The Efficacy of Suvorexant in the Residential Treatment of Patients With Substance Use Disorder and Insomnia: A Pilot Open Trial
Phase: PHASE2
Conditions: Sleep Disturbance, Craving, Cortisol; Hypersecretion
Sponsor: Milton S. Hershey Medical Center

Document Section Cover Sheet 
 
Official Title: The Efficacy of Suvorexant in Treatment of Patients With Substance Use Disorder 
and Insomnia: A Pilot Open Trial 
NCT number: NCT03412591 
Document: Study Protocol and Statistical Analysis Plan 
Document date: 10/02/2023 

Page 1 of 27 (V.04/27/2020)
HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
The Efficacy of Suvorexant in the Residential Treatment of Patients with Substance Use Disorder and Insomnia: A Pilot 
Open Trial  
Principal Investigator:
Name: Scott Bunce, PhD
Department:  Psychiatry and Behavioral Health
Telephone: 215-510-8295 (cell)
E-mail Address:  sbunce@pennstatehealth.psu.edu
Version Date:
06th December 2022
Clinicaltrials.gov Registration #:
NCT03412591
Important Instructions for Using This Protocol Template:
1.
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7. 
2.
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval. 
3.
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable.
4.
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol.
5.
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes. 
If you need help…
University Park and other campuses:
Office for Research Protections Human Research Protection Program
The 330 Building, Suite 205
University Park, PA 16802-7014
Phone: 814-865-1775
Fax: 814-863-8699
Email: irb-orp@psu.edu
College of Medicine and Hershey Medical Center:
Human Subjects Protection Office
90 Hope Drive, Mail Code A115, P.O. Box 855
Hershey, PA 17033
(Physical Office Location: Academic Support Building Room 1140)
Phone: 717-531-5687
Fax number: 717-531-3937
Email: irb-hspo@psu.edu
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Confidentiality, Privacy and Data Management
10.0
Data and Safety Monitoring Plan
11.0
Risks
12.0
Potential Benefits to Subjects and Others
13.0
Sharing Results with Subjects
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
15.0
Economic Burden to Subjects
16.0
Resources Available
17.0
Other Approvals
18.0
Multi-Site Research
19.0
Adverse Event Reporting
20.0
Study Monitoring, Auditing and Inspecting
21.0
Future Undetermined Research: Data and Specimen Banking
22.0
References
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1.0
Objectives
1.1
Study Objectives
The literature supports the case for an open trial of suvorexant, an orexin 1 / 2 receptor antagonist, in 
patients in residential treatment for substance dependence disorders, who complain of sleep 
disturbance. The patients will be at least 5 days post-withdrawal, in order to minimize the residual sleep 
complaints associated with that phase of treatment. In previous, well-designed, placebo-controlled 
clinical trials in patients with insomnia (1), suvorexant has been shown to be efficacious compared with 
placebo.  However, substance dependent patients with insomnia were not included in these studies.  
Although, as a new sleep medication, suvorexant has been placed in Schedule IV by the FDA, the drug 
has not been studied in the context of its potential abuse liability when administered at bedtime at the 
therapeutic dose among patients in residential treatment for substance dependence disorders. We will 
therefore incorporate a modified abuse liability protocol in this pilot study.
Importantly:
1. Data from animal models of opioid dependence suggest that orexins may be involved in reward 
seeking behavior, and that an orexin 1 receptor antagonist reduced heroin self-administration and cue-
induced heroin seeking behavior in the rat (2).
2. Chronic stress and compulsive drug seeking are influenced by orexin transmission throughout the 
hypothalamic, extended amygdala, brainstem, and meso limbic pathways (3). These dysregulated states 
of hyperarousal may be normalized by an orexin 1 receptor antagonist 
3. Finally, whereas the drug has been placed in Schedule IV by the DEA and the FDA, the FDA Briefing 
Document stated that “the potential abuse liability of suvorexant in patients with insomnia is considered 
to be low . . . suvorexant was not self-administered in non—human primates . . . Based on the outcome 
of these studies, there was no evidence that suvorexant has the potential for abuse or dependence” (1). 
Hypotheses:
1. Relative to a baseline, patients being treated with suvorexant will experience an increase in total 
sleep time, fewer awakenings after sleep onset, and improved subjective sleep quality.
2. Relative to baseline, patients being treated with suvorexant are more likely to experience decreased 
total daily salivary cortisol over the course of 7 days of treatment. 
3. Relative to baseline, patients being treated with suvorexant are more likely to report improved 
moods, and decreased ambient craving.
4. Patients being treated with suvorexant are not likely to endorse scale items associated with abuse 
liability 30 minutes after drug administration or the following morning.
1.2
Primary Study Endpoints
1)
To determine if patients taking suvorexant will have improved sleep quality (increased total sleep 
time, fewer awakenings), as measured through, sleep wrist actigraphy, actigraphy logs, modified 
Pittsburgh Sleep Quality Index (PSQI), and modified Insomnia Severity Index (ISI). 
2)
To assess whether or not patients endorse scale items on a modified abuse liability assessment 
battery. 
3)
To determine if associations between daily reports of mood, stress, craving and sleep using 
Ecological Momentary Assessment (EMA data) change during the course of the study. 
4)
To determine if patients taking suvorexant will have a decrease in total daily salivary cortisol over 
the course of the study by collecting samples at five time points for two consecutive days at two 
different times in the study. 
1.3
Secondary Study Endpoints
1)    To assess reactivity of EMA ratings of craving and mood in response to naturally occurring stressors,   
        determining if these associations change during the course of medication.
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2)
To use advanced statistical techniques to holistically characterize systemic dysregulation (including 
self-reported daily mood, stress and craving) and emerging patterns of re-regulation while taking 
suvorexant. 
2.0
Background
2.1
Scientific Background and Gaps
It is now generally recognized that a number of factors contribute to the heightened risk of relapse in 
patients with substance use disorders (SUDs). These elements include, but are not limited to: 1) 
dysregulation of the HPA axis; 2) sleep complaints (including delayed sleep onset, time awake after sleep 
onset, total sleep time, and/or complaints of poor sleep quality); and 3) negative moods, ambient and 
cue-related craving and anhedonia (4-7). Persistent sleep disturbances following withdrawal from drugs 
of abuse are common and frequently continue over the course of a typical 28 to 30 days stay in 
residential treatment. Sleep abnormalities (8) have been associated with HPA axis dysregulation. 
Together, these findings suggest that complaints of insomnia in patients with alcohol or opioid 
dependence may represent an important but relatively untreated element in the complex 
neuropsychobiology contributing to risk of relapse. 
2.2
Previous Data
The general study design of this research proposal builds on a NIDA funded study (Prescription Opioid 
Dependence: Physiology, Emotion & Treatment Outcome (R01 DA035240; STUDY 00044050)) that 
robustly predicted treatment outcomes in a cohort of patients with opioid dependence. Sleep 
complaints, and changes in daily and within day craving and mood and salivary cortisol over time, were 
assessed in a cohort of opioid dependent patients. In a subsample (n=13) of patients who remained in 
residential treatment for a period of 60 days; 5 relapsed while 8 remained abstinent 90 days after 
residential treatment discharge.  These subjects were assessed for cortisol and sleep at two time points 
approximately 30 and 60 days following detox.  Cortisol levels were assessed 5 times per day for two 
successive days during each data assessment period.  There was no difference between those that 
relapsed or abstained during the initial assessment.  However, cortisol levels were decreased in those 
that abstained and remained constant in those that relapsed after 60 days of treatment (P=0.007).  
Sleep was also objectively assessed with actigraphy across the full 12 day data collection period. Again, 
there was no difference between those that relapsed and those that did not during the first assessment 
period, but those that abstained demonstrated an increase in total sleep time while total sleep time in 
those that relapsed remained constant (P=0.048).  In summary, an improvement in both cortisol and 
sleep during the 60 days of residential treatment was associated with abstinence of at least 90 days post 
discharge.
2.3
Study Rationale
Sleep complaints during the first weeks following detoxification should be considered a result of drug 
withdrawal, meeting the DSM-V criteria of substance induced sleep disorder- insomnia type (9). We can 
anticipate that HPA axis activation occurs in all phases of insomnia symptoms, i.e., substance induced 
sleep disorder – insomnia type, acute insomnia or chronic insomnia.  Sleep complaints were common 
among opioid dependent patients in residential treatment for 30 days following medically assisted 
withdrawal in our NIDA-supported study (R01 DA035240; STUDY 00044050)). Patients who remained in 
residence for 60 days or more, showed either a worsening or an improvement in sleep symptoms. 
Individuals whose total sleep time increased over the 60-day period were more likely to remain 
abstinent following discharge than patients whose total sleep time decreased. At this juncture, there has 
been no systematic study on the effects of suvorexant on sleep complaints at any stage of recovery from 
opioid or alcohol dependence.  
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Neuroadaptations that occur in the course of addiction disrupt the normal function of the HPA axis. The 
HPA axis is a major neuroendocrine system that controls reactions to stress and regulates many body 
processes, including sleep, mood, and emotions. When patients are withdrawn from drugs of abuse, 
they experience a cluster of symptoms, including diminished motivation for natural rewards 
(anhedonia), an increase in reward thresholds, hypersensitivity to stress, chronic irritability, emotional 
pain, dysphoria, and significant sleep disturbances. These symptoms have been described in the early 
stages of withdrawal from alcohol, opiates, cocaine, cannabis, stimulants, and polysubstance abuse, and 
are thought to significantly contribute to patient relapse.  In numerous patients, these symptoms are 
present for several months following withdrawal, and many patients continue to complain of sleep 
disturbances even when utilizing currently available prescription and nonprescription sleep medications.
A medication that can improve sleep and normalize HPA axis function may help to alter mood and 
craving in patients with alcohol and/or opioid drug dependence. Suvorexant, an orexin 1/2 receptor 
antagonist, is a new type of sleep medication that works not only on the sleep response, but also on 
mood and emotion (1). Whereas orexin 2 receptors influence sleep, a compound that blocked orexin 1 
receptors reduced heroin self-administration and cue-induced heroin seeking behavior in rats (2).  Brain 
areas that are influenced by orexin transmission are involved in the regulation of responses to chronic 
stress and compulsive drug seeking (3). In summary, suvorexant may be a more efficacious medication 
for SUD patients with sleep disturbance, as it works on brain systems associated with mood and 
emotions, as well as sleep.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1.
Sex:  male or female
2.
Age:  21-64 (inclusive) years old 
3.
Caron Foundation residential alcohol or opioid dependent patients that have a history of daily or 
near daily substance use for the month prior to admittance.
Group 1:  At least 5 days post medically assisted withdrawal for alcohol dependence, and 
complain of problems falling asleep, remaining asleep after sleep onset, or poor sleep quality 
on current sleep medication (antidepressant/melatonin) for at least 3 days.
Group 2: At least 5 days post medically assisted withdrawal for opioid dependence and 
complain of problems falling asleep, remaining asleep after sleep onset, or poor sleep quality 
on current sleep medication (antidepressant/melatonin)for at least 3 days.
4.
Fluent in written and spoken English. 
3.2
Exclusion Criteria
1.
Patients who are concurrently receiving a psychoactive drug for the treatment of an Axis I 
disorder, but not including sedating antidepressants trazadone or mirtazapine that have been 
prescribed for the treatment of sleep disturbance.
2.
Patients with current major depressive disorder greater than mild or moderate, schizophrenia, 
bipolar disorder, or a history of traumatic brain injury. 
3.
Patients with a history of narcolepsy or REM related phenomenon.
4.
Patients with chronic respiratory problems including asthma, COPD, or other respiratory issues 
that can lead to sleep disturbances at night.
5.
Patients with current suicidal ideation or a history of previous suicide attempts.
6.
Patients with severe liver impairment.
7.
Women who are pregnant or breastfeeding.
8.
Patients who are severely obese.
9.
Decisional impairment
10. Prisoners or under legal mandate.
11. On any medication that would interfere with study participation
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12. Hypersensitivity to medications in the same class as suvorexant
13. Any chronic conditions or exclusionary criteria that would prevent participation in the study or 
lead to participant at risk of untoward effect because of participation in the study. 
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Subjects are free to withdraw at any time without any influence impacting their ongoing 
treatment. If a patient experiences side effects, these will be documented and reported to the 
FDA, as required.
3.3.2
Follow-up for withdrawn subjects
The primary reason for participant study withdrawal would be due to early discharge from the 
Caron treatment program prior to successful completion. There would be no follow up with 
these patients. 
4.0
Recruitment Methods
4.1
Identification of subjects
Participants will be identified using two methods:
•
The Caron based study coordinator will review the electronic medical records (EMR) of recently 
admitted patients and check for the inclusion/exclusion criteria  
•
Participants will also be identified through research flyers, which will be displayed in all units at 
the Caron Foundation.  Interested patients will approach the Caron staff/counsellors who will in 
turn refer the subjects to the Caron based study coordinator. The Caron based study 
coordinator will check for inclusion/exclusion criteria by reviewing their EMR.
4.2
Recruitment process
Recruitment will use a two-step process:
o
The Caron based study coordinator will complete a comprehensive REDCap screening and 
eligibility checklist to verify study eligibility based on established inclusion/exclusion criteria. It will 
be reviewed with the study coordinator at Hershey Medical Center (HMC) and the PI or his 
designee.  If a  Subject is deemed eligible to participate in the research based upon the preliminary 
assessment and if aggregable by the HMC coordinator and the PI of his designee, the Caron-based 
study coordinator will approach the participant to inquire about possible interest in the study. This  
study coordinator will review the study design, suvorexant information packet, and the 
inclusion/exclusion criteria with each prospective research participant.
o
.  Only subjects approved by the Hershey staff (study coordinator at Hershey Medical center and 
the PI or his designee) will be asked to review and sign an informed consent form if they wish to 
participate.
4.3
Recruitment materials
Flyers will be displayed on the treatment units at the Caron Foundation.
REDCap Screening Form (see the document “Screening Checklist” attached in CATS)
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4.4
Eligibility/screening of subjects
In addition to the medical record review, participants may be asked questions designed to inform 
determination of eligibility from an additional screening script prior to signing the consent document .
5.0
Consent Process and Documentation
5.1
Consent Process 
 
5.1.1
Obtaining Informed Consent
5.1.1.1
Timing and Location of Consent
Consent will be obtained on Day 0 (see study design) at the Caron Foundation 
by the Caron study coordinator after discussing the study in detail. 
5.1.1.2
Coercion or Undue Influence during Consent
Subjects will be informed that participation is voluntary and that their decision 
to participate will not affect treatment at the Caron Foundation.  The Caron-
based study coordinator will comprehensively discuss the study with the 
patients, review consent documents, and answer all questions.
5.1.2
Waiver or alteration of the informed consent requirement
A waiver of consent is requested to review medical record information to determine preliminary 
eligibility to participate in the research.
 
5.2
Consent Documentation
5.2.1
Written Documentation of Consent
The consent process will be documented in writing with the long form of consent 
documentation:
•
The current IRB approved consent form will be obtained.
•
We will verify that we are using the most current IRB-approved version of the study specific 
consent form and that the consent form is in language understandable to the subject.
•
A copy of the consent form will be provided to the subject. Whenever possible the consent 
form will be provided to the subject in advance of discussion.
5.2.2
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
The study team intends to potentially ask subjects eligibility questions prior to written consent. 
The study team will obtain verbal consent from the participant to ask questions detailed in the 
additional screening script. 
5.3
Consent – Other Considerations 
5.3.1
Non-English Speaking Subjects
Not applicable.
5.3.2
Cognitively Impaired Adults
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5.3.2.1 Capability of Providing Consent
Not applicable. 
5.3.2.2
Adults Unable To Consent
Not applicable.
5.3.2.3 Assent of Adults Unable to Consent
Not applicable.
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
5.3.3.1 Parental Permission
Not applicable.
5.3.3.2 Assent of subjects who are not yet adults
Not applicable.
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1 Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol.
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6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
Upon study completion, all electronic patient research information will be deleted 
from all research sources.  Any hard copy patient information collected for 
research will be placed in one of HMC's patient information bins to be shredded in 
compliance with HIPAA regulations and PSU research document retention policies.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
Information must be obtained from the subject’s electronic medical record at Caron during 
recruitment to determine eligibility and, in some cases, to confirm information discussed with 
the subject in regard to their medical history.
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
The waiver is requested only for recruitment to determine subject eligibility to ensure that no 
medical conditions that fall into the exclusion criteria are present and would thus preclude 
enrollment.  This waiver will minimize the enrollment of subjects’ who may ultimately fail to 
meet the study inclusion/exclusion criteria.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
Open label, pilot observational study of suvorexant, an orexin 1 / 2 receptor antagonist, for the 
treatment of sleep disturbance in patients in residential treatment for opioid or alcohol use disorder.
7.2
Study Procedures
When a medication is studied for a new indication, or in a new population, it is common (in clinical 
neuropsychopharmacology) to conduct the first study in an open trial. We plan to study two groups of patients in an 
open 7-day trial of 20 mg suvorexant HS, following a two-day baseline during which patients will be taking a previously 
prescribed sleep medication (i.e. trazodone, mirtazapine, or melatonin) before switching to suvorexant. The study 
design includes a combination of assessments, and the collection of biological samples. Participants will be enrolled in 
the study for a total of 10 days (9 nights).  Table 1 references the daytime questionnaires and procedures, and Table 2 
represents the night questionnaires and procedures. Night is considered to be the time after the patient takes the 
medication. In our study, the night falls after the day. 
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Table 1. Daytime questionnaires and procedures. 
Table 2. Night questionnaires and procedures.
*Optional saliva for patients with opioid use disorder only 
**Current medicine regime including antidepressants/melatonin 
Abbreviations: EMA, ecological momentary assessment; ISI, Insomnia Severity Index; PSQI, Pittsburgh Sleep Quality 
Index. 
 
7.2.1
Consent and Screening: Study Day 0 
After signing the informed consent document, the Caron based study coordinator will complete 
a comprehensive screening assessment with each participant to further evaluate their eligibility 
in the study. The comprehensive screening assessment includes questionnaires to evaluate 
psychiatric comorbidities, sleep quality, depression and previous drug/alcohol use. The 
screening assessment questionnaires will be administered to the patients by the Caron based 
study coordinator on paper/ electronic tablet using the REDCap software. The screening 
questionnaires will include: 
• The M.I.N.I International Neuropsychiatric Interview (M.I.N.I. 7.0.2; if applicable) (10) which 
provides psychiatric diagnosis.
Study Day
0 
1
2
3
4
5
6
7
8
9
Consent and 
Screening (Form 
90 AI/DI, MINI 
Screen/MINI 7.0.2, 
HAM-D) 
X
EMA 
X
X
X
X
X
X
X
X
X
Modified ISI 
X
X
Modified PSQI 
X
 DNA Collection* 
X
Cortisol Collection 
X
X
X
X
Abuse Liability 
Battery – Morning 
X
X
Study Night
0 
1
2
3
4
5
6
7
8
Suvorexant 
 
 
1
2
3
4
5
6
7
Baseline**
X
X
Suvorexant 
Administration  
X
X
X
X
X
X
X
Actigraphy/Logs 
X
X
X
X
X
X
X
X
X
Abuse Liability 
Battery - Night
X
X
Observer Rated 
Questionnaire
X
X
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• The Hamilton Depression Rating Scale (HAM-D; 11) will be used to provide a continuous 
measure of depressive symptomatology and severity.  
• The Form 90-AI or Form 90-DI (12) will be administered to assess recent and lifetime history of 
drug and alcohol use, respectively. Recent substance use will document the 90 days prior to 
residential treatment admittance.  
The Pittsburgh Sleep Quality Index (PSQI; modified) (13) will be used to document the 
subjective severity of sleep complaints.
• The Insomnia Severity Index (ISI; modified) (14) will measure insomnia related symptoms. This 
assessment will also be administered on Study Day 9.
The study coordinator at Caron will also provide the patient with an actigraph, sleep log and 
EMA smartphone which the patient will return after completing the study.
Optional Research:  Participants who are being treated for opiate dependence will be asked if 
they would like to give a DNA sample from saliva using an Oragene collection kit to be used for 
DNA extraction. This is not mandatory. The samples will be stored at Department of Psychiatry, 
Penn State Hershey Medical center until the end of the study. When the study is complete, the 
samples will be shipped to Dr. David J. Vandenbergh at University Park  who will process the 
data for genotyping. He will purify the DNA from the saliva in his laboratory. Genotypes will be 
established from approximately 5 million sites in the genome. Candidates for single genes to 
study include the opioid receptor genes and the alcohol dehydrogenase genes. He will include 
these new genes in the analyses of the relation between suvorexant and opioid use. In addition 
to testing for genotype (the bases present in DNA), he will test for patterns of DNA methylation, 
which is an underpinning of epigenetics.
7.2.2
Study Days 0-9 
Sleep data: Sleep disturbances are common among actively-using opiate and alcohol dependent 
individuals, severe during the withdrawal phase, and are considered as a long-term risk factor 
for substance abuse relapse. Chronic insomnia is associated with increased cortisol levels over a 
24-hour period. Sleep disturbances and HPA axis activation are expected to be strongly 
correlated; normalization of HPA axis is predicted to be associated with normal sleep.
The collection of both objective and subjective sleep data and subjective non-sleep activity data 
will allow an assessment of the validity of the subjective and objective estimates of sleep quality 
in the effectiveness of suvorexant administration.  Sleep data will be collected in 3 ways:
1)
Objective wrist actigraphy sleep measurements will be collected nightly (Study Nights 0 
to 8)
2)
Subjective sleep and activity data will be obtained the following morning using actigraph 
logs and EMA survey questionnaires (Study Days 1 to 9). Subjective sleep data will include 
time to bed, estimated time to fall asleep, night-time awakenings, wake-time in the AM, 
and quality of sleep.
3)
4)
Standardized measures of sleep quality will be collected. Subjects will complete a 
modified version of the PSQI at baseline.  We will use a modified version of the ISI to 
measure subjective sleep at baseline (Day 0) and on completion of the study (Day 9) to 
determine the improvement in sleep quality over the study period. 
EMA Daily Diary Data Collection: Ecological momentary assessment (EMA) data refers to the 
intensive measurement of intra-individual processes in real context (i.e., ecological) and in real 
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time (i.e., momentary). In the proposed study, such data will be collected via Motorola Droid 
smart phones that are programmed to elicit the participants’ response four times per day, 
during each of the 9 full study days (Study Days 1 to 9), resulting in approximately 36 
assessments per individual. Instructions on how to use the smart phone for the EMA surveys, 
and what to do if a survey is missed, will be provided verbally on Day 0 to the participant using 
an approved EMA script. EMA survey administration times will be established to occur at 4 
specific time points on a daily basis in order to take advantage of the highly structured patient 
schedule, maximize compliance, and reduce patient burden. Using the data collection paradigm 
developed for the National Study of Daily Experiences as a framework (12), EMA surveys will be 
administered in the morning, early afternoon, late afternoon and evening with minor 
fluctuations in collection times being adjusted to accommodate specific treatment unit 
schedules. Research staff will contact the participant using Passport, an in-house simple 
message system (SMS) used to contact patients while they are at Caron, to remind them to take 
the EMA surveys. Passport communication does not extend outside of the Caron Treatment 
Center. EMA reminders will be sent twice daily, at approximately  11 am and 4 pm. If an EMA 
survey is missed, paper versions of the surveys are provided to the participant to fill out 
retroactively.
Multiple domains of affect will be drawn from the Extended version of the Positive and Negative 
Affect Scale and assessed on a daily basis at the four established collection times (PANAS-X; 15). 
Items included will cover the circumplex spectrum, and include hostility, guilt, sadness, stress, 
anxiety, fatigue, and happiness. Similarly, formatted items will be used to assess the occurrence 
and degree of participants craving (16) within each of the 4 EMA surveys. In addition to items 
inquiring about mood, stress, and craving, the morning assessment will include subjective items 
related to sleep. These sleep items will record estimated time to fall asleep, night-time 
wakenings, quality of sleep, daytime sleepiness, and the nightly experience of dreams that 
involve alcohol/drug content. Two identical and brief mid-day surveys will inquire about mood, 
stress, and craving using repeated items as described above. The evening survey will expand 
upon the repeated measures of mood, stress, and craving to capture aspects of late day 
experience such as 12 Step meeting attendance and patient perceptions about their day. Thus, 
our study will be able to capture both the variability in affect/craving and the temporal ordering 
of stressors and affect necessary to characterize within-day reactivity as well as changes 
observed in subjective and objective indices of sleep associated with suvorexant administration.
The smart phones that will be used for EMA data collection will have a security application 
installed that prevents user access to all other applications that are not associated with survey 
data collection. Smart phones will not be activated on a cellular network resulting in the 
disabling of voice, text, and internet functions. Research staff will use brief in-person meetings 
(every other day) as a means to ensure devices are being charged, build rapport, answer 
participant questions, monitor compliance, and to manually download data for backup storage 
on the RAs laptop and then uploaded to a secure server, Virtual COLO, at University Park
in State College, PA. The server has all of the latest security updates applied as well as the 
physical security of the data center itself. The only people with access to the server are James 
Mundie, Tim Brick, and Zita Oravecz. Access to the web-facing application is controlled by 
CoSign (The standard university login system). Only encrypted communications are used to and 
from the device, and there is only access to the database through the localhost. The database 
containing user responses will be backed up periodically (hourly). 
Diurnal cortisol: (Study Days 1,2,7,8) Saliva will be collected for cortisol measurement at 5-time 
points for two consecutive days at two different periods in the study, i.e. 8:00 AM before 
breakfast, 12:00 PM before lunch, 3:00 PM, 6:00 PM and 9:00 PM. The research staff will visit 
with the participant at approximately 3 PM (Day 0, 6, 9), 8 AM and 3 PM (Days 1, 2, 7, 8)  to 
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provide fresh cortisol collection kits needed for the next collection and to collect provided saliva 
samples. Instructions on how to provide saliva samples will be given to the participant on Day 0. 
Specimens are collected using a cotton swab kit (Salivette, item #51.1534). It has been 
demonstrated that five samples are adequate to examine circadian variation of cortisol 
secretion. Cortisol levels will be determined using a commercially-available, high-sensitivity 
salivary cortisol enzyme immunoassay kit (Catalog # 11-CORHU-E01-SLV; Alpco, Salem, New 
Hampshire) designed to standardize the measurement of salivary cortisol across research and 
biomedical laboratories. Saliva cortisol assaying will be done by a certified lab technician in the 
research laboratory at the Penn State College of Medicine. 
7.2.3
Abuse liability: Study Nights 1, 7, and the days following it (Study Days 2 and 8)
Abuse liability will be assessed with a modified protocol which includes the abuse liability 
battery morning, abuse liability battery night and the observer rated questionnaire. It is based 
on questions used in previous studies of abuse liability (17). The abuse liability –night battery 
will be completed by each research participant 30 min after medication administration on study 
Nights 1 and 7. The abuse liability battery – morning will be completed the morning after drug 
administration on study Day 2 and 8.  The abuse liability battery- morning and night has the 
same questions related to drug liking, drug value questionnaire, drug effects questionnaire 
except that there are additional questions asking to categorize the medication effect to one of 
the seven classed of psychoactive substances on the abuse liability battery-night . The observer 
rated assessment will be completed by the medication nurse as described below.   Our primary 
measures of abuse liability on the abuse liability battery- morning, night and the observer rated 
assessment will include the following 5 measures: 
1.
Drug Liking, with questions asking 1) if the drug made them feel high/euphoric, and if 
they liked the euphoric effect; 2) if the drug made them sleepy, and/or if they liked the 
sleep effects, or 3) if they disliked the effects of the drug. Each question is scored on a 5-
point Likert scale. 
2.
A three-item Drug Value questionnairewill ask participants 1) if they would use the drug 
to get high; 2) whether they thought that the drug might be addicting; 3) if they would 
buy the drug illegally to get high. 
3.
The Drug Effect questionnaire, (DEQ) will be used to evaluate how strong a drug effect 
was felt on a 5-item response scale, ranging from No Drug Effect to Very Strong Effect. 
4.
To further measure abuse liability, patients will also be asked to categorize the drug 
effect according to one of 7 classes of psychoactive medications. It will be administered 
on the abuse liability battery – morning on the morning of Study Day 2 and 8.  
5.
The Observer-Rated assessment (ORA) will be completed by the medication nurse on 
the evening of Study Day 1 and 7, 30 min after drug administration.
Abuse Liability Battery Scope (Detailed)
Study Day
1, 7
2, 8
Night/Day
Night
Day
Onset/Morn
O
M
Measures
 
 
DLQ
X
X
DVQ
X
X
DEQ
X
X
Categorize
 
X
O-RA
 X
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O = Onset of Action (30 min after taking medication); M = Morning; DLQ = Drug 
Liking Questionnaire; DVQ = Drug Value Questionnaire; DEQ = Drug effects 
questionnaire; Categorize; O-RA = Observer-Rated Assessment
7.2.4
Suvorexant: Study Nights 2-8
Patients will participate in an open 7-day trial of 20 mg suvorexant at night.
7.3
Duration of Participation
Participants will be enrolled in the study for a total of 9 days. 
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Subjects will continue on their current off label sleep medication including trazodone, 
mirtazapine or melatonin for the initial two nights of the study period and then on the study 
medication, suvorexant for 7 nights.
Trazodone is a sedative triazolopyridine antidepressant, used for the treatment of 
depression and insomnia because it possesses antidepressant and also anxiolytic and 
hypnotic activities (18,19). When prescribed as a hypnotic, it is habitually used at low-
doses (i.e., 50-150 mg daily at bedtime). The effects of trazodone on sleep have been 
evaluated in a variety of subjects, including patients with insomnia, depression, 
substance dependence and normal controls. In general, most studies with Insomnia 
have shown that trazodone improves subjective and objective sleep. In substance 
dependent patients, it has shown mixed results, with some studies improving sleep 
(20,21) and others not in substance dependent subjects (22).
Mirtazepine is an antidepressant used in the treatment of depression and off label for 
the treatment of Insomnia. It acts by increasing the central noradrenergic and serotonin 
levels by antagonism of pre synaptic α 2 adrenergic inhibitory auto receptors. 
Mirtazepine also has potent anti-histaminergic effect at lower doses of 7.5 to 15 mg and 
hence is used off label for the treatment of insomnia in general population and in 
substance use disorder subjects (23). 
Melatonin is a hormone produced by the pineal gland. Exogenous melatonin is available 
over the counter in 1 to 20 mg dosage. It is an agonist on melatonin 1, 2 and 3, which 
improves sleep and stabilizes circadian rhythms. It is found to be efficacious in the 
treatment of insomnia in the general population (24) but has shown mixed results in the 
treatment of insomnia in substance use disorders (25). 
The sleep medication, suvorexant, has been placed in Schedule IV by the FDA and DEA, and is 
approved for treatment of Insomnia. The form of the drug will be a 20 mg capsule (1). The drug, 
to be administered for seven nights under supervision of a nurse, will help determine overall 
sleep quality, levels of cortisol, and potential abuse liability. The dosage of 20mg was chosen 
following a recommendation by the lead investigator of the Phase-3 clinical trial for suvorexant 
performed by Merck. It has been suggested that the difference in side effects between 10 and 
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20mg is minimal. It has also been suggested that 10mg would have similar effects to a placebo, 
and that the higher dose of 20mg will be necessary. 
7.4.2
Treatment Regimen
During the 9 day study period, subjects will be on their current dosage of medication prescribed 
by the Caron Foundation physician including trazodone, mirtazapine or melatonin for two nights 
followed by 7 suvorexant trial. Participants will be administered one 20 mg suvorexant capsule 
per night for 7 nights. In total, participants will receive 1 capsule per night for a total of 7 nights. 
There will be no dose adjustments during this trial. All capsules will be taken orally. 
7.4.3
Method for Assigning Subject to Treatment Groups
Since this is an open medication trial, there will be no randomization process for assigning 
treatment to the research subjects stratified by alcohol dependence or opioid dependence.
7.4.4
Subject Compliance Monitoring
Medication compliance will be monitored and documented by the nursing staff at the Caron 
Foundation during the study. Any compliance issues will be documented and reported to the 
physician at Caron immediately by the nursing staff at Caron, and Dr. Scott Bunce will also be 
notified within 12 hours. A modified abuse liability assessment will also be administered on the 
evening of Study Night 1 and 7 as well as the following morning (Study Day 2 and 8). On the 
evening of Study Nights 1 and 7, nursing staff at Caron will complete an observer-rated form 30 
minutes after medication administration, to further validate subjective patient reports assessing 
abuse liability and adverse effects. 
7.4.5
Blinding of the Test Article
Not applicable.   
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The drug capsules will be ordered and received by Synergy Pharmacy, an off-site 
pharmacy that works with Caron. The Pharmacy will order the medication after 
receiving a scanned signed informed consent from Caron. The capsules will be 
ordered in blister packs that contain 7 capsules. These blister packs will be 
labeled according to FDA and Penn State Pharmacy guidelines. 
7.4.6.2
Storage
The storage of the medication will be at the medical detox unit at the Caron 
Foundation. In this unit is a locked room (nurses station) that contains a locked 
medication cart, with a locked drawer where the medication will be stored. 
Therefore, the medication will be double locked. Only ‘charge nurses’ will have 
access to the medication. Since the medication does not need to be 
refrigerated, it will be stored at room temperature in the medication cart. In 
addition to the study medication, the nurses will also have access to a log 
containing participant names, in order to observe patient compliance and to 
perform the appropriate abuse liability questionnaires on the evening of Study 
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Night 1,7. This log will also be kept with the medication in the locked room at 
the medical detox unit. 
7.4.6.3
Preparation and Dispensing
The drug will be ordered by the medical staff at Caron and stored in the medical 
unit. Caron Foundation nursing staff will administer medication, one capsule per 
night for 7 nights, and will be overseen by the Foundation’s medical staff.  As 
mentioned in section 7.4.6.2, the nursing staff will keep a log of subject names 
to ensure compliance.
7.4.6.4
Return or Destruction of the Test Article
Final reconciliation of the medication will take place at the Caron Foundation, if 
appropriate. The Caron Foundation performs these procedures according to 
DEA regulations. Non-controlled substances are stored in locked medical bins, 
which are then shipped to a company that will safely destroy the medication. 
Controlled substances are placed in medical bags where a charcoal-like liquid is 
added to make the medication ‘inactive’. After this procedure, the medication 
can then be thrown into the trash. Patients who do not complete the entire 
study will have their medication destroyed via Caron’s established medication 
disposal protocols. Patients will then be redirected to their doctors to discuss 
any outstanding sleep issues. 
7.4.6.5
 Prior and Concomitant Therapy
The subjects recruited will be current patients in a residential facility for the 
treatment of alcohol or opioid dependence. Since the doctors at Caron will be 
approving patient eligibility, they will know current and past patient medication 
regimes. Subjects may be taking concomitant medicines/therapies for various 
reasons at the treatment center. The pharmacy staff at Caron will also know 
which medications may not be permitted to take with the medication during the 
study, due to potential counteracting affects. Patients who are concurrently 
receiving a psychoactive drug for the treatment of an Axis I disorder excluding 
sedating antidepressants that have been prescribed for the treatment of sleep 
disturbance, will be excluded, as described in section 3.2.  
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
The total sample size will consist of 36 participants stratified by alcohol (n=22) or opioid dependence 
(n=14).  This sample size of convenience is expected to yield 10 evaluable data sets from the opioid 
group and 15 evaluable data sets from the alcohol group for statistical analysis.
8.2
Sample size determination
The purpose of this pilot study is to determine the feasibility of the study and explore the hypotheses of 
interest.  A sample size of 10 in the opioid group and 15 in the alcohol group will be sufficient to provide 
meaningful assessment of the study outcomes. The findings from this study will be used to plan a future 
study. 
8.3
Statistical methods
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The primary analyses will be mostly descriptive. Summary statistics and graphical methods will be used 
to examine the distribution of the data. Any potential outliers or leverage points of concern will be 
evaluated. The outcomes of interest will be summarized and plotted over time for each study group to 
explore the effect of treatment. Linear or generalized linear mixed effects models will also be used to 
evaluate the patterns of changes in study outcomes after the treatment of insomnia. Subjects with 
missing data can be incorporated in the mixed model analysis when data are missing at random. 
Adverse events and medication compliance will be documented and summarized.
A priori hypotheses derived from the literature as well as from our previous data will be tested 
separately in alcohol use disorder and opioid use disorder using paired Student’s t-tests for pre-post 
medication contrasts. Specific hypotheses are that both objective measures (sleep actigraphy measures 
of total sleep time, number of awakenings) and subjective measures of sleep (PSQI, sleep quality) will 
improve over the course of 10 days on suvorexant. EMA measures of negative mood are expected to 
decline, and positive moods are expected to increase from baseline to Day 10.
9.0
Confidentiality, Privacy and Data Management 
9.1
Confidentiality
Refer to the Data Plan Review Form.
10.0 Data and Safety Monitoring Plan
10.1
Periodic evaluation of data
Our data and safety monitoring plan will be under the jurisdiction of the PI, Dr. Scott Bunce. For this 
study, the main source of adverse events will be medication related. A potential adverse event includes 
a breach of data confidentiality. According to the Penn State College of Medicine IRB’s Standardized 
Operation Procedure “Reporting and Review of Unanticipated Problems Involving Risks to Participants 
or Others”, all participants and research staff who have direct interaction with the participant or with 
the confidential data of the participant, will be instructed to report any unexpected discomforts or any 
potential breach of confidentiality of participant’s data to the Principal Investigator responsible for the 
related components of data collection involved. Within 12 hours of any reported event, the PI will 
gather detailed information on the episode (See 19.2). If the event is considered to be an unexpected 
adverse event or a serious adverse event (SAE) it will be reported promptly to the IRB. The IRB will 
conduct its independent review and decide whether the episode represents an unexpected problem or 
an SAE. After a confirmed episode of an unexpected adverse event or SAE, the IRB will decide what, if 
any, corrective action is required. A summary of all events will also be reported to the IRB at the time of 
annual review.
10.2
Data that are reviewed
Data that will be reviewed include any reported side effects, adverse events (see below) or 
complications from the study. 
Adverse event: Any untoward or unfavorable medical occurrence associated with the subject’s 
participation in the research, whether or not considered related to the study intervention. 
Serious adverse event: Any event temporally associated with the subject’s participation in research that 
meets any of the following criteria:

Results in death;

Is life-threatening (places the subject at immediate risk of death from the event as it occurred);
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
Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in a persistent or significant disability/incapacity;

Results in a congenital anomaly/birth defect;

Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
participant’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse); or

Results in a severely debilitating situation for the subject, such as psychological distress, financial 
hardship or damaging impact on social standing or employability. 
Unexpected adverse event: A adverse event is considered “unexpected” if it is not listed in the general 
investigational plan or protocol; or is not listed at the specificity or severity that has been previously 
observed and/or specified.
10.3
Method of collection of safety information
Data will be collected during study procedures and through reports from staff and participants.
10.4
Frequency of data collection
The principal investigator , Dr. Scott Bunce will promptly review documented adverse events and 
abnormal test findings to determine 1) if the abnormal test finding should be classified as an adverse 
event; 2) if there is a reasonable possibility that the adverse event was caused by the study 
intervention(s); and 3) if the adverse event meets the criteria for a serious adverse event.  The PI, Dr. 
Scott Bunce, will consult the study physician Dr. Adam Scioli as needed.
10.5
Individuals reviewing the data
All participants and research staff who have direct interaction with the participant or with the 
confidential data of the participant, will be instructed to report any unexpected discomforts or any 
potential breach of confidentiality of participant’s data to the reference physician and Principal 
Investigator responsible for the related components of data collection involved.
10.6
Frequency of review of cumulative data
Not applicable. 
10.7
Statistical tests
Not applicable. 
10.8
Suspension of research
The report of a serious adverse event. 
11.0 Risks
Medication: Suvorexant is a new class of approved hypnotic drug that acts as an orexin 1 /2 receptor antagonist, 
suppressing wakefulness. It has been approved for the treatment of insomnia in adults at a dose of 10 or 20 mg 
– for complaints related to sleep onset and/or sleep maintenance. Adverse reactions which were reported to the 
FDA included central nervous system depression, amnesia, hallucinations, complex sleep – related behavior, 
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exacerbation of symptoms of depression, suicidal ideation and potential substance abuse, and impaired next 
day mental alertness. Common, but less serious, reactions included somnolence, headache, dizziness, abnormal 
dreams, diarrhea, cough, sleep paralysis, and cataplexy like symptoms (1).
Suvorexant should not be used concurrently with alcohol or a CNS depressant. Suvorexant should not be given 
to patients who have a hypersensitivity to drugs of the same class. Suvorexant should not be given to patients 
with narcolepsy, to patients with major depression or impaired respiratory function. The drug should be used 
with caution in patients with a history of alcohol or drug abuse; but, complaints about insomnia are highly 
prevalent in this group of patients – and insomnia is strongly associated with risk of relapse following a period of 
abstinence. While the patients in the proposed study will have a history of current alcohol or drug dependence, 
they are all in residence in a treatment facility where they will be closely monitored. We will be employing a 
modified abuse liability protocol to assess the relative risk of developing some form of dependence on 
suvorexant. Importantly, neither tolerance nor withdrawal effects were observed with suvorexant in the pre-
marketing studies. Suvorexant was not self-administered in non-human primate models.
As per the exclusion criteria, we will not be including pregnant or nursing female patients or patients with a 
current or history of major psychiatric disorder including depression, schizophrenia, or bipolar disorder; and, we 
will be excluding patients with current suicidal ideation and/or a past history of suicidal behavior.
Actigraphy:  There is no known risk to wearing the wrist actigraphs.  A minor skin rash may develop from the 
wristband, but this risk is very slight.
Questionnaires: The interviews and forms are routine, standardized forms for sleep research and psychology 
research.  They pose no known risks, although certain questions may be mildly upsetting because they may 
probe sensitive psychological areas and others inquire about family history of medical and psychological illness 
or alcohol and substance use. Appropriate referrals are offered if areas of concern arise in the course of 
collecting this information.  Research participants are free to skip any questions that make them uncomfortable.
Loss of confidentiality: The main risk of allowing us to obtain limited health information for research is a 
potential loss of privacy.
12.0 Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
Sleep quality may improve (total sleep time, less frequent awakenings) over the course of the study. 
12.2
Potential Benefits to Others 
The results of this study may guide future treatment of insomnia in patients with opioid and alcohol 
dependency. 
13.0 Sharing Results with Subjects
Not applicable.  We will not be sharing results with participants or others.
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14.0 Subject Stipend (Compensation) and/or Travel Reimbursements
Patients who are research participants will receive a $10 gift card for each day in the study. Upon completion of 
the entire medication period, they will get a bonus of a $50 gift card. The total amount they will receive for 
completing the entirety of the study will be $150 in gift cards. 
Although the institutional standard now is to provide payment via Greenphire clincard, the population for this 
study are patients in a residential treatment center for substance use disorder. Compensation for participation 
in the study is given in the form of Target gift cards as alcohol or tobacco cannot be purchased at Target and 
Greenphire clincards could be used at vendors that sell alcohol and tobacco. As such, the study team has 
received an exception from the controller’s office to continue using gift cards (approved 08/08/2020).
15.0 Economic Burden to Subjects
15.1
Costs 
Not applicable. Participants will not be responsible for any costs related to participation in the research. 
15.2
Compensation for research-related injury
Not applicable. There are no plans for HMC/PSU to provide financial compensation or free medical 
treatment for any research-related injury.
16.0 Resources Available
16.1
Facilities and locations
Recruitment and study procedures will be performed at the Caron Foundation, a treatment facility in 
Wernersville, PA. 
16.2
Feasibility of recruiting the required number of subjects
Based on our previous studies at the same treatment center, we were able to recruit 80 patients with 
opiate dependence within 19 months, resulting in an average of 4 patients per month. We had similar 
results for our alcohol study.  
We will be recruiting from all units at Caron. 
OUD: During a recent census, there were 31 patients on the Men’s Primary Care Unit, 9 patients on the 
Women’s Primary Care Unit, 3 on the Young Adult Female Unit, 13 on the Young Adult Men’s Unit, 3 on 
the Grand View Manner Unit, and 13 on the Health Care Professionals Unit that had a primary diagnosis 
of OUD (not including Heroin). Ten (10) patients had a diagnosis of OUD only (9 Male, 1 Female); the 
remaining patients had a history of at least one other co-morbid SUD (e.g., cannabis, alcohol, cocaine) 
(47 Male, 14 Female). The men ranged in age from 18-69; the women from 18-59. Duration of Opioid 
use ranged from several months to 30+ years. Throughout April-June 2017, the Caron Treatment Center 
admitted (in those selected units) 71 patients with a diagnosis of OUD (approximately 23 
patients/month).
AUD: During the most recent census, there were 63 patients on the Men’s Primary Care Unit, 33 
patients on the Women’s Primary Care Unit, 6 on the Young Adult Female Unit, 24 on the Young Adult 
Men’s Unit, 19 on the Grand View Manner Unit, and 11 on the Health Care Professionals Unit that had a 
primary diagnosis of AUD. A total of 74 patients had a diagnosis of AUD only (46 Male, 28 Female); the 
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remaining patients had a history of at least one other co-morbid SUD (e.g., cannabis, opiates, cocaine). 
The men ranged in age from 19-68; the women from 21-61. Duration of alcohol use ranged from several 
months to 30+ years. Throughout April-June 2016, the Caron Treatment Center admitted (in those 
selected units) 156 patients with a diagnosis of AUD (approximately 52 patients/month).
Not all patients will qualify or consent to be in the study. Our goal is to finish recruitment within a 1-year 
time period. 
16.3
PI Time devoted to conducting the research
The PI will be able to devote 50% of time to conducting and completing the research, considering 
outside responsibilities. 
16.4
Availability of medical or psychological resources
Medical and/or psychological resources will be primarily available at the Caron Foundation through their 
counselors and medical staff. However, the PI, Scott Bunce is a fully trained and licensed psychologist, 
will also be available for consultation with participants should any participant request one; and, will be 
on-call 24/7 if there are any complaints, questions, or concerns about the research, in regards to the 
study medication. 
16.5
Process for informing Study Team
The research team will be given specific duties to conduct the research study. The study coordinators 
will be provided with training to conduct the screening process (obtain informed consent, and to 
oversee patient self-reports on the M.I.N.I 7.0.2, HAM-D, Form 90AI or DI, PSQI and ISI), and instruct 
participants on how to use the actigraphs, cortisol tubes and smart phones that are used to collect the 
EMA data. Staff members and nurses at Caron will be instructed on medication distribution and abuse 
liability procedures. 
17.0 Other Approvals
17.1
Other Approvals from External Entities
The Caron Foundation has granted approval to use their facility to conduct research.
17.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens in 
a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or gene 
therapy). 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
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- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.  
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
18.0 Multi-Site Research
18.1
Communication Plans
Not applicable. 
19.0 Adverse Event Reporting
19.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
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threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
19.2
Recording of Adverse Events
Subjects will be routinely questioned about adverse events from nursing staff at Caron during each 
nightly administration (all 9 nights of the study). Information will also be collected through the modified 
abuse liability assessment where patients will be given the Drug Effect questionnaire, administered 30 
minutes after drug administration, and the next morning, to be used to evaluate how strong a drug 
effect was felt on a 5-item response scale, ranging from No Drug Effect to Very Strong Effect. This 
assessment will be administered in the evening of Study Night 1, as well as the morning of Study Day 2. 
Nursing staff will also complete an observer-rated questionnaire 30 minutes after drug administration 
on Study Night 1 and 7. 
All adverse events should be reported immediately and will be addressed by the physician and other 
staff at Caron. The staff at Caron will then complete a Suvorexant Adverse Reaction Documentation 
form. All forms will be sent to and reviewed by the PI on our study team, Dr. Scott Bunce. In the event of 
a serious or life threatening adverse reaction, Caron medical staff will be immediately informed and 
address the situation.  Dr. Scott Bunce will be contacted within 12 hours. Subjects are also encouraged 
to call the PI (with the assistance of the staff at Caron), Dr. Scott Bunce at 215- 510- 8295 (cell) if they 
have questions, complaints or concerns about the research or believe they may have been harmed by 
being in the research study.  
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study drug(s) or device(s) will be followed until the event (or its 
sequela) or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator.
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met:

The test finding is accompanied by clinical symptoms
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
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; 
including significant additional concomitant drug treatment or other therapy
NOTE: Simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event.

The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study

The test finding is considered an adverse event by the investigator.
19.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
19.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
19.4.1 Written IND/IDE Safety Reports
Not applicable. 
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
Not applicable. 
19.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
19.6
Unblinding Procedures
Not applicable. 
19.7
Stopping Rules
In the event of an adverse reaction, the participant will consult with the nursing and doctoral staff at Caron to 
determine if they should continue with study. If deemed appropriate, participants will be removed from the 
study. If this event occurs, or the patient refuses to continue with the study, they will consult their doctors, and 
the medication will be properly destroyed, as described in section 7.4.6.4.
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20.0 Study Monitoring, Auditing and Inspecting
20.1
Study Monitoring Plan
20.1.1 Quality Assurance and Quality Control
The study will be monitored by Clinical Trial Monitoring Team from the Department of Public 
Health Sciences at Penn State Hershey College of Medicine.
 
Staff within the Department of Public Health Sciences will be monitoring the study for protocol 
compliance, data quality, and regulatory compliance. This will include reviewing the informed 
consent process and completed forms, verifying the presence of essential documents in the 
study regulatory binder, completing source document verification for data entered into REDCap, 
ensuring the study is implemented as planned, reviewing adverse events and the reporting of 
serious adverse events, and ensuring that all data quality rules have been executed and resolved 
and all data queries are resolved and closed.
 
The monitor will create a detailed report following each scheduled monitoring session to 
forward to the PI and will verify that proposed action items are addressed and completed.  The 
monitoring will occur at regular intervals as specified in the monitoring plan developed by Public 
Health Sciences and PSU Sponsor Investigator.
20.1.2 Safety Monitoring
The Principal Investigator will confirm that all adverse events (AE) are correctly entered into the 
AE case report forms by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; and will notify the IRB, FDA, sponsor and/or DSMB of all 
applicable AEs as appropriate. All assessments of AEs will be made by the PI, a licensed medical 
professional.
The Research Coordinator will complete the appropriate report form and logs; assist the PI to 
prepare reports and notify the IRB, FDA and/or DSMB of all Unanticipated Problems/SAE’s.
The Monitor will confirm that the AEs are correctly entered into the case report forms. The 
Monitor will also confirm that the adverse events are consistent with the source documents and 
are reported to the appropriate regulatory bodies as required.
Under the direction of Dr. Bixler, in his role as Vice Chair for Research, the research coordinator 
will ensure that all data is collected and analyzed appropriately. 
21.0 Future Undetermined Research: Data and Specimen Banking
Not applicable. 
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2. Smith, RE, Aston-Jones, G. (2012) Orexin/hypocretin 1 receptor antagonist reduces heroin self – 
administration and cue – induced heroin seeking. Eur. J. Neurosci. 35 (5) 798-804
3. Giardino, WJ., deLecea, L. (2014) Hypocretin (orexin) neuromodulation of stress and reward pathways. 
Current Opinion in Neurobiology 29: 103 – 108
4. Koob, G., & Kreek, M. (2007). Stress, dysregulation of drug reward pathways, and the transition to drug 
dependence. American Journal of Psychiatry, 164, 1149–1159.
5. Goldstein, R. Z., & Volkow, N. D. (2011). Dysfunction of the prefrontal cortex in addiction: neuroimaging 
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6. Brower KJ.  (2001) Alcohol’s effects on sleep in alcoholics. Alcohol Research & Health. 25(2):110–25.
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of Sciences, 1248(1), 1-17.
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and abuse potential. Psychopharmacology, 145(1), 39-51.
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Insomnia: diagnosis and treatment. Colchester, UK: Informa Healthcare; p: 397-409
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syndrome: polysomnographic and clinical evaluations. J. Clin. Psychopharmacol. 2003;23:377–383.
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22. Stein, M. D., Kurth, M. E., Sharkey, K. M., Anderson, B. J., Corso, R. P., & Millman, R. P. (2012). 
Trazodone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled 
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23. Cruickshank, C. C., Montebello, M. E., Dyer, K. R., Quigley, A., Blaszczyk, J., Tomkins, S. And Shand, D. (2008). 
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28. James, S. P., & Mendelson, W. B. (2004). The use of trazodone as a hypnotic: a critical review. Journal 
of Clinical Psychiatry, 65(6), 752-755.
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