Conditions: Multiple Sclerosis Fatigue Insomnia
Keywords: Multiple Sclerosis Fatigue Insomnia Suvorexant Belsomra Sleep disorder Sleep
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: no

Brief summary:
This study assesses the safety, tolerability, and efficacy of suvorexant in multiple sclerosis patients. Enrolled subjects will receive 2 weeks of treatment during treatment period 1 with either suvorexant or matching placebo (1:1). After treatment period 1, subjects will undergo a washout period of 1 week then 2 weeks of the alternate treatment (either suvorexant or placebo). The primary hypothesis is that suvorexant will provide greater improvement in sleep, as measured by symptom rating scales, compared to placebo.

Detailed description:
The target enrollment number is 30 people with multiple sclerosis who meet inclusion criteria. After informed consent is given, potential subjects will be screened to ensure they meet eligibility criteria. Subjects who meet eligibility criteria will complete baseline assessments and will then be randomized to receive 2 weeks of treatment (Treatment Period 1) with either suvorexant or matching placebo (1:1). The initial dose of suvorexant will be 10 mg at bedtime, with optional titration to 20 mg after 5-7 days. Study drug will be dispensed by an independent research pharmacist, keeping both study staff and the subject blinded. All subjects, whether in placebo or active arm, will receive a wearable sleep monitor to be worn for 7 days at baseline, and during both treatment periods. All subjects will keep 7-day sleep diaries at baseline and during each study period. At the end of Treatment Period 1 (2 weeks), subjects will undergo efficacy assessments with repeated clinical scales. Subjects will then go through a 1-week open-label off-drug washout period. Subjects will then be crossed over into the alternate treatment group, which will once again be double-blinded; those on active treatment (suvorexant) in Treatment Period 1 will be switched to placebo, and those on placebo in Treatment Period 1 will be switched to active treatment. Treatment Period 2 will also be 2 weeks long, and at the end of this, subjects will undergo final assessment with clinical scales.

Arms:
arm 1: Suvorexant - 10 mg (one tablet) taken by mouth once daily at bedtime with option to up-titrate to 20 mg (two tablets) taken by mouth once daily at bedtime. arm 2: Placebo - one tablet taken by mouth once daily at bedtime and two tablets taken by mouth daily at bedtime if subject up-titrates.

Interventions: intervention 1: Suvorexant intervention 2: Placebo
Intervention descriptions: intervention 1: See detailed information in associated Arm Description. intervention 2: Sugar pill manufactured to mimic suvorexant 10 mg tablet.

Protocol document:
Prot_SAP_000.pdf: 
Brown, Suvorexant IIT v.3 2019_10_29 
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Study Title:  
DREAM: A Double-blind, CrossoveR, placebo-controlled Study to compare the 
Effects of Nighttime Administration of suvorexant in Patients with Multiple 
Sclerosis fatigue and insomnia 
 
PROTOCOL NUMBER: 
TRB 2017.2 
 
DATE: 
October 29, 2020 
 
 
 
INVESTIGATORS: 
Theodore R. Brown, MD, MPH1 
 
Virginia I. Simnad, MD1 
 
AFFILIATION: 
1EvergreenHealth Multiple Sclerosis Center 
Evergreen Neuroscience Institute 
 
Evergreen Medical Center, Kirkland, WA 
 
 
 
 
Principal Investigator: 
Theodore R. Brown, MD, MPH 
Office:   
 
 
EvergreenHealth MS Center, Evergreen Neuroscience Institute 
Evergreen Medical Center, 12039 NE 128th St, Ste. 300 
Kirkland, WA 
Fax:    
 
 
425-899-5355  
 
 
E-Mail:  
 
 
trbrown@evergreenhealth.com 
 
 
 
 
Sub-Investigator: 
 
Virginia I. Simnad, MD 
Office:   
 
 
EvergreenHealth MS Center, Evergreen Neuroscience Institute 
Evergreen Medical Center, 12039 NE 128th St, Ste. 300 
Kirkland, WA 
Fax:    
 
 
425-899-5355  
 
 
E-Mail:  
 
 
VSimnad@evergreenhealth.com 
 
 
 
 


Brown, Suvorexant IIT v.3 2019_10_29 
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TABLE OF CONTENTS 
 
1. Title page  
 
 
 
 
 
 
 
 
 
1 
2. Table of Contents  
 
 
 
 
 
 
 
 
2 
3. Schedule of Events 
 
 
 
 
 
 
 
 
4 
4. List of Abbreviations 
 
 
 
 
 
 
 
 
5 
5. Introduction and Rationale 
 
 
 
 
 
 
 
5 
6. Study Objectives  
 
 
 
 
 
 
 
 
7 
6.1. Primary Objective 
 
 
 
 
 
 
 
 
7 
6.2. Secondary Objective  
 
 
 
 
 
 
 
7 
7. Methodology and Timeline 
 
 
 
 
 
 
 
7 
7.1. Methodology  
 
 
 
 
 
 
 
 
7 
7.2. Interventions  
 
 
 
 
 
 
 
 
8 
8. Study Population  
 
 
 
 
 
 
 
 
8 
8.1. Inclusion Criteria 
 
 
 
 
 
 
 
 
8 
8.2. Exclusion Criteria 
 
 
 
 
 
 
 
 
9 
9. Prohibited Medications 
 
 
 
 
 
 
 
 
10 
10. Visit Schedules and Assessments  
 
 
 
 
 
 
12 
10.1. 
Enrollment 
 
 
 
 
 
 
 
 
12 
10.2. 
Screening Clinic Visit 1 
 
 
 
 
 
 
12 
10.3. 
Baseline Clinic Visit 2 
 
 
 
 
 
 
13 
10.4. 
Phone Visit 1              
 
 
 
 
 
 
13 
10.5. 
Crossover Clinic Visit 3 
 
 
 
 
 
 
14 
10.6. 
Phone Visit 2  
 
 
 
 
 
 
 
14 
10.7. 
Phone Visit 3  
 
 
 
 
 
 
 
14 
10.8. 
Termination Clinic Visit 4 
 
 
 
 
 
 
14 
10.9. 
Unscheduled Visits 
 
 
 
 
 
 
 
15 
11. Outcome Measures 
 
 
 
 
 
 
 
 
15 
11.1. 
Primary Efficacy Measures 
 
 
 
 
 
 
15 
11.2. 
Secondary Efficacy Measures 
 
 
 
 
 
15 
11.3. 
Exploratory Efficacy Measures 
 
 
 
 
 
16 
12.  Safety Monitoring 
 
 
 
 
 
 
 
 
17 
12.1. 
Safety Measures 
 
 
 
 
 
 
 
17 
12.2. 
Adverse Events 
 
 
 
 
 
 
 
17 
12.3. 
Serious Adverse Events 
 
 
 
 
 
 
18 
12.4. 
Serious Adverse Events Reporting 
 
 
 
 
 
18 
13. Data Management and Statistical Analysis 
 
 
 
 
 
19 
13.1. 
Sample Size Considerations  
 
 
 
 
 
19 
13.2. 
Statistical Analysis 
 
 
 
 
 
 
 
19 


Brown, Suvorexant IIT v.3 2019_10_29 
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14. Study Management 
 
 
 
 
 
 
 
 
20 
14.1. 
Patient stipend 
 
 
 
 
 
 
 
20 
14.2. 
Ethics and Good Clinical Practice 
 
 
 
 
 
20 
15. References 
 
 
 
 
 
 
 
 
 
21


Brown, Suvorexant IIT v.3 2019_10_29 
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SCHEDULE OF EVENTS 
Parameter 
Screening 
Clinic Visit 1 
Baseline 
Clinic Visit 2  
Phone 
Visit 1 
 
Phone Visit 2 
Phone Visit 3 
Phone 
Visit 4  
Phone Visit 5 
Unscheduled 
Visits 
 
Week # 0 
Week # 1-2 
 
Week #3-4 
Week #5-6 
 
Week #7-8 
 
Medical History 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Physical Examination/ 
Visit with MD 
X 
Ŧ 
 
 
 
 
 
X 
Vital Signs 
X 
 
 
 
 
 
 
 
Urine pregnancy test for 
females * 
X 
 
 
 
 
 
 
 
Laboratory testing ** 
X 
 
 
 
 
 
 
 
Beck Depression 
Inventory II 
X 
 
 
X 
 
 
X 
 
BDI - Q9 
 
 
X 
 
 
X 
 
 
Current Medication 
X 
X 
 
X 
X 
X 
X 
X 
 
EDSS 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Drug dispensing 
 
X 
 
 
 
 
 
 
Fatigue Severity Scale 
X 
 
 
 
 
 
 
 
MFIS 
 
X 
 
X 
 
 
X 
 
Insomnia Severity Index 
 
X 
 
X 
 
 
X 
 
Fatigue VAS 
 
X 
 
X 
 
 
X 
 
Sleep diary 
 
X 
 
X 
 
 
X 
 
Wearable sleep monitor 
review 
 
X 
 
X 
 
 
X 
 
Step count 
 
X 
 
X 
 
 
X 
 
Global impression 
 
X 
 
X 
 
 
X 
 
Adverse Event 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
Study drug pill counts 
 
 
 
 
 
 
X 
 
Ŧ Optional, indicated for any safety issues that arise 
* As indicated by fertility status 
** Laboratory testing: CBC, CMP 


Brown, Suvorexant IIT v.3 2019_10_29 
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4. LIST OF ABBREVIATIONS 
AE  
 
Adverse event 
AHI 
 
Apnea - Hypopnea Index 
BDI 
 
Beck Depression Inventory 
BDI- Q9 
 
Beck Depression Inventory, question 9 (suicidality) 
CBC 
 
Complete Blood Count 
CMP 
 
Comprehensive Metabolic Panel 
CNS 
 
Central Nervous System 
COPD 
 
Chronic Obstructive Pulmonary Disease 
DSM-5 
 
Diagnostic and Statistical Manual of Mental Disorders Edition 5 
EDSS 
 
Expanded Disability Status Scale 
EDSS 
 
Expanded Disability Status Scale 
FDA 
 
Food & Drug Administration 
GCP 
 
Good Clinical Practice 
hCG 
 
Human chorionic gonadotropin 
ICF 
 
Informed Consent Form 
IRB 
 
Institutional Review Board 
ISI 
 
Insomnia Severity Index 
MFIS 
 
Modified Fatigue Impact Scale 
MS 
 
Multiple sclerosis 
OSA 
 
Obstructive Sleep Apnea 
PFT 
 
Pulmonary Function Test 
PI  
 
Principal Investigator 
PSG 
 
Polysomnography 
sQUAL                       Subjective Quality of Sleep 
sFRESH                      Subjective Refreshed Feeling on Waking 
SAE  
 
Serious adverse event 
VAS  
 
Visual Analogue Scale 
VAS-F 
 
Fatigue Visual Analogue Scale 
WSM 
 
Wearable Sleep Monitor 
 
 
5. Introduction and Rationale 
Over 400,000 Americans have multiple sclerosis (MS), a chronic neurological disease 
characterized by demyelination and axonal degeneration.  Despite their high prevalence in 
general adult populations, recently published studies provide compelling data that the prevalence 
of sleep disorders is further increased in individuals with MS (Merlino et al. 2009).  Up to 40 % 
of MS patients may be at risk of having chronic insomnia disorder (Brass, Li, Auerbach 2014). 
MS-related symptoms including neurogenic bladder, pain, depression and spasticity should be 
viewed as potential triggers for insomnia and appropriately treated. Multiple medications 
frequently used by patients with MS, including stimulants, serotonin reuptake inhibitors and 


Brown, Suvorexant IIT v.3 2019_10_29 
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beta-interferon may also contribute to insomnia. (Hurwitz et al. 2008) Recent studies suggest that 
daytime sleepiness and nocturnal sleep disturbances contribute to physical and cognitive fatigue 
in MS (Braley, Bondreau 2016, Stanton, Barnes, Silber 2006, Beran, Ainley 2005, Attarian et al. 
2004).  Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to 
ameliorate some of the daytime fatigue experienced by patients with MS.  
In the mid-1980s, fatigue came to light as an important MS symptom.(Kraft, Freal, Coryell 1986, 
1984).  Subsequent studies have found fatigue prevalence rates of 78% or more amongst MS 
patients (Bakshi et al. 2000, Krupp et al. 1988).  For people with MS, fatigue is defined as “a 
sense of physical tiredness and lack of energy, distinct from sadness or weakness.” (Krupp 2004) 
Fatigue may be brought on by exertion or be non-exertional. Because it is often the limiting 
factor for activity, it has been termed the single most frequent and often most disabling symptom 
of the disease (Bergamaschi et al. 1997, Fisk et al. 1994). 
Non-medical treatments of fatigue include exercise, napping, energy conservation and cooling 
through application or consumption of cold substances.  Fatigue is frequent in MS and yet there 
are no FDA-approved treatments for this indication.  Therefore, drugs that have FDA approval 
for other indications are frequently used off-label.  The following pharmacological agents are 
commonly used or have been used off-label in MS: modafinil, armodafinil, amantadine and 
methylphenidate. There is no convincing evidence of efficacy of any drug for MS fatigue and 
none of these drugs have been sufficiently tested in the population of MS patients (Stankoff et al. 
2005, Rammohan et al. 2002, Zifko et al. 2002, Wingerchuk et al. 2005, Canadian MS Research 
Group 1987, Cohen, Fisher 1989, Tomassini et al. 2004, Gillson et al. 2002, Lebrun et al. 2006). 
Sleep disturbances have been strongly associated with MS fatigue [Veauthier 2011].  One study 
found that poorer sleep was associated with worse perceived cognitive dysfunction and that this 
relationship was partially mediated by fatigue [Hughes 2016].  Assessment and treatment of 
sleep disorders is an important component of MS fatigue management [Tur 2016Braley 2016].  
Two studies have demonstrated that treatment of sleep disorders in general or sleep apnea in 
particular improved symptoms of fatigue in individuals with MS [Veauthier 2013, Cote 2013]. 
Only one study could be found that included an intervention for insomnia in multiple sclerosis.  
Baron et al used a telephone-based psychotherapy approach to reduce the rate of insomnia in 
depressed MS patients [Baron 2011] 
Suvorexant (MK-4305, Belsomra®) which is approved by the FDA for the treatment of insomnia 
characterized by difficulties with sleep onset and sleep maintenance, is a selective antagonist for 
orexin receptors (OX1R and OX2R). Suvorexant has been shown to improve sleep efficiency in 
healthy, non-elderly adults with primary insomnia (Herring et al. 2012, Sun et al. 2013). It is 
believed that suvorexant does not pose a risk of physical dependence or rebound insomnia as do 
the benzodiazepines and non-benzodiazepine soporifics (Bennett, Bray, Neville 2014).  


Brown, Suvorexant IIT v.3 2019_10_29 
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Suvorexant may have other advantages that are of benefit specifically in the MS population. 
Suvorexant appears not to adversely affect next-day balance in healthy non-elderly subjects.  In 
addition, suvorexant appears not to affect memory as measured by word recall. MS patients often 
have ataxia and cognitive impairment as a result of their disease.  Orexins are considered to be 
involved in arousal and maintenance of the waking state. As such, suvorexant may provide 
unique clinical benefit as a treatment of MS fatigue with co-morbid insomnia. 
This project proposes to study objective and clinical measures of insomnia, daytime sleepiness 
and fatigue in patients with MS fatigue and co-morbid insomnia while treated short-term with 
suvorexant 10-20mg versus placebo. Those qualifying will receive suvorexant and placebo for 
each of 14 nights in a cross over design with 7 nights of washout between treatments. There will 
be an optional titration to suvorexant 20mg (or matching placebo) after 5-7 days of each active 
treatment period.  Primary outcome to be measured will be change in ISI on both conditions 
(Suvorexant 10/20mg versus placebo). 
The primary outcome to be measured will be change from baseline for the two conditions 
(suvorexant 10/20 mg and placebo) on the Insomnia Severity Index. 
Suvorexant is approved at doses up to 20 mg daily (Prescribing Information, Merck 2015). 
People with MS may be more sensitive to the therapeutic and adverse effects of suvorexant. It is 
also likely that subjects in a MS trial will be on other medications that may increase daytime 
somnolence. For these reasons, we are proposing a study of the 10-mg dose only. If suvorexant is 
found to be well-tolerated at a dose of 10 mg daily, future MS studies can explore the safety and 
efficacy of 20 mg daily. 
 
6. Study Objectives 
6.1 Primary Objective 
1. To assess the efficacy of suvorexant in treating insomnia in Multiple Sclerosis patients 
with fatigue 
6.2 Secondary Objective 
2. To assess the effect of suvorexant on fatigue and daytime sleepiness in this population 
 
7. Methodology and Timeline 
7.1 Methodology: 
• Multi-center (Evergreen as principal site) 
• N= 50.  Confirmed MS diagnosis, age 18-75, inclusive.   
• Double-blind, cross-over trial 


Brown, Suvorexant IIT v.3 2019_10_29 
8 
 
• Four clinic visits: Screening, baseline, cross-over, termination 
• Timeline: 
o 1) Screening 
o 2) Treatment 1 (baseline) 
 Subjects who meet eligibility criteria will be randomized to receive 2 
weeks of treatment (treatment period 1) with either suvorexant 10 mg or 
matching placebo (1:1) with optional titration (see 7.2). Drug will be 
dispensed by the independent research pharmacist, keeping both study 
staff and the subject blinded. All subjects, whether in placebo or active 
arm, will receive a wearable sleep monitor to be worn continuously 
throughout the study. The subjects will be allowed to keep the wearable 
sleep monitor in addition to a small monetary reimbursement per visit.  
o 3) Washout (14 days post baseline) 
 At the end of treatment period 1 (2 weeks), subjects will undergo efficacy 
assessment with repeated clinical scales. Subjects will then go through a 1-
week open-label off-drug washout period. Subjects will then be crossed 
over into the alternate treatment group, which will once again be double-
blinded; those on active treatment for period 1 will be switched to placebo, 
and those on placebo in period 1 will be switched to active treatment.  
o 4) Treatment 2 (7 days post washout, 21 days post baseline) 
 Treatment period 2 will also be 2 weeks long, with crossover from Period 
1 - either suvorexant 10mg or matching placebo, with optional titration 
(see 7.2). At the end of this, subjects will undergo final assessment with 
clinical scales.  
7.2 Interventions:  
Study medication, to include 10-mg suvorexant and matching placebo, will be provided by 
Merck. The active medication will be suvorexant 10 mg every bedtime. The research pharmacist 
at EvergreenHealth will randomize the subject and the subject is provided active and placebo, in 
separate containers labeled for proper order of consumption based on study assignment.  Study 
medication will be dispensed at randomization (Visit 2, start of Treatment Period 1) with 
separate pill bottles marked “Period 1, use this bottle first” and “Period 2, use this bottle after the 
break.”   An extra 6-day supply of medication will be provided for each study period to allow a 
window for scheduling of appointments. 
 
Optional Drug Titration: There will be an optional titration to two pills at night (changes to 
suvorexant 20mg or matching placebo) after 5-7 days of each active treatment period.  This will 
be based on a phone interview entailing answering questions about drug tolerance and whether 
the participant would like to escalate the dose of drug.  
 


Brown, Suvorexant IIT v.3 2019_10_29 
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8. Study Population:  
8.1 Inclusion criteria 
• Diagnosis of MS made at least 3 months prior based on McDonald criteria.   
• Age 18-75 inclusive 
• Expanded Disability Status Scale (EDSS) 0- 7.5. 
• Clinical stability defined as no MS exacerbation or change in disease modifying therapy 
for 60 days prior to screening. 
• Screening Fatigue Severity Scale score of ≥4.0. 
• Has Insomnia Disorder defined by diagnostic criteria published in the Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition (DSM-5); namely, subject report of all 
of the following:  
o One of the following: difficulty initiating sleep; difficulty maintaining sleep; or 
early morning waking. 
o Sleep disturbance causes clinically significant distress or impairment in social, 
occupational, educational, academic, behavioral, or other important areas of 
functioning. 
o Sleep difficulty has occurred on 3 or more nights per week. 
o Sleep difficulty has been present for at least the past 3 months. 
o Sleep difficulty occurs despite adequate opportunity for sleep. 
o Insomnia is not explained by another sleep disorder. 
o Insomnia is not attributable to physiological effects of a consumed substance. 
• May use other medications that could influence sleep, other than those specifically 
prohibited, as long as the dose is stable for 4 weeks preceding screening, with no dose 
changes during the study. 
• Signed and dated IRB-approved informed consent form before any protocol-specific 
screening procedures have been performed. 
8.2 Exclusion criteria 
• Use of potential MS-associated fatigue drugs within 3 days of screening until study 
completion, including modafinil, armodafinil, amantadine, methylphenidate, products 
with amphetamine or dextroamphetamine. 
• Use of any of any prohibited medication (see below) from 3 days prior to screening to 
termination visit. 
• Female who is breast-feeding, pregnant, or has the potential to become pregnant during 
the course of the study (fertile and unwilling/unable to use effective contraceptive 
measures). 
• History of narcolepsy. 


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• Has a diagnosis of severe chronic obstructive pulmonary disease (COPD), defined by 
FEV1 < 50% of predicted on most recent available pulmonary function test (PFT).  PFT 
is not required if the subject has never been diagnosed with COPD. 
• Has a history of severe obstructive sleep apnea (OSA), with severe OSA defined as 
having an apnea-hypopnea index (AHI) > 30 on prior polysomnograph (PSG).  PSG is 
not required if there is no history suggesting severe OSA. 
• Is concurrently using other central nervous system(CNS) depressants, including alcohol, 
except that one alcoholic drink per day will be allowed for those with normal hepatic 
function provided the drink is consumed at least 2 hours prior to or 8 hours after taking 
the study drug.  Medical marijuana is allowed if consumed at the patient’s usual dose at 
least 2 hours prior to or 8 hours after taking the study drug.  Recreational marijuana is not 
allowed from screening until end of study.   
• Has evidence at screening of severe hepatic impairment as defined by a Child-Pugh score 
> 10. 
• Cognitive impairment that in the opinion of the investigator would prevent completion of 
study procedures or the ability to provide informed consent. 
• Suicidality or severe depression as measured by screening Beck Depression Inventory II 
(BDI) score > 28 or score of >1 on BDI Q9 (suicidality screen) at any time during the 
study. 
• Any other serious and/or unstable medical condition. 
 
9. Prohibited Medications 
 
The following medications are not permitted to be used from 3 days prior to screening through 
the duration of the subject’s participation in the study: 
 
• Fatigue Medications 
o Modafinil 
o Armodafinil 
o Amantadine 
o Methylphenidate 
o Products with amphetamine or dextroamphetamine  
• Digoxin; 
• CNS depressants such as: 
o Benzodiazepines 
 Alprazolam 
 Chlorazepate 
 Chlordiazepoxide 
 Clonazepam 
 Diazepam 
 Estazolam 
 Flurazepam 


Brown, Suvorexant IIT v.3 2019_10_29 
11 
 
 Halazepam 
 Lorazepam 
 Midazolam 
 Oxazepam 
 Prazepam 
 Temazepam 
 Triazolam 
o Barbiturates 
 Amobarbital 
 Mephobarbital 
 Pentobarbital 
 Phenobarbital 
 Primidone 
 Secobarbital 
 Sodium thiopental 
o Opiates 
 Codeine 
 Hydrocodone 
 Hydromorphone 
 Methadone 
 Morphine 
 Oxycodone 
o Zolpidem 
o Zaleplon 
o Eszopiclone 
• Moderate or strong inhibitors of CYP3A, such as: 
o Aprepitant 
o Atazanavir 
o Bromocriptine 
o Chloramphenicol 
o Ciprofloxacin 
o Clarithromycin 
o Cobicistat 
o Conivaptan 
o Darunavir 
o Desipramine 
o Diltiazem 
o Dronedarone 
o Erythromycin 
o Felodipine 
o Fluconazole 
o Fluvoxamine 
o Fosamprenavir 
o Grapefruit Juice 
o Imatinib 
o Indinavir 


Brown, Suvorexant IIT v.3 2019_10_29 
12 
 
o Itraconazole 
o Ketoconazole 
o Lopinavir 
o Nefazadone 
o Nelfinavir 
o Nicardipine 
o Posaconazole 
o Quinidine 
o Quinupristin 
o Ritonavir 
o Saquinavir 
o Telaprivir 
o Telithromycin 
o Verapamil 
o Voriconazole 
• Strong inducers of CYP3A, such as: 
o Carbamazepine 
o Dexamethasone 
o Phenobarbital 
o Primidone 
o Phenytoin 
o Rifampin 
o St. John’s Wart 
 
10. Visit Schedules and Assessments 
10.1 Enrollment 
Subjects who may qualify for this study will be identified in the context of clinical care at the 
participating site. Such eligible patients may receive a copy of the informed consent form (ICF) 
at the time of their clinic visit. Recruitment may also occur through local educational 
opportunities, referrals from other area neurologists, sleep medicine physicians, the National MS 
Center website, and the website of EvergreenHealth or other site. Patients may contact a 
participating site after reading a notice about the study on the Institute’s website or other online 
postings. Subjects who are not established patients at a participating site will be offered the 
chance to undergo a telephone screening using an institutional review board (IRB) approved 
telephone screening text.  Subjects will be requested to send pertinent outside medical records 
for chart review by the principal investigator and be scheduled for a screening visit. 
10.2 Screening Clinic Visit 1 
Office Visit 1 is the screening visit. At this clinic visit, subjects will provide written, informed 
consent. Once consent is provided, a unique identification number will be assigned. This will be 
the only identification number assigned to the subject for the duration of the study. After consent 


Brown, Suvorexant IIT v.3 2019_10_29 
13 
 
is obtained, subjects will be assessed for eligibility. A history of the patient’s MS diagnosis, past 
medical history and sleep symptoms will be reviewed. Diagnosis of MS will be confirmed based 
on revised McDonald Criteria (Polman et al. 2011). Diagnosis of insomnia will be confirmed 
following DSM-5 criteria. Rating of MS fatigue will be based on the Fatigue Severity Scale. 
Beck depression index (BDI) will be performed.  Current medication list will be reviewed. 
Eligible subjects will have a stable MS medication regimen for 60 days prior to the screening 
visit and remain on a stable regimen for the duration of the study. Eligible patients will also not 
be concomitantly taking any of the prohibited medications for at least 3 days prior to the 
screening visit. The patient’s history of medication allergies will be reviewed. 
Physical examination will be performed, both a general medical examination including vital 
signs and a neurological examination. Neurological exam will include disability rating by 
expanded disability status scale (EDSS) (Kurtzke 1983). Laboratory testing will include 
complete blood count (CBC), complete metabolic panel (CMP), with calculation of the Child-
Pugh score for any subjects with liver dysfunction. Pre-menopausal women without surgical 
sterilization will have urine human chorionic gonadotropin (hCG) measured.  
The wearable activity/sleep monitor will be dispensed at this visit to all subjects who meet 
eligibility criteria. This will be a FitBit™ device worn by the subjects throughout the remainder 
of the study.  The research coordinator will oversee patient education around FitBit use. The 
FitBit is easy for subjects to put on and requires minimal user programming to upload data.  
Recorded outcomes are described below (see outcome measures). Subjects will be encouraged to 
wear the monitor 24-hours per day.  Patients will be instructed to complete a sleep diary for 
seven days prior to next visit (see 11. Outcome measures). 
10.3 Baseline Clinic Visit 2 
Clinic Visit 2 will occur within 7-14 days after the screening visit. In addition to screening for 
eligibility, medications will be reviewed again to ensure stability of the MS medication regimen 
and absence of any prohibited medications.  
Following confirmation of eligibility, an eligible patient will complete the baseline assessments 
of the insomnia severity index (ISI), modified fatigue impact scale (MFIS), Fatigue visual 
analogue scale (VAS-F), Global impression. The following measures will be provided for the 
participants to take home for use at the time of Phone Visit 2 and Phone Visit 5: Study scales 
(ISI, MFIS, VAS-F, BDI, Global impression).  Sleep diaries will be provided for use after Phone 
Visit 1 and Phone Visit 3.   
Following confirmation of eligibility, an eligible patient will be randomized in a 1:1 
randomization scheme to receive suvorexant 10 mg qhs or placebo. Randomization will occur at 
the research pharmacy of EvergreenHealth using a computer-generated randomization list. The 
pharmacist will maintain a codebook indicating the treatment allocation of each subject. Study 
medication will be delivered by the research pharmacist to the research study staff from the 


Brown, Suvorexant IIT v.3 2019_10_29 
14 
 
research pharmacy (a separate locked room containing only research medications). The 
investigating physicians and research coordinator will be blinded as to treatment arm until the 
code is broken. The randomization code may be broken by the investigator only in a medical 
emergency. The reasons for such an emergency will be documented carefully. The subjects will 
receive 2 pill bottles, each containing identical appearing active or placebo study medication 
tablets, with identification known only to the research pharmacist.   See Section 7.2 regarding 
study medication preparation and distribution. 
The patient will be provided with pre-stamped and pre-addressed envelopes for return of unused 
study medication and study diaries at end of study.   
10.4 Phone visit 1 
Phone Visit 1 will occur 5-7 days after Clinic Visit 2 to review safety and tolerability through 
questioning about adverse events. BDI Q9 (suicidality risk) will be administered.  Subjects with 
answer of 2 or 3 will be asked to discontinue study medication immediately and unscheduled 
visit or emergency referral will be arranged.  Subjects with BDI Q9 score 0 or 1 who report no 
AEs on suvorexant 10 mg po QHS (or matched placebo) and who report a persistent sleep 
disturbance will be titrated to suvorexant 20 mg po QHS (or matched placebo) using a titration 
decision algorhythm. At this visit, subject will be reminded to wear sleep monitors and to start 
recording sleep diaries every morning. 
10.5 Cross-over Phone Visit 2 (14 days post treatment) 
Phone Visit 2 will occur at the completion of the first treatment period (day 14 following 
baseline). Medications will be reviewed again to ensure absence of any prohibited medications. 
Any possible adverse events (AE) will be assessed. 
Study scales (ISI, MFIS, VAS-F, BDI, Global impression) will be self-administered by the 
participant with study staff oversight, as needed. Data from the wearable activity / sleep monitor 
will be collected. Completion of the 7-days sleep diary and scales (sQUAL and sFRESH) will be 
verified remotely.   
Subjects will be instructed to take no study medication for one week, then to start taking the 
study medication (active or placebo) for Period 2.  
10.6 Phone Visit 3 : Start of Treatment Period 2  
Phone Visit 3 will occur 1 week after Phone Visit 2 (day 21 after baseline) and will mark the 
beginning of treatment period 2. Medications will be reviewed again to ensure stability of the 
MS medication regimen and absence of any prohibited medications. Any possible adverse events 
(AEs) will be assessed.  


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Subjects will be instructed to begin taking drug from the bottle marked “Period 2.”. All subjects 
who received active medication in treatment period 1 will take placebo, and all subjects who 
received placebo in treatment period 1 will take active medication (10mg) while double blind. 
10.7 Phone Visit 4 
Phone Visit 4 will occur 5-7 days after Phone Visit 3 to review safety and tolerability through 
questioning about adverse events. BDI Q9 (suicidality risk) will be administered.  Subjects with 
answer of 2 or 3 will be asked to discontinue study medication immediately and unscheduled 
visit or emergency referral will be arranged.  Subjects with BDI Q9 score 0 or 1 who report no 
AEs on suvorexant 10 mg po QHS (or matched placebo) and who report a persistent sleep 
disturbance will be titrated to suvorexant 20 mg po QHS (or matched placebo) using a titration 
decision algorhythm.  At this visit, subjects will be reminded to wear sleep monitors and to start 
recording sleep diaries. 
10.8 Termination Phone Visit 5 
Phone Visit 5 (final visit) will occur 2 weeks after Phone Visit 3 (day 35 after baseline). 
Medications will be reviewed again. Any possible AE will be assessed.  
Study scales (ISI, MFIS, VAS-F, BDI, Global impression) will be self-administered by the 
participant with study staff oversight, as needed. Data from the wearable activity / sleep monitor 
will be collected. Completion of the 7-days sleep diary and scales (sQUAL and sFRESH) will be 
verified remotely.  Patients will be instructed to stop taking study medication and place all 
unused study medication from Period 1 and Period 2 in the mailing envelope.  They will be 
asked to include all study materials (surveys and diaries) in the envelope and to mail it as soon as 
possible.    
10.9 Unscheduled Visits 
Subjects may return to the clinic for safety evaluation or to receive additional study medication 
as needed. Unscheduled visits will include a review of concomitant medications and any adverse 
effects, and, if needed in the estimation of the study physician, physical examination in whole or 
in part.   
 
11. Outcome Measures 
All outcome measures will be based on end of treatment period compared to baseline visit. 
11.1 Primary Efficacy Measure:  
• Insomnia Severity Index (ISI) 


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The ISI is a 7-question survey assessing symptoms of insomnia over the past 
week. Maximum score is 28, with higher scores indicating greater severity. The 
ISI has been validated for use in insomnia research (Bastien, Vallieres, Morin 
2001).   
11.2 Secondary Efficacy Measures: 
• sQUAL (Subjective Quality of Sleep) 
This is a single question, “How would you describe the quality of your sleep last night?”  
There are 4 choices to answer:   
Choices: 1= poor, 2 = fair, 3= good, 4= excellent 
 
• sFRESH (Subjective refreshed feeling on waking) 
This is a single question, “How refreshed do you feel this morning?”  There are 5 choices 
to answer:   
Choices: 1= not at all refreshed, 2 = a little refreshed, 3= moderately refreshed, 4= quite a 
bit refreshed, 5= extremely refreshed 
 
• Change in Modified Fatigue Index Scale (MFIS) Score at 2 weeks vs baseline. 
The MFIS is a well-validated fatigue measure in MS (Tellez et al. 2005).  The 
MFIS has a Cronbach’s alpha of 0.81 (National MS Society). In MS, it has been 
found to have intratest reliability, no ceiling or floor effects and greater sensitivity 
to change than the FSS (Kos et al. 2003). The test has 21 items with physical, 
cognitive and psychosocial subscales.  Subjects will complete the MFIS as the 
first test conducted on the day of visit.  Their ratings on the 21-item questionnaire 
will be based on their fatigue experience over the previous 1 week.  The total 
MFIS score will be used for primary efficacy measure.   
• Fatigue Visual Analogue Scale (VAS-F) 
The VAS-F is a 10-cm line that asks subjects to rate fatigue on a scale of 0 (no 
fatigue) to 100 (fatigue “as bad as it can be”) by marking their fatigue level on the 
line (See appendix).  The VAS-F has been validated as a measure of response to 
therapy in MS fatigue populations (Rammohan et al.2002, Weinshenker et al. 
1992). Ratings will be based on their fatigue experience over the previous 1 week.   
• Wearable Sleep Monitor (WSM) 
A Fitbit device will be worn throughout the study.  A 7-night average for screening 
period will be compared with the final 7-night average for both treatment periods.   
Outcome measures based on the wearable sleep monitor will include: 
o Total minutes asleep 
o Minutes awake during time in bed 
o Number of awakenings 
o Time in bed 


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• Subjective Global Impression of Change 
This is a single question: “How would you rate change in your level of physical 
and mental function, during the study?”  Response ranging from "Extremely 
improved", "Much improved", "Slightly improved", "No change", "Slightly 
worse", "Much worse", and "Extremely worse".   
11.3 Exploratory Efficacy Measures: 
• Daily step count  
Data obtained from wearable activity monitor will be recorded. The average of 7 
days will be calculated. 
• Beck Depression Inventory 
Note on sleep diary content 
During screening and each treatment period, patients will complete a 7-day sleep diary.  They 
will be asked to record each morning the following: 
1. The time they went to bed 
2. Approximate time they went to sleep 
3. Number of awakenings 
4. Approximate time they awoke for the last time (in the morning) 
5. Time they got out of bed in the morning 
6. sFRESH 
7. sQUAL 
 
Note on the Use of the Wearable Sleep Monitor and activity monitor 
Of note, inability or unwillingness to use the WSM or activity monitor are specifically not 
exclusion criteria. Those subjects who are unable or unwilling to use the WSM or activity 
monitor correctly will be allowed in the study (provided all eligibility criteria are otherwise met), 
and the observations from their WSM activity monitor variables will be treated as missing data. 
 
12. Safety Monitoring 
12.1 Safety measures: 
Laboratory testing: All subjects: CBC, CMP.  As-indicated: urinary pregnancy testing 
Safety will be monitored by adverse event (AE) reporting, physical examination, laboratory 
evaluation. 
Monitoring for suicidality: The BDI is being performed due to suvorexant being a central nervous 
system depressant, which could cause suicidal ideation and behavior. This test is performed at 
screening, baseline and final visit.  At phone visits 2 and 5, the BDI is administered and at phone 


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visit 1 and 4, question 9 of the BDI is administered to ascertain suicidal thoughts or wishes.  A 
score of 2 or 3 on BDI question 9 indicates that the patient would be at significant suicide risk.   A 
high score on the BDI or BDI question 9 at any point would result in immediate discontinuation 
of the study medication and unscheduled visit or emergency room referral, as indicated. 
12.2 Adverse Events 
Subjects will be monitored for adverse events throughout the trial. The occurrence of adverse 
events will be ascertained by observation, telephone monitoring and questioning by the 
investigator. Safety assessments will consist of monitoring and recording all adverse events, 
including serious adverse events.  
An AE is any symptom, physical sign, or medical condition that emerges during the study or, if 
present at screening, worsens during the study, regardless of the suspected cause. Adverse events 
include adverse drug reactions, illness with onset during the study, exacerbations of pre-existing 
conditions or clinically significant changes in physical examination or significantly abnormal 
objective test findings. Medical conditions/diseases present before starting study treatment are 
only considered adverse events if they worsen after starting study treatment. All adverse events 
will be recorded and graded as mild, moderate or severe by the principal investigator in 
accordance with general guidelines of clinical research, outlined here: 
• MILD: An event that causes transient or minimal symptoms and that does not interfere 
with daily activities. 
• MODERATE: An event that causes symptoms sufficient to interfere with but not prevent 
daily activities. 
• SEVERE: An event that prevents normal, everyday activities. 
 
Adverse events will also be classified by their relationship to the study medication by the 
principal investigator in accordance with general guidelines of clinical research, outlined here: 
• Unrelated: There is no reasonable association between the study treatment and the 
suspected event and the event could have been produced by the patient’s clinical state or 
other therapy administered to the patient. 
• Possibly related: The suspected AE may or may not follow a reasonable temporal 
sequence from study treatment administration but seems to be the type of reaction that 
cannot be dismissed as unlikely. The event could have been produced or mimicked by the 
patient’s clinical state or other therapy administered to the patient. 
• Probably related: The suspected AE follows a reasonable temporal sequence from study 
treatment administration, abates upon discontinuation of the treatment, and cannot be 
reasonably explained by the known characteristics of the patient’s clinical state or other 
treatments. 


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• Definitely related: The suspected AE follows a reasonable temporal sequence from study 
treatment administration, abates upon discontinuation of the treatment, and, if 
appropriate, resumes upon re-introduction of the treatment. Additionally, the suspected 
AE cannot be reasonably explained by the known characteristics of the patient’s clinical 
state or other treatments. 
 
The principal investigator and all other research staff except the research pharmacist will be 
blinded towards randomization of active drug versus placebo until after completion of study.   
12.3 Serious Adverse Events 
A serious adverse event (SAE) is any AE that meets one of more of the following criteria: 
• Is fatal or life-threatening 
• Requires hospitalization or prolongs a current hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly 
• Requires medical or surgical intervention to prevent one of the above outcomes 
 
If any SAE occurs, the treatment status of the subject(s) may be revealed, as clinically indicated.  
If a patient discontinues medication use due to an AE, the event will be followed, when possible, 
until resolution. No interim analysis of safety data is planned because the entire study will be 
conducted over 2 months. However, the frequency of AEs will be under continuous scrutiny 
during the trial with comparison to AE rates that have been recorded in published PD drug trials.  
12.4 Serious Adverse Events Reporting 
The Food and Drug Administration (FDA) will be informed of SAEs as soon as possible or 
within 15 calendar days. In addition, the Investigator will notify the FDA of any unexpected fatal 
or life-threatening experience associated with the use of the drug as soon as possible, or within 7 
calendar days, by telephone or facsimile. When the principal investigator has determined that an 
SAE requires reporting to the FDA (unexpected and possibly related to study drug), the 
following actions will be taken: 
• Telephone the FDA immediately (day of awareness) in the case of reportable death or 
life-threatening events. 
• Complete FDA Form 3500. 
• Send the completed Form 3500 to the FDA (preferably by fax at 1-800-FDA-0178) 
within the timelines mentioned above. 
Attach the photocopy of all examinations, medical notes and records related to the SAE and 
document the dates these were made. For laboratory results, include the laboratory normal ranges. 
For hospitalizations, Admission H&P, Discharge Summary, Consultative reports, etc. could be 
very helpful. In the case of a fatal event, provide an autopsy report, when it becomes available.   


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13. Data Management and Statistical Analysis 
Sample Size Considerations 
This is a prospective, double-blinded, randomized controlled pilot study. The purpose is to test a 
hypothesis in a preliminary fashion in this population with a specific neurological disease. In our 
initial statistical plan, the study was underpowered, based on an enrollment target of 30 subjects.   
We  later increased the enrollment to 50 subjects to adequately power the study.  We assume that 
no more than 10% of subjects will withdraw, be lost to follow-up or be dropped for protocol 
violations, leaving 45 subjects for final analysis.   Power calculation is based on a cross-over 
design. We assume that the true difference in mean Insomnia Severity Index (ISI) between the 
treatments will be 1.75 units based on the findings of a cross-over trial by Herring et al for 
treatment effect of suvorexant on ISI in patients with primary insomnia. (Herring et al, 2012)  
We assume that our cohort with MS with adjustable dose titration (10mg and 20mg) will yield a 
slightly lower treatment response than that of the Herring cohort at 20mg (-2.0 units).  We 
assume a normal distribution with standard deviation of the difference in the ISI is 4.1, based on 
normative data from Bastien, et al, who conducted the primary validation study. (Bastien et al, 
2001)  With these assumptions, the probability (power) is 81 percent that the study will detect a 
treatment difference at a two-sided 5.000 percent significance level. (PS Power and Sample Size 
Calculations, version 1.7.15, http://hedwig.mgh.harvard.edu/sample_size/size.html#cross)   
Statistical Analysis 
Statistical analysis will be performed by a consulting statistician contracted with 
EvergreenHealth and whose services we have used on recent studies in MS. All data will remain 
blinded throughout the data analysis and will be un-blinded only in the event of a medical 
emergency.  
Generally, the mean over the week prior to visit 2 (baseline) will be compared to the mean over 
the final week of Treatment Period 1 and the mean over the final week of Treatment Period 2 for 
treatment effects. This will be done by treatment arm.  Level of significance will be p < 0.05. 
Minimum drug adherence for per-protocol criteria will be 75%.  We plan to do both intention to 
treat and per-protocol analyses. 
 
14. Study Management 
14.1 Patient stipend 
The subjects will be allowed to keep the wearable sleep monitor given at screening.  They will 
also receive a small monetary stipend per completed in-office and phone visit.   


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14.2 Ethics and Good Clinical Practice 
This study will be performed according to the principles of Good Clinical Practice [Chapter 2 of 
the ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP)], the declaration of 
Helsinki, and national laws and regulations about clinical studies. The study may not start 
without written Institutional Review Board/Independent Ethics Committee/Research Ethics 
Board approval and the written informed consent of the patient. 
 
 
 
 


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