Clinical trial NCT02729714
Conditions: Insomnia
Sponsor: Burdick, Daniel, M.D.
Start date: 2016-04-01; Completion date: 2022-04-01
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to see if the study drug, suvorexant, is safe and effective in treating symptoms of insomnia in people with Parkinson's Disease. It is anticipated that a total of 20 subjects, 30 to 80 years of age, with Parkinson's Disease and symptoms of insomnia will participate in the study at this site

Detailed description:
The proposed study is a randomized, double-blind, placebo-controlled, cross-over trial to assess the safety, tolerability, and efficacy of suvorexant specifically in a cohort of 20 Parkinson's Disease patients between the ages of 30 and 80 (inclusive) who have a complaint of insomnia. After informed consent is given, potential subjects will be screened to ensure they meet eligibility criteria. This will include an overnight polysomnogram, which will serve both as a baseline and a screening polysomnogram. Active drug will be suvorexant 10 mg orally at bed time with an optional up-titration to 15 mg orally at bedtime after 2 weeks. The first treatment period will be 4 weeks long, in which subjects will be randomized 1:1 to receive active drug or matching placebo. At the end of treatment period 1, subjects will undergo efficacy assessment with repeat polysomnogram and clinical scales. This will be followed by a 2-week washout period with placebo; this period only will be single-blinded, as subjects only will be blinded to treatment. 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. Treatment period 2 will also be 4 weeks long, and at the end of this, subjects will undergo final assessment with polysomnogram and clinical scales.

Arms: arm 1: 10 Suvorexant or Placebo mg orally at bedtime with an optional up-titration to 15 mg Suvorexant or Placebo orally at bedtime after 2 weeks. The first treatment period will be 4 weeks. Subjects will be randomized 1;1 to receive Suvorexant or matching placebo. Followed by a 2 week washout period with placebo. Subjects will then be crossed over into the alternate treatment group. Subjects on active treatment for period 1 will be switched to placebo, those on placebo in period 1 will switch to Suvorexant arm 2: First treatment period will be 4 week which subjects will be randomized 1;1 with either Suvorexant or placebo. Followed by 2 week washout period with placebo. Subjects will then be crossed over into the alternate treatment group. Subjects on active treatment for period 1 will be switched to placebo, those on placebo in period 1 will switch to Suvorexant.
Interventions: intervention 1: Suvorexant intervention 2: Placebo
Intervention descriptions: intervention 1: 10 mg Suvorexant or matching Placebo orally at bedtime with optional up-titration to 15 mg Suvorexant or matching Placebo orally at bedtime after 2 weeks. intervention 2: 10 mg Suvorexant or matching Placebo orally at bedtime with optional up-titration to 15 mg Suvorexant or matching Placebo orally at bedtime after 2 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Confidential**  Daniel J. Burdick, MD 
 
 
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Protocol DJB-2015-01; Suvorexant for insomnia in PD  
version: 3.0 March 8, 2016 
 
 
A Randomized, Double-Blind, Placebo-Controlled Pilot Study 
of Suvorexant for Insomnia in Parkinson Disease 
Principal 
Investigators 
Daniel J. Burdick, MD 
Pinky Agarwal, MD, FAAN 
 
Sub-Investigators 
Raymond Park, MD  
Henry Su, MD 
Alida Griffith, MD 
 
Affiliations  
The Booth Gardner Parkinson’s Care Center &  
The EvergreenHealth Sleep Disorders Center 
EvergreenHealth Medical Center, Kirkland, WA  
Phase  
IV 
 
Protocol No. 
DJB-2015-01 
 
Contact 
Daniel J. Burdick, MD 
Booth Gardner Parkinson’s Care Center 
12039 NE 128th St, Ste. 300 
Kirkland, WA 98034 
Ph.: 425-899-3108 
Fax: 425-899-3114 
djburdick@evergreenhealth.com 
 
 
 
 
 


Confidential**  Daniel J. Burdick, MD 
 
 
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Protocol DJB-2015-01; Suvorexant for insomnia in PD  
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Table of Contents 
    TITLE PAGE 
 
 
 
 
 
 
 
 
 
  1 
 
    TABLE OF CONTENTS  
 
 
 
 
 
 
 
  2 
 
    LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
  5 
 
1. SYNOPSIS  
 
 
 
 
 
 
 
 
 
  7 
 
2. BACKGROUND AND RATIONALE 
 
 
 
 
 
 
14 
 
2.1 Insomnia in PD 
 
 
 
 
 
 
 
 
14 
 
2.2 Suvorexant for Insomnia  
 
 
 
 
 
 
14 
 
2.3 Wearable Sleep Monitors in Insomnia 
 
 
 
 
 
15 
 
3. STUDY OBJECTIVES & HYPOTHESES 
 
 
 
 
 
16 
 
3.1 Primary Objective  
 
 
 
 
 
 
 
16 
 
3.2 Secondary Objectives 
 
 
 
 
 
 
 
16 
 
3.3 Primary Hypothesis 
 
 
 
 
 
 
 
16 
 
3.4 Secondary Hypotheses 
 
 
 
 
 
 
 
16 
 
4. INVESTIGATIONAL PLAN 
 
 
 
 
 
 
 
17 
 
4.1 Overall Study Design 
 
 
 
 
 
 
 
17 
 
4.2 Enrollment 
 
 
 
 
 
 
 
 
17 
 
4.3 Screening   
 
 
 
 
 
 
 
 
17 
 
 
4.3.1 Office Visit 1 
 
 
 
 
 
 
 
17 
 
 
4.3.2 PSG 1 
 
 
 
 
 
 
 
 
18 
 
4.4 Treatment Period 1 
 
  
 
 
 
 
 
18 
 
 
4.4.1 Office Visit 2 
 
 
 
 
 
 
 
18 
 
 
4.4.2 Phone Visit 1 
 
 
 
 
 
 
 
19 
 
 
4.4.3 Phone Visit 2 
 
 
 
 
 
 
 
19 
 
 
4.4.4 Phone Visit 3 
 
 
 
 
 
 
 
19 
 
 
4.4.5 PSG 2 
 
 
 
 
 
 
 
 
19 
 
4.5 Washout Period (Office Visit 3)  
 
 
 
 
 
19 
 
4.6 Treatment Period 2 
 
 
 
 
 
 
 
20 
 
 
4.6.1 Office Visit 4 
 
 
 
 
 
 
 
20 
 
 
4.6.2 Phone Visit 4 
 
 
 
 
 
 
 
20 
 
 
4.6.3 Phone Visit 5 
 
 
 
 
 
 
 
20 
 
 
4.6.4 Phone Visit 6 
 
 
 
 
 
 
 
20 
 
 
4.6.5 PSG 3 
 
 
 
 
 
 
 
 
21 
 
4.7 Final Visit (Office Visit 5) 
 
 
 
 
 
 
21 
 
4.8 Unscheduled Visits 
 
 
 
 
 
 
 
21 
 
5. STUDY POPULATION 
 
 
 
 
 
 
 
 
22 


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5.1 Inclusion Criteria  
 
 
 
 
 
 
 
22 
 
5.2 Exclusion Criteria  
 
 
 
 
 
 
 
23 
 
 
5.2.1 Note on the Use of the Wearable Sleep Monitor 
 
 
23 
 
5.3 Prohibited Medications 
 
 
 
 
 
 
 
24 
 
5.4 Removal of Patients from Study  
 
 
 
 
 
25 
 
5.5 Screen Failures & Rescreening 
 
 
 
 
 
 
26 
 
6. TREATMENTS 
 
 
 
 
 
 
 
 
 
27 
 
6.1 Investigational Drug 
 
 
 
 
 
 
 
27 
 
6.2 Randomization and Blinding 
 
 
 
 
 
 
27 
 
6.3 Concomitant Therapy 
 
 
 
 
 
 
 
28 
 
6.4 Treatment Compliance 
 
 
 
 
 
 
 
28 
 
7. DESCRIPTION OF ASSESSMENTS 
 
 
 
 
 
 
29 
 
7.1 Safety Monitoring  
 
 
 
 
 
 
 
29 
 
 
7.1.1 Physical Examination  
 
 
 
 
 
29 
 
 
7.1.2 Laboratory Evaluations  
 
 
 
 
 
29 
 
 
7.1.3 Pregnancy Status 
 
 
 
 
 
 
29 
 
 
7.1.4 Adverse Events  
 
 
 
 
 
 
29 
 
 
7.1.5 Serious Adverse Events  
 
 
 
 
 
30 
 
 
 
7.1.5.1 Serious Adverse Events Reporting 
 
 
 
31 
 
 
7.1.6 Special Note on Suicidality as an Adverse Event 
 
 
31 
 
7.2 Efficacy Assessment Based on PSG 
 
 
 
 
 
31 
 
 
7.2.1 Sleep Efficiency  
 
 
 
 
 
 
31 
 
 
7.2.2 Wake After Sleep Onset 
 
 
 
 
 
32 
 
 
7.2.3 Latency to Persistent Sleep 
 
 
 
 
 
32 
 
 
7.2.4 Muscle Tonicity  
 
 
 
 
 
 
32 
 
7.3 Efficacy Assessment Based on Clinical Rating Scales 
 
 
 
32 
 
 
7.3.1 Insomnia Severity Index 
 
 
 
 
 
32 
 
 
7.3.2 Epworth Sleepiness Scale 
 
 
 
 
 
32 
 
 
7.3.3 Subject’s Global Impression of Change 
 
 
 
32 
 
 
7.3.4 Clinician’s Global Impression of Change 
 
 
 
32 
 
 
7.3.5 Montreal Cognitive Assessment 
 
 
 
 
33 
 
 
7.3.6 Beck Depression Inventory – II  
 
 
 
 
33 
 
 
7.3.7 Beck Anxiety Inventory 
 
 
 
 
 
33 
 
 
7.3.8 MDS-UPDRS  
 
 
 
 
 
 
33 
 
7.4 Efficacy Assessment Based on Wearable Sleep Monitor  
 
 
34 
 
8. STATISTICAL METHODS 
 
 
 
 
 
 
 
35 
 
8.1 Statistical Analysis 
 
 
 
 
 
 
 
35 
 
8.2 Sample Size Considerations 
 
 
 
 
 
 
35 
 
8.3 Study Population  
 
 
 
 
 
 
 
35 
 
8.4 Baseline and Demographic Characteristics 
 
 
 
 
35 
 
8.5 Efficacy Analysis  
 
 
 
 
 
 
 
35 
 


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9. STUDY MANAGEMENT  
 
 
 
 
 
 
 
37 
 
9.1 Ethics and Good Clinical Practice 
 
 
 
 
 
37 
 
9.2 Informed Consent  
 
 
 
 
 
 
 
37 
 
10. REFERENCES 
 
 
 
 
 
 
 
 
 
38 
 
11. APPENDICES 
 
 
 
 
 
 
 
 
 
40 
 
 


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List of Abbreviations 
AE 
 
 
Adverse Event 
AHI 
 
 
Apnea-Hypopnea Index 
ALT 
 
 
Alanine Aminotransferase 
ANCOVA 
 
Analysis of Covariance 
AST 
 
 
Aspartate Aminotransferase 
BAI 
 
 
Beck Anxiety Inventory 
BDI 
 
 
Beck Depression Inventory – II 
CBC  
 
Complete Blood Count 
CGI-C  
 
Clinician’s Global Impression of Change 
CMP  
 
Comprehensive Metabolic Panel 
CNS 
 
 
Central Nervous System 
COPD  
 
Chronic Obstructive Pulmonary Disease 
C-SSRS 
 
Columbia Suicide Severity Rating Scale 
CYP3A 
 
Cytochrome P450, 3A 
DSM-5 
 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ENI 
 
 
EvergreenHealth Neuroscience Institute 
ESS 
 
 
Epworth Sleepiness Scale 
FDA  
 
United States Food and Drug Administration 
FEV1  
 
Forced Expiratory Volume, 1 second 
GCP 
 
 
Good Clinical Practice 
hCG 
 
 
Human Chorionic Gonadotropin 
HEENT 
 
Head, Eyes, Ears, Nose, Throat 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonisation 
INR 
 
 
International Normalized Ratio  
IRB 
 
 
Institutional Review Board 
ISI 
 
 
Insomnia Severity Index 
LEDD  
 
Levodopa Equivalent Daily Dose 
LPS 
 
 
Latency to Persistent Sleep 
MDS  
 
Movement Disorder Society 


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MDS-UPDRS  
MDS Unified Parkinson Disease Rating Scale 
mHY  
 
Modified Hoehn & Yahr Scale 
MoCA  
 
Montreal Cognitive Assessment 
OSA  
 
Obstructive Sleep Apnea 
PD 
 
 
Parkinson Disease 
PFT 
 
 
Pulmonary Function Test 
PO 
 
 
Per os (by mouth) 
PRN 
 
 
Pro re nata (as needed) 
PSG 
 
 
Polysomnogram 
QHS  
 
Quaque hora somni (every night at bedtime) 
RBD  
 
REM Sleep Behavior Disorder 
REM  
 
Rapid Eye Movement 
SAE 
 
 
Serious Adverse Event 
SGI-C  
 
Subject’s Global Impression of Change 
UKBB  
 
United Kingdom Parkinson Disease Society Brain Bank 
WASO 
 
Wakefulness After Sleep Onset 
WPDR  
 
Washington State Parkinson Disease Registry 
WSM  
 
Wearable Sleep Monitor 
 
 
 
 


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1. SYNOPSIS 
1.1 Study Title 
A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Suvorexant for Insomnia in 
Parkinson Disease 
1.2 Study Drug 
Suvorexant 10-15 mg PO QHS 
1.3 Study Subjects 
20 subjects with Parkinson disease (PD) and insomnia   
1.4 Study Design 
Multiple-dose, randomized, placebo-controlled prospective, single-site, investigator-initiated 
trial. 
1.5 Study Overview 
The proposed study is a randomized, double-blind, placebo-controlled, cross-over trial to assess 
the safety, tolerability, and efficacy of suvorexant specifically in a cohort of 20 PD patients 
between the ages of 30 and 80 (inclusive) who have a complaint of insomnia. After informed 
consent is given, potential subjects will be screened to ensure they meet eligibility criteria. This 
will include an overnight polysomnogram (PSG), which will serve both as a baseline and a 
screening PSG. Active drug will be suvorexant 10 mg po QHS with an optional up-titration to 15 
mg po QHS after 2 weeks. The first treatment period will be 4 weeks long, in which subjects will 
be randomized 1:1 to receive active drug or matching placebo. At the end of treatment period 1, 
subjects will undergo efficacy assessment with repeat PSG and clinical scales. This will be 
followed by a 2-week washout period with placebo; this period only will be single-blinded, as 
subjects only will be blinded to treatment. 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. Treatment period 2 will also be 4 weeks long, and at the end of this, subjects will 
undergo final assessment with PSG and clinical scales. 
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 lieu of a monetary reimbursement for Office Visit 1; subjects will receive a small 
monetary reimbursement per visit for each office visit after Office Visit 1. 
1.6 Study Hypothesis 
1.6.1 Primary hypothesis 


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Suvorexant will provide greater improvement in sleep, as measured by polysomnographic 
parameters and symptom rating scales, compared to placebo, with no clinically significant 
increase in adverse events.  
1.6.2 Secondary Hypotheses 
 On nights of PSG, total hours of sleep and WASO as measured by a wearable sleep 
monitor will not be significantly different from those values as measured by PSG. 
 Suvorexant will not worsen motor symptoms or non-motor symptoms of PD compared to 
placebo; motor signs and motor and non-motor symptoms will be assessed by the 
Movement Disorder Society’s Unified Parkinson Disease Rating Scale; specific non-
motor symptoms will be assessed by the Beck Depression Inventory, the Beck Anxiety 
Inventory, and Montreal Cognitive Assessment; REM behavior disorder will be assessed 
by muscle tonicity during PSG. 
1.7 Study Timeline 
Each subject’s participation in this study will last 11-15 weeks. This includes a 1- to 5-week 
screening period (depending on the scheduling of the initial PSG), two 4-week treatment periods, 
and a 2-week washout period between the treatment periods.  
1.8 Treatment Regimen 
1.8.1 Treatment Period 1 
Group A will receive suvorexant 10 mg to be taken by mouth every night, at most 30 minutes 
before the intended bedtime and at least 7 hours before the intended time of awakening. At 
Phone Visit 2, those who are eligible to up-titrate will be instructed to begin taking an additional 
5-mg tablet, for a total of suvorexant 15 mg by mouth every night.  
Group B will receive placebo that matches suvorexant 10 mg with the same instructions. At 
Phone Visit 2, those who are eligible to up-titrate will be instructed to begin taking an additional 
placebo matching the suvorexant 5 mg tablet. 
1.8.2 Treatment Period 2 
The regimen will be the same as in treatment period 1 but the groups will be reversed. 
1.9 Inclusion and Exclusion Criteria 
1.9.1 Inclusion Criteria  
An eligible patient: 
 Has signed and dated an IRB-approved informed consent form before any protocol-
specific screening procedures are performed;  
 Has a diagnosis of Parkinson disease according to the United Kingdom Parkinson 
Disease Society Brain Bank Criteria (UKBB); 


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 Has a modified Hoehn and Yahr (mHY) Stage of 1-3, inclusive; 
 Is aged 30-80 years old, inclusive; 
 Has had no change in PD medications during the 4 weeks preceding screening, with no 
dose changes during the study, except that PRN (as needed) doses of carbidopa/levodopa 
will be allowed to address periodic worsening of parkinsonian symptoms;  
 Is willing and able to complete PSG; 
 Is willing and able to abstain from alcohol, caffeine, and marijuana for 6 hours prior to 
and during each study-related PSG; 
 Is willing and able to abstain from products containing nicotine during each study-related 
PSG; 
 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; 
 On screening PSG, has a latency to persistent sleep > 20 minutes OR total wakefulness 
after sleep onset > 45 minutes; 
 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; and 
 Has valid health insurance coverage at the time of study enrollment and expects this 
coverage to remain valid for the duration of the study period. 
1.9.2 Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following:  
 Is a woman 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); 
 Has an implanted deep brain stimulator; 
 Has a history of narcolepsy; 
 Has a diagnosis of severe COPD, defined by FEV1 < 50% of predicted on most recent 
available pulmonary function test (PFT) (a PFT is not required if the subject has never 
been diagnosed with COPD); 


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 Has a history of severe obstructive sleep apnea (OSA) or evidence of severe OSA on 
screening PSG, with severe OSA defined as having an apnea-hypopnea index (AHI) > 
30; 
 Is concurrently using other 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, and no alcohol 
will be permitted for 6 hours before PSG visits; 
 Is concurrently using digoxin; 
 Is concurrently using any moderate or strong inhibitor of CYP3A; 
 Is concurrently using any strong inducer of CYP3A; 
 Has evidence at screening of severe hepatic impairment as defined by a Child-Pugh score 
> 10; 
 Has evidence at screening of severe cognitive impairment as defined by a MoCA score < 
15, or has cognitive impairment that in the opinion of the investigator would prevent 
completion of study procedures or the ability to provide informed consent. 
 Has evidence at screening of suicidal ideation in the past 6 months as defined by a 
positive response to any one of Questions 2-5 on the Columbia Suicide Severity Rating 
Scale (C-SSRS); or of a lifetime history of suicidal behavior as defined by any positive 
response to the suicidal behavior section of the C-SSRS. 
 
1.9.3 Note on the Use of the Wearable Sleep Monitor 
 
Of note, inability or unwillingness to use the WSM is specifically not an exclusion criterion. 
Those subjects who are unable or unwilling to use the WSM correctly will be allowed in the 
study (provided all eligibility criteria are otherwise met), and the observations from their WSM 
variables will be treated as missing data. 
 
1.10 Efficacy Assessment 
1.10.1 Primary Outcome Measure 
The primary outcome measure will be sleep efficiency as measured by PSG, defined as (total 
sleep time / total time in bed) * 100% 
1.10.2 Secondary Outcome Measures based on PSG 
Secondary outcome measures based on PSG will include: 
 Wake after sleep onset 
 Latency to persistent sleep 
 Muscle tonicity (as measure of REM Behavior Disorder) 
1.10.3 Secondary Outcome Measures based on Clinical Rating Scales 
The following clinical rating scales will be administered as secondary outcomes measures: 


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 Insomnia Severity Index 
 Epworth Sleepiness Scale 
 Subject’s Global Impression of Change 
 Clinician’s Global Impression of Change. 
 Montreal Cognitive Assessment  
 Beck Depression Inventory 
 Beck Anxiety Inventory 
 MDS-UPDRS Total Score 
 MDS-UPDRS Part 1 (Non-Motor) Score 
 MDS-UPDRS Question 1.7 (Sleep Problems) Score 
 MDS-UPDRS Question 1.8 (Daytime Sleepiness) Score 
1.10.4 Secondary Outcome Measure based on Wearable Sleep Monitor 
The secondary outcome measure based on the wearable sleep monitor (WSM) will include: 
 Total hours of sleep per night, mean over final 7 nights of treatment period compared to 
mean over final 7 nights of screening period 
 Wakefulness after sleep onset (WASO), mean over final 7 nights of treatment period 
compared to mean over final 7 nights of screening period  
 
1.11 Statistical Methods 
Analysis of primary and secondary outcome measures will include: 
 Summary statistics (n, mean, standard deviation, median, minimum and maximum) at 
baseline, Office Visit 3 and Office Visit 5 by treatment.  
 For clinical rating scales, summary of % change from baseline to Office Visit 3, from 
baseline to Office Visit 5, and from Office Visit 4 to Office Visit 5, by treatment 
 For PSG variables, summary of % change from PSG 1 to PSG 2 and from PSG 1 to PSG 
3, by treatment 
 For wearable sleep monitor, summary of % change in total hours of sleep and WASO. 
Mean over the week prior to Office Visit 2 (baseline) will be compared to the mean over 
the final week of Treatment Period 1 and to the mean over the final week of Treatment 
Period 2. Mean over the week prior to Office Visit 4 (during washout) will be compared 
to the mean over the final week of Treatment Period 2. This will be done by treatment 
arm.   
 Significance testing 
 
The following characteristics will be summarized descriptively for placebo and drug groups: 
 Demographics (age, gender, race) 
 Parkinson disease characteristics at baseline (disease duration, date of onset, initial 
symptom, modified Hoehn and Yahr stage in the ON state, and MDS-UPDRS part 3 
score in the ON state) 


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 Levodopa-equivalent daily dose (LEDD), calculated according to published formulae 
(Tomlinson 2010, Rytary Prescribing Information, Duopa Prescribing Information). 
 
Outcome measures will be compared between groups using analysis of covariance (ANCOVA) 
or other method as deemed appropriate by the consulting statistician. Demonstration of 
superiority will depend on achieving statistical significance for the primary endpoint. Level of 
significance will be defined as p = 0.05. All statistical tests will be two-sided.  
 
The study population will include all patients who pass screening and undergo randomization. 
Data will be analyzed in an intent-to-treat fashion. 
This is an exploratory study.  Therefore, a small sample size is appropriate.  Any treatment effect 
could be used to power a future larger study.  
 
Statistical analysis will be performed by a consulting statistician contracted with 
EvergreenHealth and whose services we have used on recent studies in PD. 
 
1.12 Safety 
Female subjects will undergo urine pregnancy testing if they are deemed to have any risk of 
being pregnant or becoming pregnant during the study.  Baseline assessment of CBC, CMP, 
albumin, and INR will be conducted to address exclusion criteria. 
Subjects will be monitored for adverse events throughout the trial in phone visits and office 
visits, both scheduled and unscheduled as needed. The occurrence of adverse events will be 
ascertained by observation, telephone monitoring if subjects call in, and by questioning by the 
investigator. Safety assessments will consist of monitoring and recording all adverse events, 
including serious adverse events. An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy). Medical conditions/diseases present 
before starting study treatment are only considered adverse events if they worsen after starting 
study treatment.  
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.  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. The principal investigator will also determine the relatedness of each adverse 
event to the study drug in accordance with general guidelines of clinical research.  
A serious adverse event is an undesirable sign, symptom or medical condition which: 1. is fatal 
or life-threatening, 2. requires or prolongs hospitalization, 3. results in persistent or significant 
disability/incapacity, 4. constitutes a congenital anomaly or a birth defect, 5. is medically 
significant, in that it may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. If any serious adverse events occur, the treatment 
status of the subject(s) may be revealed, as clinically indicated.  Subjects who discontinue 
medication use will be followed for adverse events until reaching the termination of adverse 


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events.  The frequency of adverse events (AE) will be under continuous scrutiny during the 
observation with comparison to AE rates that have been recorded in published PD drug trials.   
 
1.13 Schedule of Events 
Please refer to the attached Schedule of Assessments for timing of procedures. 
 
1.14 Expected Study Timeline 
Study duration is estimated at 17 months (start-up period of 2 months and enrollment period of 
15 months), with an additional 2 months for data analysis and manuscript preparation. 


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2. BACKGROUND AND RATIONALE 
2.1 Insomnia in PD 
Parkinson disease (PD) is the second most common neurodegenerative disease behind Alzheimer 
disease. Prevalence is estimated to be 0.3% of the general population and 1% of the population 
over the age of 60 (de Lau 2006). It is estimated that there were over 4 million cases worldwide 
in 2005, and that number is expected to more than double by 2030, to 8.7 million (Dorsey 2007). 
Prevalence in the United States is expected to nearly double over the same time period, with a 
projected 610,000 cases in the US by 2030 (Dorsey 2007). 
 
Sleep disorders are common in PD. In one community-based survey (Tandberg 1998), disrupted 
sleep had an estimated prevalence of 60% among PD patients, compared to 33% in the healthy 
elderly population. Nearly 32% of the PD patients in this study reported trouble falling asleep, 
39% reported frequent awakening, and 23% reported early awakening. More than 40% reported 
taking a medication to help them sleep. This corresponds with findings of a more recent survey, 
in which nearly half of respondents scored 8 or greater on the Insomnia Severity Index (Chung 
2013).  
 
The reasons for the prevalence of insomnia in Parkinson disease are not entirely clear, but have 
been attributed to physical symptoms, depression, and direct effects of PD on the neural control 
of sleep onset and maintenance (Tandberg 1998). Since some currently used insomnia 
medications may adversely affect mood and PD symptoms, it is important in studies of insomnia 
in PD to measure the severity of motor and non-motor symptoms, especially mood. 
 
Despite the high prevalence of insomnia in PD, there are relatively few studies specifically in PD 
of medications to improve insomnia. Doxepin has shown benefit (Rios Romenets 2013) and 
dopamine agonists may increase somnolence generally but have not been shown to specifically 
improve insomnia in published reports. Melatonin has shown improvement in subjective sleep 
quality in 2 small studies in PD but not other measures of sleep disturbance (Dowling 2005, 
Medeiros 2007). Clonazepam is frequently used when REM behavior disorder is present 
(Gagnon 2006). Other soporifics are used on the basis of standard clinical practice rather than 
evidence from randomized clinical trials in Parkinson disease patients.  
 
2.2 Suvorexant for insomnia 
Suvorexant (MK-4305, Belsomra®) is a recently FDA-approved medication for the treatment of 
insomnia in the general population. Suvorexant has a novel mechanism of action. The first 
orexin-receptor antagonist on the market, suvorexant has been shown to improve sleep efficiency 
in healthy, non-elderly adults with primary insomnia (Herring 2012, Sun 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 2014).  
 


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Suvorexant may have other advantages that are of benefit specifically in the PD population. 
Suvorexant appears not to have a deleterious effect on next-day balance in healthy non-elderly 
subjects. This could be a significant advantage for suvorexant in patients with PD, who already 
have impaired balance and for whom, therefore, benzodiazepines may not be safe. In addition, 
suvorexant appears not to affect memory as measured by word recall. Again, this may be a 
distinct benefit in people with PD, who often have cognitive impairment as a result of their 
disease.  
 
In addition to insomnia itself, people with PD have high rates of other conditions that may be 
improved by more efficient sleep, including depression and anxiety. REM behavior disorder 
(RBD), also experienced at high rates by people with PD, has limited treatment options. The 
effects of suvorexant in these ancillary conditions in PD are unknown and warrant study.  
 
Suvorexant is approved at doses up to 20 mg daily (Prescribing Information, Merck 2015). 
Although this dose has been found to be safe in a healthy geriatric population, people with PD 
may be more sensitive to the therapeutic and adverse effects of suvorexant. It is also likely that 
subjects in a PD trial will be on other medications that may increase daytime somnolence. For 
these reasons, we are proposing a study of the 10-mg and 15-mg doses only. If suvorexant is 
found to be well-tolerated at a dose of 10 or 15 mg daily, future studies can explore the safety 
and efficacy of 20 mg daily in a PD population. 
 
2.3 Wearable Sleep Monitors in Insomnia 
The use of wearable sleep monitors has become increasingly common in the general population. 
However, the role these devices may play in diagnosing or monitoring insomnia and other sleep 
disorders is unknown. For this study, the FitBit Charge will be used. This device was chosen for 
its practicality and affordability, which makes it a device consumers are already using. 
Understanding how the feedback from this commonly used device relates to data from PSG and 
clinical ratings will be important in informing discussions with patients in the future. 
 
 
 


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3. STUDY OBJECTIVES & HYPOTHESES 
3.1 Primary Objective 
To assess the safety and efficacy of suvorexant in treating insomnia in Parkinson disease  
3.2 Secondary Objectives 
1. To assess the precision of a wearable sleep monitor in measuring total hours of sleep and 
WASO as compared to nocturnal polysomnogram (PSG). 
2. To assess the effect of suvorexant on motor and non-motor symptoms of PD, including 
REM behavior disorder (RBD). 
 
3.3 Primary Hypothesis 
Suvorexant will provide greater improvement in sleep, as measured by polysomnographic 
parameters and symptom rating scales, compared to placebo, with no clinically significant 
increase in adverse events.  
 
3.4 Secondary Hypotheses 
1. On nights of PSG, total hours of sleep and WASO as measured by a wearable sleep 
monitor will not be significantly different from those values as measured by PSG. 
2. Suvorexant will not worsen motor symptoms or non-motor symptoms of PD compared to 
placebo. 
 
 
 


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4. INVESTIGATIONAL PLAN 
 
4.1 Overall Study Design 
 
This study is a randomized, double-blind, placebo-controlled 15-week study of suvorexant for 
the treatment of insomnia in a cohort of 20 PD subjects between the ages of 30 and 80. Active 
drug will be suvorexant 10 mg at bedtime with an optional up-titration to 15 mg at bedtime after 
2 weeks. Subjects will be enrolled based on a clinical history of insomnia as defined by the 
DSM-5 and on results of a screening PSG. The primary outcome measure will be change in sleep 
efficiency as measured on PSG. Participants will also receive a wearable sleep monitor to assess 
sleep efficiency over a longer period of time.   
 
The study is composed of 5 office visits, 3 overnight sleep studies (PSGs), and up to 6 phone 
visits over the course of 11-15 weeks. 
 
4.2 Enrollment 
 
Subjects who may qualify for this study will be identified in the context of clinical care at the 
EvergreenHealth Neuroscience Institute or the EvergreenHealth Sleep Disorders Center. 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 promotional opportunities, referrals from other 
area neurologists, sleep medicine physicians, and the Washington State Parkinson Disease 
Registry. Patients may contact the EvergreenHealth Neuroscience Institute without clinic 
visitation after reading a notice about the study on the Institute’s website or other online 
postings. Subjects who are not established patients at EvergreenHealth 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. 
 
4.3 Screening 
 
4.3.1 Office 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 
is obtained, subjects will be assessed for eligibility (excluding those eligibility criteria requiring 
completion of a PSG). A history of the patient’s PD symptoms and sleep symptoms will be 
taken, and the patient’s past medical history will be reviewed. Diagnosis of PD will be confirmed 
based on UK PD Society Brain Bank criteria (Hughes 1992). Current medication list will be 
reviewed, and a levodopa-equivalent daily dose will be calculated based on the patient’s current 
PD medication list and on published conversion factors (Tomlinson 2010, Rytary Prescribing 
Information, Duopa Prescribing Information). Eligible subjects will have a stable PD medication 
regimen for 4 weeks prior to the screening visit and remain on a stable regimen for the duration 


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of the study. Eligible patients will also not be concomitantly taking any of the prohibited 
medications for at least 14 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 (blood pressure, heart rate, and respiratory rate) and a neurological examination. 
Neurological exam will include a general neurological exam as well as MDS-UPDRS part 3 
evaluation and modified Hoehn and Yahr (HY) staging of PD (Goetz 2004). Laboratory testing 
will include CBC, CMP, albumin, and INR, with calculation of the Child-Pugh score for any 
subjects with liver failure. Pre-menopausal women will have urine hCG measured. MoCA and 
the C-SSRS will be performed. 
 
The wearable sleep monitor will be dispensed at Office Visit 1 to all subjects who meet non-PSG 
eligibility criteria. This will be worn by the subjects throughout the study and will record sleep 
efficiency on every night of the study. The wearable monitor will be the FitBit Charge, which is 
easy for subjects to put on and use, and provides automatic detection of sleep, calculating sleep 
duration and sleep efficiency. The FitBit Charge will be kept by the subjects as an honorarium 
for their time. 
 
4.3.2 PSG 1 
 
For all subjects who meet non-PSG eligibility criteria, the screening/baseline PSG will be 
completed within 3 weeks (0-21 days) after Office Visit 1. This will be performed at 
EvergreenHealth’s Sleep Disorders Center according to their standard clinical protocol. At a 
minimum, PSG interpretation will report latency to persistent sleep (LPS), wakefulness after 
sleep onset (WASO), sleep efficiency, and apnea-hypopnea index (AHI). In addition to screening 
for eligibility, the screening PSG will provide baseline values for the PSG variables of interest. 
Eligibility will be confirmed based on the results of the PSG according to the eligibility criteria 
listed in section 5.1. 
 
4.4 Treatment Period 1 
 
4.4.1 Office Visit 2 
 
For those who satisfy all eligibility criteria, Office Visit 2 will occur within 7-14 days after the 
screening PSG. Medications will be reviewed again to ensure stability of the PD medication 
regimen and absence of any prohibited medications.  
 
Following confirmation of eligibility, an eligible patient will complete the baseline assessments 
of the MDS-UPDRS (only parts 1, 2, and 4; the data from part 3 that was collected at Office 
Visit 1 as a part of the screening will serve as the baseline for this measure), ISI, ESS, BDI, and 
BAI during Office Visit 2. Data from the wearable sleep monitor will be collected.  
 
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 


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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 research pharmacy (a separate locked room 
containing only research medications). The investigating physicians, research coordinator(s), and 
study subjects 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 identical appearing active or 
placebo study medication tablets, with identification known only to the research pharmacist. 
 
4.4.2 Phone Visit 1 
 
Phone Visit 1 will occur 3-4 days after Office Visit 2 to review safety and tolerability through 
questioning about adverse events.  
 
4.4.3 Phone Visit 2: Titration in Treatment Period 1 
 
Phone Visit 2 will occur 2 weeks (12-15 days) after Office Visit 2 to review safety and 
tolerability through questioning about adverse events. The SGIC and C-SSRS will also be 
administered over the phone. Those subjects 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 
15 mg po QHS (or matched placebo). 
 
4.4.4 Phone Visit 3 
 
Only for those subjects who are titrated to 15 mg, Phone Visit 3 will occur 3-4 days after Phone 
Visit 2 to review safety and tolerability through questioning about adverse events. For those who 
remain on 10 mg, Phone Visit 3 will not be conducted. 
 
4.4.5 PSG 2 
 
Overnight PSG 2 will occur after 4 weeks (25-32 days) after Office Visit 2 and will mark the last 
night of Treatment Period 1. Subjects will continue to take the study medication on the night of 
PSG 2. This will be performed at EvergreenHealth’s sleep lab according to their standard clinical 
protocol. At a minimum, PSG interpretation will report latency to persistent sleep (LPS), 
wakefulness after sleep onset (WASO), and sleep efficiency. 
 
4.5 Washout Period (Office Visit 3) 
 
Office Visit 3 will occur within 7 days after PSG 2. In addition to PSG review, medications will 
be reviewed again to ensure stability of the PD medication regimen and absence of any 
prohibited medications. Any possible adverse events (AEs) will be assessed. General physical 
exam will be performed, including vital signs (blood pressure, heart rate, and respiratory rate). 
 
PD symptoms and signs will be assessed with the complete MDS-UPDRS. Study scales (MoCA, 
ISI, ESS, BDI, BAI, CGI-C, SGI-C, C-SSRS) will be administered. Data from the wearable 


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sleep monitor will be collected. Laboratory testing will be performed as deemed appropriate by 
the investigator. 
 
A new supply of study pills will be dispensed. For the washout period, all subjects will be given 
the placebo matching the dose being administered most recently (i.e. in the second half of 
treatment period 1). 
 
4.6 Treatment Period 2 
 
4.6.1 Office Visit 4 
 
Office Visit 4 will occur 2 weeks (11-18 days) after Office Visit 3 and will mark the beginning 
of treatment period 2. Medications will be reviewed again to ensure stability of the PD 
medication regimen and absence of any prohibited medications. Any possible adverse events 
(AEs) will be assessed.  
 
To serve as baseline scores for treatment period 2, PD symptoms and signs will be assessed with 
the complete MDS-UPDRS and study scales (MoCA, ISI, ESS, BDI, BAI, CGI-C, SGI-C) will 
be administered. Data from the wearable sleep monitor will be collected. Laboratory testing, 
including urine hCG, will be performed as deemed appropriate by the investigator. 
 
A new supply of study pills will be dispensed in a crossover fashion. All subjects who received 
study drug in treatment period 1 will be given placebo in treatment period 2, and all subjects who 
received placebo in treatment period 1 will be given study drug in treatment period 2. For 
treatment period 2, double-blinding will be resumed. Initial dose for all subjects will be 10 mg 
qhs.  
 
4.6.2 Phone Visit 4 
 
Phone Visit 4 will occur 3-4 days after Office Visit 4 to review safety and tolerability through 
questioning about adverse events.  
 
4.6.3 Phone Visit 5: Titration in Treatment Period 2 
 
Phone Visit 5 will occur 2 weeks (12-15 days) after Office Visit 4 to review safety and 
tolerability through questioning about adverse events. The SGIC and C-SSRS will also be 
administered over the phone. Those subjects 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 
15 mg po QHS (or matched placebo). 
 
4.6.4 Phone Visit 6 
 
Only for those subjects who are titrated to 15 mg, Phone Visit 6 will occur 3-4 days after Phone 
Visit 5 to review safety and tolerability through questioning about adverse events. For those who 
remain on 10 mg, Phone Visit 6 will not be conducted. 


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4.6.5 PSG 3 
 
PSG 3 will occur 4 weeks (25-32 days) after Office Visit 4 and will mark the last night of 
Treatment Period 2. Subjects will continue to take the study medication on the night of PSG 3. 
This will be performed at EvergreenHealth’s sleep lab according to their standard clinical 
protocol. At a minimum, PSG interpretation will report latency to persistent sleep (LPS), 
wakefulness after sleep onset (WASO), and sleep efficiency. 
 
4.7 Final Visit (Office Visit 5) 
 
Office Visit 5 will occur within 7 days after PSG 3. Medications will be reviewed again to ensure 
stability of the PD medication regimen and absence of any prohibited medications. Any possible 
adverse events (AEs) will be assessed. General physical exam will be performed, including vital 
signs (blood pressure, heart rate, and respiratory rate). 
 
PD symptoms and signs will be assessed with the MDS-UPDRS and study scales (MoCA, ISI, 
ESS, BDI, BAI, CGI-C, SGI-C, C-SSRS) will be administered. Data from the wearable sleep 
monitor will be collected. Laboratory studies will be performed (CBC, CMP). Pregnancy testing 
with urine hCG will be performed if deemed appropriate by the investigator. 
 
4.8 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.   
 
 
 


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5. STUDY POPULATION 
 
The population for this study is PD patients aged 30-80 years old (inclusive) with symptoms of 
insomnia who meet all of the inclusion criteria (section 5.1) and who do not meet any of the 
exclusion criteria (section 5.2). 
 
5.1 Inclusion Criteria 
 
An eligible subject: 
 
 Has signed and dated an IRB-approved informed consent form before any protocol-
specific screening procedures are performed;  
 Has a diagnosis of Parkinson disease according to the United Kingdom Parkinson 
Disease Society Brain Bank Criteria (UKBB); 
 Has a modified Hoehn and Yahr (mHY) Stage of 1-3, inclusive; 
 Is aged 30-80 years old, inclusive; 
 Has had no change in PD medications during the 4 weeks preceding screening, with no 
dose changes during the study, except that PRN (as needed) doses of carbidopa/levodopa 
will be allowed to address periodic worsening of parkinsonian symptoms;  
 Is willing and able to complete PSG; 
 Is willing and able to abstain from alcohol, caffeine, and marijuana for 6 hours prior to 
and during each study-related PSG; 
 Is willing and able to abstain from products containing nicotine during each study-related 
PSG; 
 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; 
 On screening PSG, has a latency to persistent sleep > 20 minutes OR total wakefulness 
after sleep onset > 45 minutes; 
 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 
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 Has valid health insurance coverage at the time of study enrollment and expects this 
coverage to remain valid for the duration of the study period. 
 
5.2 Exclusion Criteria 
 
A subject will be excluded from the study if he or she meets any of the following:  
 
 Is a woman 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); 
 Has an implanted deep brain stimulator; 
 Has a history of narcolepsy; 
 Has a diagnosis of severe COPD, defined by FEV1 < 50% of predicted on most recent 
available pulmonary function test (PFT) (a PFT is not required if the subject has never 
been diagnosed with COPD); 
 Has a history of severe obstructive sleep apnea (OSA) or evidence of severe OSA on 
screening PSG, with severe OSA defined as having an apnea-hypopnea index (AHI) > 
30; 
 Is concurrently using other 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, and no alcohol 
will be permitted for 6 hours before PSG visits; 
 Is concurrently using digoxin; 
 Is concurrently using any moderate or strong inhibitor of CYP3A; 
 Is concurrently using any strong inducer of CYP3A; 
 Has evidence at screening of severe hepatic impairment as defined by a Child-Pugh score 
> 10; 
 Has evidence at screening of severe cognitive impairment as defined by a MoCA score < 
15, or has cognitive impairment that in the opinion of the investigator would prevent 
completion of study procedures or the ability to provide informed consent. 
 Has evidence at screening of suicidal ideation in the past 6 months as defined by a 
positive response to any one of Questions 2-5 on the Columbia Suicide Severity Rating 
Scale (C-SSRS); or of a lifetime history of suicidal behavior as defined by any positive 
response to the suicidal behavior section of the C-SSRS. 
 
5.2.1 Note on the Use of the Wearable Sleep Monitor 
 
Of note, inability or unwillingness to use the WSM is specifically not an exclusion criterion. 
Those subjects who are unable or unwilling to use the WSM correctly will be allowed in the 
study (provided all eligibility criteria are otherwise met), and the observations from their WSM 
variables will be treated as missing data. 
 
 


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5.3 Prohibited Medications 
 
The following medications are not permitted to be used within 14 days prior to screening nor for 
the duration of the subject’s participation in the study: 
 
 Digoxin; 
 CNS depressants such as: 
o Benzodiazepines 
 Alprazolam 
 Chlorazepate 
 Chlordiazepoxide 
 Clonazepam 
 Diazepam 
 Estazolam 
 Flurazepam 
 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 


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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 
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 Wort 
 
5.4 Removal of Patients from Study 
 


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A patient will be considered to have completed the study when he or she has completed all study 
visits through the final visit. Every patient has the right to discontinue study participation at any 
time at his/her own request, or may be withdrawn at any time at the discretion of the investigator 
for safety, behavioral, or administrative reasons. Criteria for early termination include, but are 
not limited to, poor adherence to study medication (less than 70% of study medication 
consumed), loss of health insurance coverage, and safety issues related to study-related or non-
study related adverse events.  
 
If a patient has a clinical necessity to alter their standard PD medications, the patient will be 
withdrawn from the trial so that changes may be made, except that occasional additional doses of 
carbidopa/levodopa will be allowed if needed to address periodic worsening of parkinsonian 
symptoms. If a patient is withdrawn due to an adverse event, the event will be followed, when 
possible, until resolution. Patients who withdraw from the study may be replaced, but withdrawn 
patients will not be re-entered into the study. 
 
All data generated up to the time of discontinuation from the study will be analyzed and the 
reason(s) for discontinuation will be recorded. 
 
5.5 Screen Failures & Re-screening  
 
Subjects who fail screening because they do not meet inclusion criteria or because of certain 
exclusions, e.g. concurrent use of a prohibited medication, may be re-screened after 4 weeks at 
the discretion of the investigator.  
 
 
 


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6. TREATMENTS 
 
6.1 Investigational Drug 
 
Study medication, to include 5-mg and 10-mg suvorexant and matching placebo, will be 
provided by Merck. The active medication will be suvorexant 10-15 mg qhs. The research 
pharmacist at EvergreenHealth will be responsible for packaging and labeling individual bottles, 
which will be done in a standard prescription bottle with child-proof cap. The pharmacist will 
dispense the active or placebo medication at randomization (Office Visit 2, start of Treatment 
Period 1) and again Office Visit 4 (start of Treatment Period 2). This will include a 4-week 
supply of 10 mg tablets (suvorexant or matching placebo) and a 2-week supply of 5 mg tablets 
(suvorexant or matching placebo). The subject will use the 5-mg tablets only if instructed to do 
so at Phone Visit 2 or Phone Visit 5. In this case, the 5-mg tablets will be taken concurrently 
with the 10-mg tablets to achieve the titration dose of 15 mg QHS. To prevent confusion, the 
bottle of 5-mg tablets will be packaged in a sealed bag with a label stating, “Open only if 
instructed to do so on ___________.” In the blank, the coordinator will write in the date of 
Phone Visit 2 or 5, as appropriate. In addition, a pictorial depiction of the titration schedule will 
be provided to the subject.  
 
At Office Visit 3 (start of washout period), placebo will be dispensed that matches what the 
subject was taking at the end of Treatment Period 1. For example, if the subject titrated to 15 mg 
at Phone Visit 2, both a 10-mg and 5-mg placebo will be dispensed at Office Visit 3. If the 
subject remained on 10 mg for the duration of Treatment Period 1, only a 10-mg placebo will be 
dispensed.  
 
An extra 7-day supply of medication will be provided for each study period to allow a window 
for scheduling of appointments. 
 
6.2 Randomization and Blinding 
 
Following confirmation of eligibility, an eligible patient will be randomized in a 1:1 
randomization scheme to receive suvorexant 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 
research pharmacy (a separate locked room containing only research medications). The 
investigating physicians, nurse, research coordinator, and study subjects 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. In the event of a medical emergency, the reasons for 
breaking the code will be documented carefully. The subjects will receive identical appearing 
active or placebo study medication tablets, with identification known only to the research 
pharmacist. 
 
 


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6.3 Concomitant Therapy 
 
All concomitant therapy will be documented. Concurrent (defined as “within 14 days of 
screening”) use of medications listed in section 5.3 will be prohibited. Medications that are likely 
to influence sleep or sleepiness may not be initiated between screening and study completion. 
They may be continued with no dose changes during the study. 
 
6.4 Treatment Compliance 
 
Patients will be asked to return all unused medication and all medication bottles, including empty 
bottles, at each visit and at the end of the study. The quantity of medication dispensed and 
returned will be documented. 
 
 
 


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7. DESCRIPTION OF ASSESSMENTS 
 
7.1 Safety Monitoring 
 
Safety will be monitored by physical examination, vital signs, laboratory evaluation, and adverse 
event (AE) reporting with particular inquiry on falls and next-day drowsiness. 
 
7.1.1 Physical Examination 
 
A general physical examination will be performed at Office Visit 1 (Screening Visit), Office 
Visit 3 (Start of Washout Period) and Office Visit 5 (Final Visit). This exam will include, at 
minimum, HEENT, heart, lungs, abdomen, musculoskeletal, and neurologic systems. Subjects 
with a range of health conditions that may put the patient at risk for adverse outcomes will be 
excluded, as listed under Section 5.2, Exclusion Criteria. 
 
7.1.2 Laboratory Evaluations 
 
All subjects will undergo baseline testing with CBC, CMP, albumin, and INR. Child-Pugh score 
will be calculated if there is a history of liver failure or if AST or ALT are elevated. Those 
subjects with a Child-Pugh score > 10 will be excluded. CBC and CMP will be assessed at 
Office Visit 3 (start of washout period) and Office Visit 5 (final visit) to ensure stability.  
 
7.1.3 Pregnancy Status 
 
All pre-menopausal women will have pregnancy screening with urine hCG at all Office Visits 
(1-5). A positive urine hCG at screening will result in exclusion from the study; a positive urine 
hCG at any other office visit will result in discontinuation of the study drug and withdrawal of 
the subject from the study. 
 
7.1.4 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 or coordinator. Safety assessments will consist of monitoring and recording all 
adverse events, including serious adverse events. Falls and next-day drowsiness will be 
specifically queried.  
 
An adverse event (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 


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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: 
 
• 
Definitely Unrelated: The AE is definitely not related to the drug. This designation is 
reserved for those events that do not follow a reasonable temporal sequence following 
drug administration (e.g. occur prior to study treatment) or for those events that cannot be 
even remotely related to study participation. 
• 
Unlikely related: 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. 
• 
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.   
 
7.1.5 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 


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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. 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.  
 
7.1.5.1 Serious Adverse Events Reporting 
 
The 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) if the case involves a reportable 
death or a life-threatening event. 
• 
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, include Admission H&P, Discharge Summary, Consultative reports, 
and other similar notes. In the case of a fatal event, if an autopsy is performed, a copy of the 
autopsy report will be provided when it becomes available. 
 
7.1.6 Special Note on Suicidality as an Adverse Event 
 
In the event that the administration of the C-SSRS at follow-up visits (Phone Visits 2 or 5 or 
Office Visits 3 or 5) reveals worsening suicidal ideation relative to baseline or any suicidal 
behavior since the last administration, the subject will be withdrawn from the study. Intervention 
will be initiated as deemed appropriate in the clinical judgment of the investigator and may 
include referral to the subject’s primary care provider, referral to the in-house psychology group 
at EvergreenHealth Neuroscience Institute, emergency referral to the EvergreenHealth 
Emergency Department, or activation of Emergency Medical Services by dialing 9-1-1. Suicidal 
ideation requiring hospitalization will be considered an SAE, and any suicidal behavior will be 
considered an SAE, with reporting requirements as per section 7.1.5.1.   
 
7.2 Efficacy Assessment Based on Polysomnogram 
 
7.2.1 Sleep Efficiency 
 
The primary outcome measure will be sleep efficiency as measured by PSG, defined as (total 
sleep time / total time in bed) * 100%. 
 


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7.2.2 Wake After Sleep Onset 
 
WASO is defined as total time spent awake after first epoch of sleep and before final awakening. 
This will be a secondary outcome measure. 
 
7.2.3 Latency to Persistent Sleep 
 
LPS is defined as total time between lights out and first epoch of sleep. This will be a secondary 
outcome measure. 
 
7.2.4 Muscle Tonicity 
 
Muscle activity during REM sleep will be recorded as a measure of REM Behavior Disorder. 
 
7.3 Efficacy Assessment Based on Clinical Rating Scales 
 
7.3.1 Insomnia Severity Index 
 
The ISI is a 7-question survey assessing symptoms of insomnia. Maximum score is 28, with 
higher scores indicating greater severity. The ISI has been validated for use in insomnia research 
(Bastien 2001). This will be performed at Office Visits 2, 3, 4, and 5, and will be a secondary 
outcome measure. 
 
7.3.2 Epworth Sleepiness Scale 
 
The ESS is an 8-question survey assessing symptoms of sleepiness. Maximum score is 24, with 
higher scores indicating greater severity. The ESS has been validated for use in the general 
population (Johns 1991) and in PD (Hagell 2007). This will be performed at Office Visits 2, 3, 4, 
and 5, and will be a secondary outcome measure. 
 
7.3.3 Subject’s Global Impression of Change 
 
The SGIC will be assessed by asking a single question at Phone Visits 2 and 5 and Office Visits 
3, 4, and 5: “Since baseline (when first starting this study), how have your sleep symptoms 
changed?” Answers will be on a 7-point scale: 1 = much improved; 2 = somewhat improved; 3 = 
minimally improved; 4 = no change; 5 = minimally worse; 6 = somewhat worse; and 7 = much 
worse. This will be performed at Phone Visits 2 and 5 and at Office Visits 3, 4, and 5, and will 
be a secondary outcome measure. 
 
7.3.4 Clinician’s Global Impression of Change 
 
The CGIC will be assessed by the investigator at Office Visits 3, 4, and 5 using a similar 
question: “Since baseline (when first starting this study), how have the subject’s sleep symptoms 
changed?” Answers will be on a 7-point scale: 1 = much improved; 2 = somewhat improved; 3 = 
minimally improved; 4 = no change; 5 = minimally worse; 6 = somewhat worse; and 7 = much 


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worse. This will be performed at Office Visits 3, 4, and 5, and will be a secondary outcome 
measure. 
 
7.3.5 Montreal Cognitive Assessment 
 
The MoCA is an assessment of global cognition using a 30-point scale and investigating 
performance in visuospatial ability, executive function, naming, attention, language, abstraction, 
delayed recall, and orientation. It will be performed at Office Visits 1, 3, 4, and 5, and will be 
used as a secondary outcome measure to assess the effect of suvorexant on cognition in PD. 
 
7.3.6 Beck Depression Inventory-II 
 
The BDI is a 21-question assessment of symptoms of depression, with higher scores indicating 
more severe depression, to a maximum score of 63. This scale has been validated for use in 
assessing depression in Parkinson disease (Leentjens 2000). It will be performed at Office Visits 
2, 3, 4, and 5, and will be used as a secondary outcome measure to assess the effect of 
suvorexant on depression in PD. 
 
7.3.7 Beck Anxiety Inventory 
 
The BAI is a 21-question assessment of symptoms of anxiety, with higher scores indicating more 
severe depression, to a maximum score of 63. This scale has been validated for use in assessing 
depression in Parkinson disease (Leentjens 2011). It will be performed at Office Visits 2, 3, 4, 
and 5, and will be used as a secondary outcome measure to assess the effect of suvorexant on 
anxiety in PD. 
 
7.3.8 Movement Disorder Society’s Unified Parkinson Disease Rating Scale (MDS-UPDRS) 
 
The MDS-UPDRS is a widely used and validated (Goetz 2008) rating scale in PD, assessing 
non-motor symptoms of PD (part I), motor symptoms of PD (part II), motor signs of PD on 
physical exam (part III), and symptoms of motor complications in PD (part IV). Part I includes 
two questions about sleep symptoms: question 1.7 (sleep problems) and question 1.8 (daytime 
sleepiness). All questions are rated on a 5-point scale (0-4), with higher scores indicating greater 
severity. The maximum score on part I is 52, on part II it is 52, on part III it is 132, and on part 
IV it is 24. Total score, the score on part I, the score on question 1.7, and the score on question 
1.8 will be secondary outcome measures. The scores on parts II, III, and IV will be used as safety 
measures to ensure no worsening of motor symptoms, motor signs, or motor complications. Part 
III will be performed at Office Visit 1; Parts I, II, and IV will be performed at Office Visit 2; and 
the full scale (parts I-IV) will be performed at Office Visits 3, 4, and 5. 
 
7.3.9 Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The Columbia Suicide Severity Rating Scale is a widely used and validated assessment of 
suicidal ideation and suicidal behavior (Posner 2011). It provides a structured interview to 
assess, over both lifetime and the past 6-months, several types of suicidal ideation and behavior, 


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stratified by risk for suicide completion. This will be used to assess suicide risk at screening and 
to monitor for an adverse event of increasing suicidality throughout the study. It will be 
administered at Office Visits 1, 3, and 5, and at Phone Visits 2 and 5.  
 
7.4 Efficacy Assessment Based on Wearable Sleep Monitor 
 
The secondary outcome measure based on the wearable sleep monitor (WSM) will include: 
 Total hours of sleep per night, mean over final 7 nights of treatment period compared to 
mean over final 7 nights of screening period 
 Wakefulness after sleep onset (WASO), mean over final 7 nights of treatment period 
compared to mean over final 7 nights of screening period  
 
 
 
 
 
 


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8. Statistical Methods 
8.1 Statistical Analysis 
Statistical analysis will be performed by a consulting statistician contracted with 
EvergreenHealth and whose services we have used on recent studies in PD. All data will remain 
blinded throughout the data analysis and will be unblinded only in the event of a medical 
emergency.  
8.2 Sample Size Considerations 
This is a prospective, double-blinded, randomized controlled pilot study. The purpose is to test a 
hypothesis in a preliminary fashion and to assess for safety in this population with a specific 
neurological disease. As such, a power calculation may be irrelevant. However, a small number 
of subjects (e.g. less than 10) may cause significant sampling error to miss a treatment effect or 
common safety issue. Some entities that establish criteria for level of evidence consider a sample 
size of 20 subjects in each arm to be a minimum representative population to be considered for 
Class III or better classification of Level of Evidence.  This will be achieved by having 20 
subjects complete both treatment and placebo arms using a crossover study design. Therefore, a 
sample size of 20 subjects is a reasonable number for a pilot study of this nature.   
8.3 Study Population 
The study population will include all patients who pass screening and undergo randomization. 
Data will be analyzed in an intent-to-treat fashion. 
8.4 Baseline and Demographic Characteristics 
The following characteristics will be summarized descriptively for placebo and drug groups: 
 Demographics (age, gender, race) 
 Parkinson disease characteristics at baseline (disease duration, date of onset, initial 
symptom, modified Hoehn and Yahr stage in the ON state, and MDS-UPDRS part 3 
score in the ON state) 
 Levodopa-equivalent daily dose (LEDD), calculated according to published formulae 
(Tomlinson 2010, Rytary Prescribing Information, Duopa Prescribing Information). 
 
8.5 Efficacy Analysis 
Analysis of primary and secondary outcome measures will include: 
 Summary statistics (n, mean, standard deviation, median, minimum and maximum) at 
baseline, Office Visit 3 and Office Visit 5 by treatment.  
 For clinical rating scales, summary of % change from baseline to Office Visit 3, from 
baseline to Office Visit 5, and from Office Visit 4 to Office Visit 5, by treatment 
 For PSG variables, summary of % change from PSG 1 to PSG 2 and from PSG 1 to PSG 
3, by treatment 


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 For wearable sleep monitor, summary of % change in total hours of sleep and WASO. 
Mean over the week prior to Office Visit 2 (baseline) will be compared to the mean over 
the final week of Treatment Period 1 and to the mean over the final week of Treatment 
Period 2. Mean over the week prior to Office Visit 4 (during washout) will be compared 
to the mean over the final week of Treatment Period 2. This will be done by treatment 
arm.   
 Significance testing 
 
Outcome measures will be compared between groups using analysis of covariance (ANCOVA) 
or other method as deemed appropriate by the consulting statistician. Demonstration of 
superiority will depend on achieving statistical significance for the primary endpoint. Level of 
significance will be defined as p = 0.05. All statistical tests will be two-sided.  
 
 
 


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9. STUDY MANAGEMENT 
 
9.1 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 approval from the appropriate Institutional Review Board or Independent Ethics 
Committee. 
 
9.2 Informed Consent 
 
For each trial patient, written informed consent will be obtained before any study-related activity 
is commenced. Both the informed consent form (ICF) and an oral explanation that occurs as part 
of the informed consent process will include information about the study objective, the nature 
and duration of the study, the action of the study drug, potential risks, inconveniences, adverse 
effects, and alternatives. The patient will be informed that he or she is free to withdraw from the 
study at any time without consequence.  
 
 
 
 


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10. REFERENCES 
1. 
Abbvie, Inc. (2015). Duopa Prescribing Information, revised January 2015. 
2. 
Bastien CH, Vallières A, Morin CM (2001). Validation of the Insomnia Severity Index as 
an outcome measure for insomnia research. Sleep Med 2(4): 297-307. 
3. 
Bennett T, Bray D, Neville MW (2014). Suvorexant, a dual orexin receptor antagonist for 
the management of insomnia. Pharmacy and Therapeutics 39(4):264-266. 
4. 
Chung S, Bohnen N, Albin RL, et al. (2013). Insomnia and sleepiness in Parkinson 
disease: association with symptoms and co-morbidities. J Clin Sleep Med 9(11):1131-
1137. 
5. 
De Lau LML and Breteler MMB (2006). Epidemiology of Parkinson’s disease. Lancet 
Neurol 5(6):525-535. 
6. 
Dorsey ER, Constantinescu R, Thompson JP, et al. (2007). Projected number of people 
with Parkinson disease in the most populous nations, 2005 through 2030. Neurol 68:384-
386. 
7. 
Dowling G, Mastick J, Colling E, et al. (2005). Melatonin for sleep disturbances in 
Parkinson’s disease. Sleep Med 6:459-466. 
8. 
Gagnon JF, Postuma RB, Montplaisir J (2006). Update on the pharmacology of REM 
sleep behavior disorder. Neurol 67:742-747. 
9. 
Goetz CG, Poewe W, Rascol O, et al. (2004). Movement Disorder Society task force 
report on the Hoehn and Yahr staging scale: status and recommendations. Mov Dis 19(9): 
1020-1028. 
10. 
Goetz CG, Tilley BC, Shaftman SR, et al. (2008). Movement Disorder Society-sponsored 
revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale 
presentation and clinimetric testing results. Mov Dis 23(15): 2129-2170. 
11. 
Hagell P, Broman JE (2007). Measurement properties and hierarchical item structure of 
the Epworth Sleepiness Scale in Parkinson's disease. J Sleep Res. 16(1): 102-9. 
12. 
Herring WJ, Snyder E, Budd K, et al. (2012). Orexin receptor antagonism for treatment 
of insomnia: A randomized clinical trial of suvorexant. Neurol 79:2265-2274. 
13. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of 
idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol 
Neurosurg Psych 55: 181–184 
14. 
Impax Laboratories, Inc. (2015). Rytary Prescribing Information, revised January 2015.  
15. 
Johns MW (1991). A new method for measuring daytime sleepiness: the Epworth 
Sleepiness Scale. Sleep 14(6): 50-55. 
16. 
Leentjens AF, Verhey FR, Luijckx GJ, Troost J (2000). The validity of the Beck 
Depression Inventory as a screening and diagnostic instrument for depression in patients 
with Parkinson’s disease. Mov Dis 15(6): 1221-1224.  


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17. 
Leentjens AF, Dujardin K, Marsh L, Richard IH, Starkstein SE, Martinez-Martin P 
(2011). Anxiety rating scales in Parkinson's disease: a validation study of the Hamilton 
anxiety rating scale, the Beck anxiety inventory, and the hospital anxiety and depression 
scale. Mov Dis 26(3): 407-415. 
18. 
Lees AJ, Blackburn NA, Campbell VL (1988). The nighttime problems of Parkinson’s 
disease. Clin Neuropharmacol 6:512-519. 
19. 
Medeiros C, Carvalhedo de Bruin P, Lopes L, et al. (2007). Effect of exogenous 
melatonin on sleep and motor dysfunction in Parkinson’s disease: A randomized, double 
blind, placebo-controlled study. J Neurol 254:459-464.  
20. 
Posner K, Brown GK, Stanley B, et al. (2011). The Columbia-Suicide Severity Rating 
Scale: Initial validity and internal consistency findings from three multi-site studies with 
adolescents and adults. Am J Psychiatry 168:1266-1277. 
21. 
Rios Romenets S, Creti L, Fichten C, et al. (2013). Doxepin and cognitive behavioural 
therapy for insomnia in patients with Parkinson’s disease – a randomized study. Park Rel 
Dis 19(7):670-675. 
22. 
Sun H, Kennedy WP, Wilbraham D, et al. Effects of suvorexant, an orexin receptor 
antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 
36(2):259-267. 
23. 
Tandberg E, Larsen JP, Karlsen K (1998). A community-based study of sleep disorders in 
patients with Parkinson’s disease. Mov Dis 13(6):895-899. 
24. 
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, et al. (2010). Systematic review of 
levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 25: 2649–2653. 
 
 


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11. APPENDIX 
 
11.1 Schedule of Assessments 
 
 
Appendix 11.1: Schedule of Assessments
Visit 1: 
Screening
PSG 1
Visit 2: Start 
Treatment 
Period 1
Phone Visit 1 Phone Visit 2 Phone Visit 3
PSG 2
Visit 3: Start 
Washout 
Period
Visit 4: Start 
Treatment 
Period 2
Phone Visit 4 Phone Visit 5 Phone Visit 6
PSG 3
Visit 5: Final
Timing
Week 0
Week 3        
(0-21 days 
post Visit 1)
Week 5       
(7-14 days 
post PSG 1)
Week 5.5      
(3-4 days 
post Visit 2)
Week 7        
(12-15 days 
post Visit 2)
Week 7.5       
(3-4 days post 
Phone Visit 2)
Week 9       
(25-32 days 
post Visit 2)
Week 9       
(0-7 days 
after PSG 2)
Week 11        
(11-18 days 
post Visit 3)
Week 11.5     
(3-4 days post 
Visit 4)
Week 13       
(12-15 days 
post Visit 4)
Week 13.5      
(3-4 days post 
Phone Visit 5)
Week 15     
(25-32 days 
post Visit 4)
Week 15       
(0-7 days 
after PSG 3)
Informed Consent
X
Study Eligibility (inclusion/exclusion)
X
X
Medical History 
X
Sleep History
X
PD History
X
Concomitant Medication  and Allergy Review
X
X
X
X
X
Levodopa-equivalent daily dose calculation
X
AE Assessment
X
X
*
X
X
X
X
*
X
Physical Exam
X
X
X
MDS-UPDRS, Part 3 (Motor Exam)
X
MDS-UPDRS, Parts 1, 2, & 4
X
MDS-UPDRS, full  assessment
X
X
X
UK Brain Bank Criteria review
X
Hoehn and Yahr Staging for Parkinson's
X
Laboratory Testing (CBC, CMP, albumin, INR)
X
X (CBC, CMP)
*
X (CBC, CMP)
Assessment of Child-Pugh Score
X
Pregnancy Testing (urine hCG)
**
**
**
**
**
Overnight Polysomnogram (Sleep Study), 
including analysis by sleep specialist
X
X
X
Calculation of Sleep Efficiency
X
X
X
Calculation of Waking after Sleep Onset (WASO)
X
X
X
Calculation of Latency to Persistent Sleep
X
X
X
Insomnia Severity Index
X
X
X
X
Epworth Sleepiness Scale
X
X
X
X
Montreal Cognitive Assessment (MoCA)
X
X
X
X
Beck Depression Inventory
X
X
X
X
Beck Anxiety Inventory
X
X
X
X
Columbia Suicide Severity Rating Scale
X
X
X
X
X
Clinician's Global Impression of Change of disease symptoms
X
X
X
Subject's Global Impression of Change of disease symptoms
X
X
X
X
X
Dispense wearable sleep monitor
X
Upload data from wearable sleep monitor
X
X
X
X
Randomization
X
Drug Dispensing
X
X (placebo)
X
*As indicated
**Urine hCG will be performed for all pre-menopausal women.