortega, J. D., Wiseman, C., Farley, C. T., & Wright, K. P. (2011). 
Influence of Zolpidem and Sleep Inertia on Balance and Cognition During 
Nighttime Awakening: A Randomized Placebo‐Controlled Trial. Journal of the 
American Geriatrics Society, 59(1), 73-81. 
 
 

 
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Johnson, Laverne C., and Cheryl L. Spinweber. Benzodiazepine Effects on 
Arousal Threshold during Sleep. No. NAVHLTHRSCHC-83-17. NAVAL 
HEALTH RESEARCH CENTER SAN DIEGO CA, 1983. 
 
Johnson, L. C., Church, M. W., Seales, D. M., & Rossiter, V. S. (1978). 
Auditory arousal thresholds of good sleepers and poor sleepers with and 
without flurazepam. Sleep, 1(3), 259-270. 
 
Tannenbaum, P. L., Stevens, J., Binns, J., Savitz, A. T., Garson, S. L., Fox, S. 
V & Tye, S. J. (2014). Orexin receptor antagonist-induced sleep does not 
impair the ability to wake in response to emotionally salient acoustic stimuli in 
dogs. Front Behav Neurosci, 8, 182. 
 
Tannenbaum, P.L., Tye, S.J., Stevens, J., Gotter, A.L., Fox, S.V., Savitz, A.T., 
Coleman, P.J., Uslaner, J.M., Kuduk, S.D., Hargreaves, R. and Winrow, C.J., 
2016. Inhibition of orexin signaling promotes sleep yet preserves salient 
arousability in monkeys. Sleep, 39(3), p.603. 
 
2.12 Publication 
Plan 
 We anticipate 1-3 manuscripts generated from the present study, 1 from 
primary objectives and 1-2 additional from exploratory analyses. However, 
total number will be dependent upon study outcomes. 
 The projected target date for manuscript submission will be August 2018 
submitted to Journal of Clinical Sleep Medicine. 
 We anticipate 3-4 abstracts generated from this protocol. 
 Results will be present by the PI and Co-Investigators at the National Sleep 
Meeting and the American Psychiatric Association National Conference. 
 
2.13 Curriculum 
Vitae 
 
Dr. Drake’s CV is attached including previous trials/grants. 
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies  
U.S. protocols should be submitted by US investigators directly or through 
the Global Research Specialist at  www.merckiisp.com   
 
Non U.S. protocols should be submitted to the MSD office by the 
investigators.