Use of a GLP-1R Agonist to Treat Opioid Use Disorder
Phase: PHASE1
Conditions: Opiate Substitution Treatment, Opioid-Related Disorders
Sponsor: Milton S. Hershey Medical Center

Document Section Cover Sheet 
 
Official Title: Use of a GLP-1R Agonist to Treat Opioid Use Disorder 
NCT number: NCT04199728 
Document: Study Protocol and Statistical Analysis Plan 
Document date: 11/21/2023 

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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Use of a GLP-1R Agonist to Treat Opioid Use Disorder
Principal Investigator:
Name: Scott Bunce
Department: Department of Psychiatry
Telephone: (215) 510-8295
E-mail Address: sbunce@pennstatehealth.psu.edu
Version Date:
10 May 2023
Clinicaltrials.gov Registration #:
NCT04199728
Investigator-Sponsored Study Proposal
Universal Trial Number (UTN): U111-1236-2694
Co-Investigators
Amy Arnold, PhD1; Timothy Brick, PhD2; Hobart Cleveland, III, PhD2; Erin Deneke, PhD3; Jessica Fournier, MD3; Patricia 
Grigson-Kennedy, PhD1; Lan Kong, PhD1; Douglas Leslie, PhD1; Jennifer Nyland, PhD1; Nazia Raja-Khan, MD1; Adam Scioli, 
MD3 
1Penn State Milton S Hershey Medical Center, Hershey, PA
2Penn State University, University Park, PA; 
3Caron Treatment Centers, Wernersville, PA 
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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
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
The long-term objective of this study is to determine whether a glucagon-like peptide-1 receptor (GLP-
1R) agonist, liraglutide (brand name is Saxenda®), can improve clinical outcomes in patients with opioid 
use disorder (OUD). We propose to study the efficacy and safety of liraglutide treatment and its effects 
on craving in OUD patients within a randomized, placebo controlled, double-blinded, parallel arm clinical 
pilot study with two objectives:
1)
To evaluate the efficacy of liraglutide (vs placebo), administered daily, in reducing craving for 
opioids in humans in residential treatment for an OUD. Well-validated measures of craving, 
including visual cue-elicited craving, and ecological momentary assessment (daily smartphone 
assessments) will be used to assess craving. Based on our preclinical studies, we hypothesize that 
liraglutide will decrease craving among patients in treatment for OUD. 
2)
To evaluate the safety of liraglutide, administered daily, in humans seeking treatment for OUD. 
We will measure how liraglutide changes respiratory rate, blood pressure, and heart rate as well 
as blood concentrations of glucose, hemoglobin A1c (HbA1c), and fructosamine, over the course 
of a 18-day titration (3-dose intervention) or 30-day titration (5-dose intervention) to full 
treatment dosage. 
1.2
Primary Study Endpoints
The primary objectives of this pilot study are 1) to determine whether liraglutide can reduce cue-elicited 
drug craving over 3-5 weeks while participants are in residential treatment for OUD, and 2) to study 
whether liraglutide can reduce ambient (daily) drug craving over approximately 21-33 days while 
participants are in residential treatment for OUD.  
1)
Cue-elicited Drug Craving. Change in self-reported cue-elicited drug craving from baseline (Day 1) to 
the end of the target drug dose (Day 19 [and additionally until Day 31 for 5-dose intervention]) will 
be measured on a 0-100 point visual analog scale (VAS), where 0= no craving, 100= maximum 
craving. Assessments are taken prior to, and immediately after, exposure to visual drug cues in the 
Cue Response Task.
2)
Ambient Drug Craving. Change in ambient drug craving over time will be measured throughout the 
study (Days 1-21 [and additionally until Day 33 for 5-dose intervention]) using a 0-100 VAS delivered 
via smartphone using Ecological Momentary Assessment (EMA) 4 times per day, on each test day 
(Days 1 and 19 [and additionally Day 31 for the 5-dose intervention]) and on the first two days and 
last 2 days of each treatment dose.
1.3
Secondary Study Endpoints
The secondary objective of this pilot study is to evaluate the safety of daily administration of liraglutide 
in humans seeking treatment for an OUD.
1)
Cardiorespiratory Function 
a.
Blood Pressure. Change in blood pressure from baseline (Day 1) to: i) the beginning of each 
study drug dose (Days 2, 8, 14, 20, 26); ii) end of the target drug dose (Day 19 [Day 31 for 5-
dose intervention]); and iii) rebound follow-up (Day 21 [Day 33 for 5-dose intervention]). 
b.
Heart Rate. Change in heart rate from baseline (Day 1) to: i) the beginning of each study 
drug dose (Days 2, 8, 14, 20, 26); ii) end of the target drug dose (Day 19, [Day 31 for 5-dose 
intervention]); and iii) rebound follow-up (Day 21 [Day 33 for 5-dose intervention]). 
c.
Respiration. Change in respiratory from baseline (Day 1) to: i) the beginning of each study 
drug dose (Days 2, 8, 14, 20, 26); ii) end of the target drug dose (Day 19 [Day 31 for 5-dose 
intervention]); and iii) rebound follow-up (Day 21 [Day 33 for 5-dose intervention]).
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2)
Body Weight (kg). Absolute and percent change in body weight from baseline through the end of 
rebound follow-up (Daily, from Days 1 to 21 [Days 1-33 for 5-dose intervention]). 
3)
Glycemic Control. Glycemic control will be monitored by fasting blood samples for fructosamine and 
A1c. Fasting blood sample measurements change slowly overtime (i.e., across weeks and months) 
and therefore will be evaluated only on Days 2 and 19 [and additionally Day 31 for 5-dose 
intervention] via venipuncture. 
4)
Adverse Events. Frequency of adverse events (AE) and serious adverse events (SAE) deemed related 
to treatment throughout the study period (Days 1-21 [1-33 for 5-dose intervention]), and at 30 days 
post-intervention (Day 49 [Day 61 for 5-dose intervention]).
1.4
Exploratory Endpoints
1)
Prefrontal Cortical Response to Drug Cues. Change in blood oxygenation level response to visual 
opioid drug cues in prefrontal cortex from baseline (Day 1) to end of the target drug dose (Day 19 
[additionally Day 31 for 5-dose intervention]) using Functional Near Infrared Spectroscopy (fNIRs).
2)
Rebound Ambient Drug Craving. Change in ambient drug craving as measured by 0-100 VAS 
delivered via smartphone using the EMA on test days and on the first two days and last 2 days of 
each treatment dose from end of rebound follow up (Day 21 [Day 33 for 5-dose intervention]) to 
baseline (Day 1) and to end of the target drug dose (Day 19 [Day 31 for 5-dose intervention]).
3)
Rebound Blood Pressure. Change in blood pressure from end of the target drug dose (Day 19 [Day 
31 for 5-dose intervention]) to rebound follow up (Day 21 [Day 33 for 5-dose intervention]).
4)
Rebound Heart Rate. Change in heart rate from end of the target drug dose (Day 19 [Day 31 for 5-
dose intervention]) to rebound follow up (Day 21 [Day 33 for 5-dose intervention]).
5)
Rebound Respiration. Change in respiratory from end of the target drug dose (Day 19 [Day 31 for 5-
dose intervention]) to rebound follow up (Day 21 [Day 33 for 5-dose intervention]).
6)
Long-term Glycemic Control. Change in HbA1c and fructosamine levels from Day 2 to end of the 
target drug dose (Day 19 [Day 31 for 5-dose intervention]).
2.0
Background 
2.1
Scientific Background and Gaps
An estimated 5.6 percent of the global population used illicit drugs in 2016, with 34 million using 
opioids; worldwide in 2015, 450,000 people died as a result of drug use, with opioids accounting for 76 
percent of deaths in those with drug use disorders [1]. In the United States, in 2017, approximately 51.8 
million people aged 12 or older used an illicit drug or abused any psychotherapeutic medication. Of 
those, 11.4 million used an opioid such as heroin or misused prescription pain relievers [2]. According to 
the Centers for Disease Control and Prevention, between July 2016 and September 2017 there was a 
30% increase in the number of emergency room visit for opioid overdose [3]. There were 70,237 drug 
overdose deaths reported in the United States in 2017, and of these, 67.8%, or 47,600, involved opioids 
[4], costing the nation an estimated $51.2 billion annually [5], or $504.0 billion (2.8% Gross Domestic 
Product) when including non-fatal impacts [6].
Glucagon-Like Peptide-1 (GLP-1) and Substance Use Disorder. A great deal of attention has focused on 
the reward pathway and the view that drugs of abuse hijack natural reward substrates [7, 8]. Drug-
seeking animals and humans, however, are driven by a need state not unlike that of water, food, or salt  
[9]. GLP-1 is a hormone produced by L cells in the small intestine that reduces intake of food, in part, by 
increasing insulin release, decreasing glucagon release, and decreasing gastric emptying [10], producing 
a ‘satiety’ effect. GLP-1 is also produced by cells in the nucleus of the solitary tract (NST), and these cells 
project widely throughout the brain including to reward and feeding circuitry [11, 12]. Treatment with 
GLP-1 receptor (GLP-1R) agonists inhibits ingestion of palatable sweets, water when thirsty, and salt 
when sodium deficient [11, 13-19]. As such, treatment with this ‘satiety’ signal, GLP-1, was predicted to 
reduce drug seeking and taking in humans, as well as rats. 
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In preclinical studies, treatment with the GLP-1R agonist, Exendin-4 (Ex-4), has been shown to reduce a 
conditioned place preference for, and the accumbens dopamine response to, nicotine, cocaine, and 
amphetamine, and reduces cocaine self-administration in rats [15, 16, 20, 21]. Likewise, treatment with 
Ex-4, in a dose that does not affect responding for sucrose, decreases fixed and progressive ratio 
responding for cocaine [18] and, when administered centrally, cocaine-induced reinstatement [22]. 
Finally, the use of a GLP-1R agonist increases insulin secretion, while inhibiting glucagon, only in 
response to increases in glucose levels [23, 24].  As such, this treatment can potentially be used in 
patients with OUD without diabetes without the risk of hypoglycemia. Substantial evidence from 
randomized controlled trials indicate that the use of a GLP-1R agonist can produce significant, sustained 
weight loss in obese but non-diabetic people without causing any adverse effects on circulating glucose 
blood pressure, HbA1c or their lipid profile [25-27],  suggesting it could be used safely in OUD patients. 
GLP-1R agonists, then, are promising for the treatment of substance use disorder (SUD) in humans. 
Further, the intervention can be readily translated for a new indication, as various formulations of GLP-
1R agonists are approved for treatment of obesity and Type 2 Diabetes Mellitus (T2DM) in humans [21, 
28] and already are in clinical trials for nicotine and alcohol use disorders [29-34].  
2.2
Previous Data
GLP-1 and OUD. No studies to date have tested 
whether a GLP-1R agonist can reduce responding 
for opioids in humans. We have shown that 
administration of Ex-4 (2.4 µg/kg ip) during 
abstinence and prior to test (i) in rats with a 
history of heroin self-administration decreased 
cue-induced heroin-seeking (Figure 1, left) and (ii) 
abolished drug-induced reinstatement of heroin-
seeking (Figure 1, right). In a second preliminary 
study, we tested the longer acting GLP-1R 
agonist, liraglutide [0.1 mg/kg subcutaneous, 
(sc)]. The half-life for liraglutide in rats is about 
4 h [35]. Our results showed that daily 
liraglutide treatment beginning on the 11th day 
of heroin self-administration and continuing 
through abstinence: (i) reduced heroin self-administration (Figure 2, left), (ii) failed to reduce seeking 
during extinction (Figure 2, middle), possibly due to a slower onset of the longer acting liraglutide 
(liraglutide was injected 1 h before extinction testing), and (iii) significantly reduced heroin-induced 
reinstatement of heroin seeking behavior (liraglutide was administered 6 h prior to the reinstatement 
Figure 1: Mean (+/- SEM) number of infusion attempts/h during 
cued extinction testing (Left) and heroin-induced reinstatement 
testing (Right) in rats with a history saline or heroin self-
administration and pretreated sc with saline (Veh) or 2.4 ug/kg 
Exendin-4 (Ex-4).
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test, Figure 2, right). Taken together, these data provide strong support that GLP-1R agonists hold 
promise as a novel intervention for OUD. 
GLP-1R agonist treatment 
in humans.  GLP-1R 
agonists have been studied 
for decades and are, as 
mentioned, an approved 
and effective treatment 
for obesity and (T2DM) in 
humans [27, 36, 37]. In 
131 patients with T2DM, 
treatment with GLP-1R 
agonists led to significant 
improvement in glycated 
hemoglobin (HbA1c) and 
BMI [38]. Likewise, GLP-1R 
agonists in patients with 
T2DM led to controlled 
blood glucose, along with positive effects on body weight, blood pressure, and cholesterol [10]. 
Furthermore, neuroimaging studies have shown that GLP-1R agonists reduce brain responses to food 
cues in obese and T2DM participants, but not in lean participants. Specifically, Van Bloemendaal et al. 
[39] demonstrated that the GLP-1R agonist exenatide (relative to placebo) decreased functional 
magnetic resonance imaging (fMRI) measures of brain activation in the amygdala, insula, putamen, and, 
importantly, orbitofrontal cortex (OFC) in response to a series of food related cues (i.e., food vs non-
food pictures) in subjects with obesity and T2DM. This effect was not observed in lean control subjects. 
The most common side effects of GLP-1R treatment are nausea and diarrhea; less common is injection-
site bruising or “reactions” (i.e. erythema, pruritus, and rash) [36]. One meta-analysis found evidence of 
a slight increase in heart rate, a modest reduction in blood pressure, and no association with 
hypertension across 60 trials employing 14 different GLP-1R formulations [40]. Further work reported 
decreased cardiovascular risk [41] and a reduction in major adverse cardiac events including nonfatal 
stroke, nonfatal myocardial infarction, and cardiovascular mortality [42] in T2DM patients treated with 
GLP-1R agonists compared with placebo.
All GLP-1R agonists are not the same with regard to treatment of obesity or T2DM. Ex-4 (exenatide) is a 
short acting GLP-1R agonist with a half-life of 2.4 h in humans [43]. Liraglutide has a longer half-life of 
about 13 h in humans [44] and, as such, has been found useful as a once/day sc injectable formulation 
for the treatment of obesity [27, 45] and T2DM [46, 47]. A meta-analysis determined no cause for 
concern regarding neuropsychiatric safety associated with liraglutide [48]. 
Although liraglutide was approved for human use in 2010, there are no data testing the effectiveness in 
patients with an OUD. The objective of the proposed research is to test whether treatment with a GLP-
1R agonist can reduce craving in humans with OUD. Here, we will conduct a pilot study to determine 
whether once daily treatment with liraglutide can safely and effectively reduce craving in patients in a 
residential treatment facility for OUD, and who are either receiving counseling (CO) or counseling plus a 
common medication assisted treatment (MAT), buprenorphine/ naloxone (BUP/NA). We chose 
liraglutide for this initial pilot study as dosing can be closely monitored due to its 13 h half-life and can 
be safely ramped up to an effective dose during a 4-6 week residential treatment program. 
This is an innovative project that will, for the first time, test the safety and efficacy of GLP-1R agonist 
treatment on opioid craving. Further, because single timepoint self-report measures of craving have not 
been found to be strong predictors of relapse behavior [49], we will assess craving using an array of 
verbal, emotional, physiological, and neural indices. Emotional and physiological feedback will be 
Figure 2: Mean (+/- SEM) number of infusions/6h in rats self-administering saline or 0.06 mg/inf 
heroin iv and treated with saline or liraglutide (0.1 mg/kg sc) (Left). Mean (+/- SEM) number of 
infusion attempts/h during cue-induced extinction (Middle) and heroin-induced reinstatement testing 
in rats with a history saline or heroin self-administration and pretreated with saline or liraglutide (1.0 
mg/kg sc) (Right).
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obtained using both EMA and a wearable device (i.e., a wristband). This will allow us to track not only 
changes in mood and craving across the day, but also changes in craving that may be elicited by the 
subcutaneous injection of the GLP-1R agonist or vehicle. 
2.3
Study Rationale
The rationale for the proposed research is to develop an acute intervention that can improve treatment 
outcomes in OUD by reducing craving, a primary factor contributing to early relapse. Although 
liraglutide was approved for human use in 2010, there are no data testing the effectiveness in patients 
with an OUD. The objective of the proposed research is to test whether treatment with a GLP-1R agonist 
can reduce craving in humans with OUD. Understanding how a ‘satiety’ agent may affect craving and 
brain responses to drug cues in an OUD population would provide entirely novel information. If 
liraglutide shows a trend towards efficacy, and safety of the GLP-1R agonist is demonstrated in this 
population, it would provide an indication to run the second phase, multi-center clinical trial of GLP-1R 
agonist in OUD patients. 
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria at 
screening:
1.
Age 18 to 75 years
2.
Diagnosed with an OUD seeking treatment at Caron Treatment Centers (CaronTC) and planning 
on being enrolled in a residential treatment plan for a minimum of 4 weeks
3.
Women of childbearing potential must consent to use a medically accepted method of birth 
control or to abstain from sexual intercourse while in the study
4.
Able and willing to provide informed consent prior to any study-related activities
5.
Must be able to read and communicate in English sufficiently to complete all study 
requirements, including EMA 
3.2
Exclusion Criteria
Patients will be excluded from study entry if any of the following exclusion criteria exist at screening:
1.
Age < 18 or > 75 years 
2.
Women who are pregnant, planning pregnancy, breastfeeding, or unwilling to use adequate 
contraceptive measures
3.
History of angioedema, serious hypersensitivity reaction, or anaphylactic reaction to liraglutide 
or another glucagon-like peptide-1 receptor (GLP1R) agonist
4.
Personal or family history of medullary thyroid carcinoma (MTC) or patients with multiple 
endocrine neoplasia syndrome type 2 (MEN 2) or thyroid nodule
5.
Type I diabetes or history of diabetic ketoacidosis
6.
Type II diabetes mellitus
7.
Hypoglycemia on intake visit (blood glucose < 70 mg/dL)
8.
End-stated renal failure on dialysis or glomerular filtration rate (GFR) <30mL/min per 1.73 
square meters or previous renal transplant
9.
Severe hepatic impairment (AST or ALT levels > 3 times upper limit of normal range) or previous 
liver transplant
10. Current or past diagnosis of pancreatitis, gastroparesis, or other severe gastrointestinal disease
11. Current or past diagnosis of gallbladder disease or gallstones
12. Serious cardiovascular disease within the past 6 months (e.g. uncontrolled hypertension, heart 
failure, significant cardiac arrhythmias, myocardial infarction, presence of angina pectoris, 
symptomatic coronary artery disease, deep vein thrombosis, pulmonary embolism, second- or 
third-degree heart block, mitral valve or aortic stenosis, hypertrophic cardiomyopathy, stroke)
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13. Severe co-occurring psychiatric disorder (e.g., bipolar disorder, psychotic disorder, 
schizophrenia) that would, in the opinion of the Principle Investigator or study physician, 
interfere with participating in the study, such as if the patient needs a higher or different level of 
care and is going to be transferred out of Caron. 
14. Suicidal ideation within the past 1 month, or history of suicide attempts within the past 1 year, 
unless participation is cleared by clinician assessment and/or judgement.
15. Treatment with any investigational drug in the one-month preceding the study
16. Previous randomization for participation in this trial
17. Abnormal physical exam findings, vital signs (blood pressure, heart rate, respiratory rate, body 
temperature), EKG measurements, and safety lab values that are deemed clinically significant by 
study physician
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Blood pressure, heart rate, and respiratory rate will be measured on Days 1, 2, 8, 14, 19, and 21. On 
each day, each measure will be recorded 3-4 times and then averaged. Participants will be withdrawn if 
they experience an average daily value for any measure on Day 1, 2, 8, 14, or 19: 

Systolic blood pressure (SBP) changes >40 mmHg, or SBP <90 mmHg or >200 mmHg, or 
clinical symptoms of hypertension (e.g. headache, dizziness, blurred vision, nausea 
edema) or hypotension (e.g. dizziness, nausea, fainting) develop 

Heart rate reaches levels <40 beats/min or >120 beats/min

Respiratory rate changes by >5 breaths/minute or reaches levels <10 breaths/minute or 
>24 breaths/minute
The investigators will also exercise discretion to end an individual’s study participation if 
they should engage in behavior that could jeopardize their own health and well-being or 
that of others
Participants who develop any new conditions described in the exclusion criteria during the 
treatment phase of clinical trial will be removed from the study
3.3.2
Follow-up for withdrawn subjects
Subjects will be withdrawn from the study if the study participant withdraws consent for any 
reason. The primary reason for the subjects’ withdrawal from the study will be recorded. 
Subjects who withdraw from the study may be replaced.
Subjects withdrawn due to pregnancy, adverse events (AEs), a medical emergency, or 
unwillingness or inability to comply with the protocol, will undergo an End of Study telephone 
call (30 days after the end of study treatment) unless the withdrawal is due to death or the 
withdrawal of consent. 
3.3.3
Discontinuation of medication 
Participants who decide to discontinue study medication, but who do not withdraw their 
consent, will be withdrawn from the study, and will cease study tasks, although their existing 
data will be kept in the data set.  These participants may be replaced.
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4.0
Recruitment Methods
4.1
Identification of subjects
Patients who plan to remain in residential treatment for a minimum of 4 weeks at CaronTC will be 
identified. Patient records will be evaluated by Caron-based study staff against the study inclusion and 
exclusion criteria.
4.2
Recruitment process
4.2.1
How potential subjects will be recruited.
All eligible patients will be approached and recruited in the same manner following the study 
protocol procedures. Only IRB-approved study team members (Physicians or staff) at CaronTC 
will first interact with the patient in a consultation session. During the initial consultation 
session, the physician/staff will briefly explain the proposed study and ask the patient if they 
would be interested in discussing further with a research study member. If the patient is 
interested, a trained research study team member will discuss the full study including any risks 
and benefits associated with participation.
4.2.2
Where potential subjects will be recruited.
Potential subjects will be recruited on the Professionals Unit at CaronTC. Subjects may also be 
drawn from other units at the CaronTC if there is a planned stay of a minimum of 4 weeks. 
4.2.3
When potential subjects will be recruited.
Potential subjects will be recruited prior to any study procedures taking place.
4.2.4
Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility. In some studies, these procedures may not take place unless HIPAA Authorization is 
obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures is 
approved by the IRB. 
Screening of subjects at admission is expected prior to obtaining consent to confirm that they 
have an established diagnosis of OUD.
Once informed consent is obtained, patients will undergo additional screening to determine if 
they are eligible to participate in the study based on the inclusion/exclusion criteria
5.0
Consent Process and Documentation 
5.1
Consent Process:
Check all applicable boxes below:
 Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
 Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6] 
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 Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
5.2
Obtaining Informed Consent 
5.2.1
Timing and Location of Consent 
An IRB-approved study team member will meet with the subject in a quiet private area. After 
careful and complete explanation of the study details, risks, and other options are provided to 
the subject, and a copy of the consent form will be provided to them for review. If they are 
interested in consenting to this study, they will be given additional time to ask questions. When 
all questions have be answered to their satisfaction by a study team member, the subject will be 
asked to sign the informed consent document.
5.2.2
Coercion or Undue Influence during Consent 
During the initial consultation session, the IRB-approved physician/staff member will briefly 
explain the proposed study and ask the patient if they would be interested in discussing further 
with a research study member. If the patient is interested, a trained research study team 
member will discuss the full study including any risks and benefits associated with participation. 
To ensure the consent process provides the patient with clear, accurate information, research 
staff involved in the consent process will undergo training to promote effective conversations as 
well as training on study-specific details.
Study team members will stress that participation is completely voluntary. Additionally, it will be 
carefully and clearly explained that if they should decide not to participate in this study, that 
decision will have no impact on the care the patient will receive.
Due to a conflict of interest by Dr. Bunce, informed consent for the study will be obtained by a 
non-conflicted, IRB-approved co-investigator or study coordinator, but he may be involved in 
the explanation of the protocol and its risks and benefits, answering patient questions, and in 
assuring that subjects meet the study entry criteria.
.
5.3
Waiver of Written Documentation of Consent 
Not applicable
5.3.1
Indicate which of the following conditions applies to this research:
  The research presents no more that minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. 
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group 
or community in which signing forms is not the norm, that the research presents no more 
than minimal risk of harm to subjects and provided there is an appropriate alternative 
mechanism for documenting that informed consent was obtained.  
Describe the alternative mechanism for documenting that informed consent was obtained:
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5.3.2
Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception).
Not applicable
5.4.1
Indicate the elements of informed consent to be omitted or altered
5.4.2
Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements
5.4.3
Describe why the research involves no more than minimal risk to subjects.
5.4.4
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
5.4.5
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
5.4.6
Debriefing 
5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
Not applicable
5.5.1
Indicate why the research could not practicably be carried out without the waiver of consent
5.5.2
Describe why the research involves no more than minimal risk to subjects.
5.5.3
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
5.5.4
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
5.5.5
Additional pertinent information after participation
5.6
Consent – Other Considerations 
5.6.1
Non-English-Speaking Subjects
Not applicable
5.6.2
Cognitively Impaired Adults
Not applicable
5.6.2.1 Capability of Providing Consent
5.6.2.2 Adults Unable to Consent
5.6.2.3 Assent of Adults Unable to Consent
5.6.3.1 Parental Permission
5.6.3.2 Assent of subjects who are not yet adults
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]
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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.
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
Minimal screening activities prior to consent may include accessing patient 
charts to confirm eligibility. No identifiers will be retained for any patient 
who does not meet eligibility requirements to participate in the study.
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.
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7.0
Study Design and Procedures
7.1
Study Design
Double-blinded, randomized, placebo-controlled pilot study to evaluate the effects of the GLP-1R 
agonist liraglutide treatment on drug craving in patients initiating residential treatment for OUD. In 
addition, the safety and feasibility of using GLP-1R agonist treatment in residential OUD patients will be 
established.
Study enrollment will not delay administration of standard of OUD therapies, such as behavioral 
treatments and/or buprenorphine/naloxone. 
All participants, at the time of consent, will be enrolled in the 3-dose study procedure which takes 21 
days to complete. As the vast majority of Caron patients remain in treatment for 28 days, the 3-dose 
procedure allows for the largest recruitment pool possible and provides a common procedure that all 
participants will complete. By Day 18 of the 3-dose procedure, participants will be asked whether they 
are able to, and willing to, continue the study for an additional 12 days (past Day 21) and receive 2 
additional doses of the treatment medication (now considered the 5-dose study procedure). It is 
expected that not all participants will be willing or able to extend their study participation; additionally 
participants may either know their expected length of stay early (i.e., at admission to residential 
treatment) or not until close to completion of treatment. The decision to transition into the 5-dose 
procedure will be based on the participant’s availability (i.e., whether the stay in treatment at Caron will 
be longer than the average 28 days) and on the participant’s choice to extend their length of study 
participation.
7.2
Study Procedures

Physical and Psychological Screening Procedures: The screening will include:
o
12-lead electrocardiogram (EKG)
o
Urine pregnancy test if female with childbearing potential
o
Psychiatric assessment including: the M.I.N.I International Neuropsychiatric 
Interview (M.I.N.I. 7.0.2), Form 90-Drug Inventory (Form 90-DI), Hamilton 
Depression scale (HAM-D), State-Trait Anxiety Inventory (STAI-Y1), and Columbia 
Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be administrated by appropriately trained personnel. All C-SSRS 
scores will be reported to the Caron Treatment Center Medical Director of Research 
and the Director of Research. At risk participants will be immediately reported to 
the Directors of Research. Any participant that reports recent suicidal ideation or 
behavior on the screening C-SSRS will be referred for further immediate evaluation 
by a clinician. Clinical judgement and additional consult with the Caron Medical 
Director, study PI, and/or study staff will be used to further clarify if the subject is 
eligible to continue in the study. Participants not at risk will be reported weekly.
The Directors will refer the clinical decision to the psychology and medical team. If 
the patient is deemed to be suicidal, and is willing to get help, the psychology staff 
will utilize their typical protocol and resources to find placement in a local 
psychiatric facility (e.g., Philhaven, Lancaster Behavioral Health). The patient may be 
transported via ambulance or via Caron transportation (depending on how safe staff 
feels it is to transfer) to the facility for admission. In the case that the participant is 
uncooperative, Service Access and Management, Inc. (SAM) will be notified to assist 
with emergency planning. Any participant who develops active suicidal ideation with 
some intent to act with or without a specific plan will be discontinued from study 
treatment.
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
Body Weight: Body weight will be measured daily throughout the study (Days 1-21 [Days 1-
33 for 5-dose intervention]). 

Blood glucose: 
o
Blood samples to assess changes in more long-term indices of glycemic control, such 
as hemoglobin A1c (HbA1c) and fructosamine, will be collected prior to the first dose 
of study drug (Day 2) and at the end of the target dose (Day 19 [and additionally at 
Day 31 for 5-dose intervention]). Samples will be analyzed by Caron’s clinical 
laboratory.

Cardiorespiratory Function: Recordings will be collected using a portable cardiovascular 
autonomic cart at CaronTC. The data will be recorded via a data acquisition system 
(PowerLab, ADInstruments). After instrumentation, participants will rest for 10 minutes, 
followed by 15 minutes of continuous recordings of cardiorespiratory parameters. 
o
Blood pressure, heart rate, and respiratory rate will be measured at baseline (Day 
1), during study drug administration (Days 2, 8, 14, 19, 20, 26, and 31), and at the 
end of rebound follow-up (Day 21 [Day 33 for 5-dose intervention]). At each of 
these time points, participants will be placed in the supine position. 

Blood pressure will be measured continuously using the finger volume 
clamp method (NOVA Finapres Medical Systems or similar) and 
intermittently by an oscillometric brachial artery cuff (Philips SureSigns VS3 
or similar). 

A 3-lead EKG will be used to continuously measure heart rate (Cardiocap/5 
GE Healthcare or similar). 

Respiratory rate will be measured using a pneumography belt, and oxygen 
saturation by pulse oximeter applied to the finger (BCI 3301 or similar). 

Cue-elicited drug craving will be evaluated. This will be evaluated using Visual Analog Scales 
(VAS) on Day 1 and Day 19 [and additionally at Day 31 for 5-dose intervention].
o
Cue-elicited craving will be measured on a 0-100 point VAS, where 0= no craving, 
100 = maximum craving. Assessments will be taken prior to, and immediately after, 
exposure to visual drug cues in the Cue Response Task.

Ecological Momentary Assessment (EMA): EMA data will be collected throughout the study 
(Days 1-21 [Days 1-33 for 5-dose intervention]) 4 times per day via smartphones for the first 
3 days (Days 1-3) and then on a rotating “4-days on, 2-days off” schedule starting Day 6. 
Data to be collected include: Ambient Drug Craving; Positive and Negative Mood; 
Pain/Discomfort; and Sleep on 0-100 point VAS. 
The smartphones that will be used for EMA data collection will have an app (the Wear-IT 
app) that will be put on the study smartphone provided to the participant while they are in 
the study. This smartphone will have a security application installed that prevents user 
access to all other applications that are not associated with data collection. Smartphones 
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 for upload to a 
secure server, Virtual COLO, at University Park in State College. Participants will need to plug 
the phone in to charge each night.

Physiological Wearables: A “wearable” wristband will be worn throughout the study (Days 
1-21 [Days 1-33 for 5-dose intervention]) to monitor stress responses, including acute 
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changes that may be associated with the drug delivery via injection. Data collected include 
heart rate, actigraphy for sleep and activity measurement, and stress responses (including 
acute changes in these measures that may be associated with the drug delivery via 
injection). A body temperature compliance sensor will be used to validate that the device is 
being worn. So that participants do not have to charge the actigraphy wristband themselves, 
participants will have up to two actigraphy wristbands assigned to them, and they will be 
charged or, if necessary, swapped out at their check-in sessions. Participants may wear the 
actigraphy wristband while showering or swimming if they wish.

Neurophysiology Lab Day Measures: Participants will be tested at baseline (Day 1) and at 
the end of the target dose (Day 19 [and additionally Day 31 for 5-dose intervention]) for 
cortical activity using Functional Near Infrared Spectroscopy (fNIRS) and VAS during:
o
Visual cue reactivity task to: (a) opioid cues; (b) non-opioid control cues; (c) natural 
reward cues (e.g., pleasant pictures of food, puppies, positive relationships, etc.) 
and (d) emotionally neutral stimuli (e.g., images of household objects) 
o
The VAS measure of craving pre-post visual cue reactivity task
o
Balloon Analogue Risk Task (BART)
fNIRs data files will be placed into the REDCap database, with access to these files provided 
to key investigators at Drexel University for signal processing and return for data analyses. 
These data will be de-identified and will consist only of the unique study id number, raw 
data, stimulus markers, and date/time stamps that have been modified so that they do not 
contain the actual visit date.

Study drug/placebo administration: Participants will be taught self-administration by 
study/nursing staff. 
o
All self-administrations will occur via blinded, multi-dose subcutaneous injection 
pens, and will be observed by nursing staff at CaronTC. 
o
Participants will receive medications daily at a specified time (prior to breakfast) 
throughout the study, starting on Day 2. 
o
Participants will be taught to inject the solutions subcutaneously in the abdomen, 
thigh, or upper arm, and will administer daily injections under the supervision of a 
study nurse or staff member. 
o
Participants will be taught by study staff nurses to attach the needle, check the 
drug/vehicle flow, select the dose, inject the dose, remove the needle, and dispose 
of the needle.
o
Participants will always use a new needle for each dose administration in the study. 

Adverse Events: Adverse events will be monitored continuously throughout the study (Days 
1-21 [Days 1-33 for 5-dose intervention]), and at 30 days post-intervention (Day 49 [Day 61 
for 5-dose intervention]). 
7.2.1
Enrollment and Baseline (Day 1)
Participants will be approached within 2-3 days of beginning residential treatment based on 
initial screening from EMR and enrolled into the study if they consent. 
The following standard of care data will be collected from the EMR for research purposes: 

Demographic information (age, gender, race, contact information)

Detailed medical history

Physical examination

Admission diagnoses
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
Results from standard laboratory safety tests performed on admission (complete blood 
count, comprehensive metabolic panel)

Current medication usage (concomitant medications)

Results of urine pregnancy test at admission (if applicable)
The following research-only activities will be performed prior to randomization:

A psychiatric assessment will be conducted:
o
M.I.N.I. 7.0.2
o
Form 90-DI
o
HAM-D
o
STAI-Y1
o
C-SSRS

Body weight will be measured

12-lead EKG will be performed

Collection of stress response, sleep, and activity measurements will be initiated via 
actigraphy wristband (a “wearable” wristband).
Any participant that reports recent suicidal ideation or behavior on the screening C-SSRS will be
referred for further immediate evaluation by a clinician. Clinical judgement and additional 
consult with the Caron Medical Director, study PI, and/or study staff will be used to further 
clarify if the subject is eligible to continue in the study.
Participant will receive the actigraphy wristband from a study coordinator. The study 
coordinator will instruct the subject on use of the actigraph.
Randomization: After obtaining written consent, subjects who fulfill study criteria will be 
randomized to either the liraglutide or placebo treatment arm of the study using an equal 
allocation ratio (1:1) permuted-block randomization.
The following research-only activities will occur after randomization and will serve as baseline 
values to compare with values obtained after study drug dosing:

Cue-elicited drug craving will be evaluated using VAS.

Neurophysiology measurements using fNIRS and VAS.

Collection of ambient drug craving, mood, and sleep data will be initiated with EMA.

Monitoring of body weight and cardiorespiratory function.

Aes and concomitant medications will be documented.
Collection of blood pressure, heart rate and respiratory rate data will be initiated with 
cardiorespiratory testing performed by study staff. 
Collection of ambient drug craving, mood, and sleep data will be initiated with EMA. Participant 
will use the smartphone containing EMA surveys they received prior to randomization. A study 
coordinator will instruct the subject on use of the phone.
Cue-elicited drug craving will be evaluated by a study coordinator using VAS.
7.2.2
Study Drug Treatment, Dose 1 (Days 2-7)
During this time, the following research-only activities will occur:

Blood samples will be collected on Day 2, prior to study drug administration, for 
monitoring of glycemic control. This will include measurements of HbA1c and 
fructosamine. Approximately 2 teaspoons of blood will be collected.
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
During Days 2-7, liraglutide/placebo control will be administered daily at 0.6 mg before 
breakfast. 

Aes and concomitant medications will be documented. 

Ambient drug craving, mood, and sleep data will be collected on Days 2, 3, 6, and 7 via 
EMA assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.

On Day 2, cardiorespiratory function will be measured as described in Section 7.2. 
Subjects will be taught administration of liraglutide by a Caron nurse on Day 2 during the first 
injection of the lowest dose. Repeated instruction on liraglutide administration may be provided 
on subsequent drug administration days if requested by the participant until they are 
comfortable with the procedure.
7.2.3
Study Drug Treatment, Dose 2 (Days 8-13)
During this time, the following research-only activities will occur:

During Days 8-13, 1.2 mg of liraglutide/placebo control will be administered daily at a 
specified time (prior to breakfast). 

Aes and concomitant medications will be documented.

Ambient drug craving, mood, and sleep data will be collected on Days 8, 9, 12, and 13 
via EMA assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.

On Day 8, cardiorespiratory function will be measured as described in Section 7.2. 
7.2.4
Study Drug Treatment, Dose 3 (Days 14-18)
During this time, the following research-only activities will occur: 

During Days 14-19, 1.8 mg of liraglutide/placebo control will be administered daily at a 
specified time (prior to breakfast). 

Aes and concomitant medications will be documented.

Ambient drug craving, mood, and sleep data will be collected on Days 14, 15, and 18 via 
EMA assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.

On Day 14, cardiorespiratory function will be measured as described in Section 7.2. 
7.2.5
Study Test Day – (Day 19)
The following research-only measures, all completed on Day 1, will be repeated on Day 19, 
regardless of intervention length (i.e., 3-dose and 5-dose interventions). Day 19 will serve as the 
final dose (1.8 mg) day for participants in the 3-dose intervention. For participants in the 5-dose 
intervention, Day 19 will be the final day at the 1.8 mg dose before moving on to the 2.4 mg 
dose on Day 20. 

Cardiorespiratory function will be assessed via measurement of blood pressure, heart 
rate, and respiratory rate as described in Section 7.2.

Blood samples will be collected for safety laboratory tests (CBC, CMP) and for 
monitoring of glycemic control. Approximately 4 teaspoons of blood will be collected.

Body weight data will be collected.
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
Cue-elicited drug craving will be evaluated using VAS.

Neurophysiology measurements will be evaluated using fNIRS during: (1) Visual cue 
reactivity and (2) BART. 

Collection of ambient drug craving, mood, and sleep data by EMA.

Stress response, sleep, and activity measurements will be collected via actigraphy 
wristband.

C-SSRS

Urine pregnancy test (if applicable)

Aes and concomitant medications will be documented.
7.2.6
 Days 20-21
For 3-dose intervention participants: Rebound Evaluation Period
During this time the following research-only measures will occur:

Collection of ambient drug craving, mood, and sleep data by EMA through Day 21, then 
discontinued.

Stress response, sleep, and activity measurements will be collected via actigraphy 
wristband through Day 21, then discontinued.

Aes and concomitant medications will be documented through Day 21.

Body weight data will be collected through Day 21.

On Day 21, cardiorespiratory function will be measured as described in Section 7.2. 
The smartphone and actigraphy wristband will be collected by a study coordinator on Day 22.
For 5-dose intervention participants: Study Drug Treatment, Dose 4
During this time, the following research-only activities will occur: 

During Days 20-21, 2.4 mg of liraglutide/placebo control will be administered daily at a 
specified time (prior to breakfast).

Aes and concomitant medications will be documented.

Ambient drug craving, mood, and sleep data will be collected on Days 20-21 via EMA 
assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.
On Day 20, cardiorespiratory function will be measured as described in Section 7.2.
7.2.7
Study Drug Treatment, Dose 4 (Days 22-25) [5-dose intervention only]
During this time, the following research-only activities will occur: 

During Days 22-25, 2.4 mg of liraglutide/placebo control will be administered daily at a 
specified time (prior to breakfast).

Aes and concomitant medications will be documented.

Ambient drug craving, mood, and sleep data will be collected on Days 24 and 25 via 
EMA assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.
7.2.8
Study Drug Treatment, Dose 5 (Days 26-30) [5-dose intervention only]
During this time, the following research-only activities will occur:

During Days 26-31, 3.0 mg of liraglutide/placebo control will be administered daily at a 
specified time (prior to breakfast).
o
Aes and concomitant medications will be documented.
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
Ambient drug craving, mood, and sleep data will be collected on Days 26, 27, and 30 via 
EMA assessment. 

Stress response, sleep, and activity measurements will be collected daily via actigraphy 
wristband. 

Body weight data will be collected daily.

On Day 26, cardiorespiratory function will be measured as described in Section 7.2.
7.2.9
Study Test Day – (Day 31) [5-dose intervention only]
The following research-only measures, all completed on Day 1 and Day 19, will be repeated on 
Day 31. 

Cardiorespiratory function will be assessed via measurement of blood pressure, heart 
rate, and respiratory rate as described in Section 7.2.

Blood samples will be collected for safety laboratory tests (CBC, CMP) and for 
monitoring of glycemic control. Approximately 4 teaspoons of blood will be collected.

Body weight data will be collected.

Cue-elicited drug craving will be evaluated using VAS.

Neurophysiology measurements will be evaluated using fNIRS during: (1) Visual cue 
reactivity and (2) BART. 

Collection of ambient drug craving, mood, and sleep data by EMA.

Stress response, sleep, and activity measurements will be collected via actigraphy 
wristband.

C-SSRS

Urine pregnancy test (if applicable)

Aes and concomitant medications will be documented.
7.2.10 Rebound Evaluation Period, (Days 32-33) [5-dose intervention only]
During this time the following research-only measures will occur:

Collection of ambient drug craving, mood, and sleep data by EMA through Day 33, then 
discontinued.

Stress response, sleep, and activity measurements will be collected via actigraphy 
wristband through Day 33, then discontinued.

Aes and concomitant medications will be documented through Day 33.

Body weight data will be collected through Day 33.

On Day 33, cardiorespiratory function will be measured as described in Section 7.2. 
The smartphone and actigraphy wristband will be collected by a study coordinator on Day 34.
7.2.11 End of Study telephone call (Day 49 [Day 61 for 5-dose intervention])
All participants will have an End of Study telephone call. This will occur 30 days (+/- 5 days) from 
the discontinuation of medication. Patients will be asked to self-report their body weight at the 
time of the call.
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Schedule of Study Activities: 3-Dose Study Drug Intervention
 
Enrollment/ 
Baseline
 Intervention
Test Day
(Final dose)
Off Drug
Rebound 
Evaluation
Equipment
Return
End of Study 
Telephone Call**
Day 1
Days
2-7
Days
8-13
Days
14-18
Day 19
Day 20
Day 21
Day 22
30 days +/- 5 days end 
of medication
Study Drug/Placebo Dose
 
0.6 mg
1.2 mg
1.8 mg
1.8 mg
-
 
-
 
Informed consent
X
Data collected from Electronic 
Medical Record1 
X
M.I.N.I International 
Neuropsychiatric Interview 
(M.I.N.I. 7.0.2)
X
Form 90-Drug Inventory (Form 
90-DI)
X
Hamilton Depression scale (HAM-
D)
X
State-Trait Anxiety Inventory 
(STAI-Y1)
X
Columbia Suicide Severity Rating 
Scale (C-SSRS)
X
X
Body weight
X
X
X
X
X
X
X
X
12-lead electrocardiogram (EKG)
X
Pregnancy test2
X
X
Cardiorespiratory function 
assessment3
X
X
X
X
X
X
Blood samples for fructosamine 
and A1c
X4
X
Cue-elicited drug craving5
X*
X

Page 21 of 46 (V.01/21/2019) 
 
Enrollment/ 
Baseline
 Intervention
Test Day
(Final dose)
Off Drug
Rebound 
Evaluation
Equipment
Return
End of Study 
Telephone Call**
Day 1
Days
2-7
Days
8-13
Days
14-18
Day 19
Day 20
Day 21
Day 22
30 days +/- 5 days end 
of medication
Study Drug/Placebo Dose
 
0.6 mg
1.2 mg
1.8 mg
1.8 mg
-
 
-
 
Neurophysiology measurements6
X*
X
Safety labs (CBC and CMP)
X
Ambient drug craving, mood, and 
sleep7
X*
X
X
X
X
X
X
Actigraphy wristband (“wearable” 
wristband)8
X
X
X
X
X
X
X
Concomitant medications
X*
X
 X
 X
  X
X
X
Adverse events
X*
X
X
X
X
X
X
X
Return of actigraphy wristband 
and smartphone
X
*Performed AFTER randomization has occurred.
**ALL participants, unless they withdraw consent, will have an end of study telephone call. 
1Demographics, medical history, admission diagnoses, and current medication usage.
2If female with childbearing potential, will collect results from test at admission as data for Day 1, with research-only pregnancy tests at Day 19.
3Performed on Day 1, Day 2, Day 8, Day 14, Day 19, and Day 21.
4Performed on Day 2 only
5Using Visual Analog Scales (VAS).
6Using fNIRS, VAS, and BART.
7Collection of ambient drug craving, mood, and sleep data will be initiated with Ecological Momentary Assessment (EMA). Collected on Days 1-3, 6-9, 12-15, and 18-21.
8Stress response, sleep, and activity measurements.

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Schedule of Study Activities: 5-Dose Study Drug Intervention
 
Enrollment/ 
Baseline
Intervention
Test Day
(Final dose) Off Drug
Rebound 
Evaluation
Equipment
Return
End of Study Telephone 
Call**
Day 1
Days
2-7
Days
8-13
Days
14-18
Day 19
Days
20-25
Days 
26-30
Day 31
Day 32
Day 33
Day 34
30 days +/- 5 days end of 
medication
Study Drug/Placebo Dose
 
0.6 mg
1.2 mg
1.8 mg
1.8 mg
2.4 mg
3.0 mg
3.0 mg
-
 
-
 
Informed consent
X
Data collected from Electronic 
Medical Record1 
X
M.I.N.I International 
Neuropsychiatric Interview 
(M.I.N.I. 7.0.2)
X
Form 90-Drug Inventory (Form 
90-DI)
X
Hamilton Depression scale (HAM-
D)
X
State-Trait Anxiety Inventory 
(STAI-Y1)
X
Columbia Suicide Severity Rating 
Scale (C-SSRS)
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram (EKG)
X
Pregnancy test2
X
X
X
Cardiorespiratory function 
assessment3
X
X
X
X
X
X
X
X
X
Blood samples for fructosamine 
and A1c
X4
X
X
Cue-elicited drug craving5
X*
X
X

Page 23 of 46 (V.01/21/2019) 
 
Enrollment/ 
Baseline
Intervention
Test Day
(Final dose) Off Drug
Rebound 
Evaluation
Equipment
Return
End of Study Telephone 
Call**
Day 1
Days
2-7
Days
8-13
Days
14-18
Day 19
Days
20-25
Days 
26-30
Day 31
Day 32
Day 33
Day 34
30 days +/- 5 days end of 
medication
Study Drug/Placebo Dose
 
0.6 mg
1.2 mg
1.8 mg
1.8 mg
2.4 mg
3.0 mg
3.0 mg
-
 
-
 
Neurophysiology measurements6
X*
X
X
Safety labs (CBC and CMP)
X
X
Ambient drug craving, mood, and 
sleep7
X*
X
X
X
X
X
X
X
X
X
Actigraphy wristband (“wearable” 
wristband)8
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X*
X
X
X
X
X
X
  X
X
X
Adverse events
X*
X
X
X
X
X
X
X
X
X
X
Return of actigraphy wristband 
and smartphone
X
*Performed AFTER randomization has occurred.
**ALL participants, unless they withdraw consent, will have an end of study telephone call. 
1Demographics, medical history, admission diagnoses, and current medication usage.
2If female with childbearing potential, will collect results from test at admission as data for Day 1, with research-only pregnancy tests at Day 19 and Day 31.
3Performed on Day 1, Day 2, Day 8, Day 14, Day 19, Day 20, Day 26, Day 31, and Day 33.
4Performed on Day 2 only
5Using Visual Analog Scales (VAS).
6Using fNIRS, VAS, and BART.
7Collection of ambient drug craving, mood, and sleep data will be initiated with Ecological Momentary Assessment (EMA). Collected on Days 1-3, 6-9, 12-15, 18-21, 24-27, and 
30-33.
8Stress response, sleep, and activity measurements.

Page 24 of 46 (V.01/21/2019) 
7.3
Duration of Participation
The total duration of study participation for each subject will be approximately 49 days (3-dose 
intervention) or 61 days (5-dose intervention).
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Liraglutide (Saxenda®, Novo Nordisk) is a glucagon-like peptide-1 (GLP-1) receptor 
agonist approved by the FDA for the treatment of T2DM (1.8 mg/day) and obesity (3.0 mg/day) 
and has been deemed safe for use in populations with a history of substance use disorder 
(American Association of Clinical Endocrinologists, 2016; see also Saxenda package insert, 
Plainsboro, NJ: Novo Nordisk A/S; 2015).
Liraglutide 6 mg/ml (Novo Nordisk), will be provided as a solution in a pre-filled, multi-dose pen 
that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3 mg of liraglutide as a subcutaneous 
injection.
Liraglutide and placebo will be delivered as a solution (liquid) in identical multidose pens.  In 
order to use Saxenda® as a blinded comparator in the clinical trial, the presentation has been 
modified from the Marketed product. For Saxenda® (Comparator) the primary packaging 
materials are identical to what is approved in the Marketing authorization, except that the 
cartridge for the comparator is produced with an army green closure cap. The closure cap in the 
currently marketed Saxenda® product is a light blue cap. The cap is not in contact with the 
product and has no impact on the stability of the comparator. For Saxenda® (Comparator) the 
pen is identical to what is approved in the Marketing Authorization, except for the color of the 
cartridge holder and the pushbutton, where the Marketed version is purple and the clinical 
comparator is light brown. The pen is not in contact with the product and its color has no impact 
on the stability of the comparator. 
New, unused liraglutide/vehicle pens will be stored according to the information stated on the 
trial product label. Pens will be disposed of after 30 days of initial use.  
7.4.2
Treatment Regimen
The recommended maximum dosage is 3 mg/day, administered any time of day. This choice in 
dosage is based on the current FDA-approved dosing regimen for liraglutide to help patients 
manage craving in obesity. The initial dose will start at 0.6 mg/day for the first 6 days, then 
titrate by 0.6 mg every 6 days – to reduce the likelihood of adverse gastrointestinal symptoms – 
until 1.8 mg/day is reached for the 3-dose intervention and 3 mg/day is reached for the 5-dose 
intervention. Participants will be taught self-administration by study/nursing staff. All self-
administrations will occur via blinded, multi-dose subcutaneous injection pens, and will be 
observed by nursing staff at CaronTC.
Participants will receive medications daily at a specified time (prior to breakfast) throughout the 
study. Participants will be taught to inject the solutions subcutaneously in the abdomen, thigh, 
or upper arm, and will administer daily injections under the supervision of a study nurse or staff 
member. Participants will be taught by study staff nurses to attach the needle, check the 
drug/vehicle flow, select the dose, inject the dose, remove the needle, and dispose of the 
needle. Participants will always use a new needle for each dose administration in the study. 
Dosages will be chosen based on current titration level in the study.
There is no provision to provide study treatment after the study.
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7.4.3
Method for Assigning Subject to Treatment Groups
Participants will receive either liraglutide or placebo in a two-arm parallel group study. 
Interventions will be randomized in a 1:1 ratio using permuted-block randomization algorithm. 
The randomization will be performed using a random number generator via the PLAN procedure 
within SAS software, version 9.4 (SAS Institute Inc., Cary, NC). Personnel in the Department of 
Public Health Sciences (PHS) will use the PLAN procedure within SAS software to generate a 
randomization list using variable-size, random permuted blocks to ensure that the number of 
participants in each arm is balanced after each set of B randomized participants, where B is the 
block size. Personnel in PHS will choose the block sizes without revealing it to any of the 
investigators or study personnel who will be collecting and reviewing outcomes data. The 
randomization sequence will be uploaded to a secure REDCap database. Synergy Pharmacy will 
be given access to this REDCap database to provide the blinded, randomized labeling prior to 
shipping the study drugs to the CaronTC 
7.4.4
Subject Compliance Monitoring
Nursing staff will chart administration of study drug into the patient’s Caron EMR and study 
personnel will monitor and document the completion of all study procedures. Compliance is also 
being assessed through the wearables discussed above (Section 7.2) by a temperature sensor.
7.4.5
Blinding of the Test Article
The study drugs will be blinded to participants and investigators (double blind) through the 
distribution of identical injection pens. Injection pens will be ordered from Novo Nordisk and 
received in boxes by Synergy Pharmacy, an off-site pharmacy that works with the CaronTC. Each 
study drug pack will be sent to Synergy Pharmacy in a box containing a de-identified label for 
blinding purposes. Each box will have a specific Dispensing Unit Number (DUN).  A total list of 
the DUNs (Total DUN list; TDL) will be supplied by Novo Nordisk indicating “liraglutide” or 
“placebo” for each DUNS number. 
Unblinded personnel at Synergy Pharmacy will be available to handle the lists that reveal if the 
blinded product contains liraglutide or placebo. The laboratory staff analyzing the blood samples 
(as opposed to study coordinators) will be unaware of the condition and the treatment of the 
participants for whom they will conduct the assays as the samples will be identified only with a 
study number. The results of the laboratory measurements will not be shared with the treating 
physicians, and will not impact patient care except in an emergent situation.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The study drug (liraglutide or placebo) will be obtained from Synergy 
pharmacy after the subject is enrolled into the study. After enrollment, 
study team members will inform Synergy Pharmacy and will provide the 
information about study subjects required for dispensing the study drug. 
Novo Nordisk will supply the clinical variant of Saxenda® (Comparator) and 
placebo in a pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, 
1.8 mg, 2.4 mg, or 3 mg of liraglutide as a subcutaneous injection. Each 1 ml 
of Saxenda solution contains 6 mg of liraglutide; each pre-filled pen contains 
a 3 ml solution of Saxenda equivalent to 18 mg of liraglutide. 
Upon receipt of study shipments from Synergy, a Caron pharmacy 
technician will inventory/check the shipment using the shipping invoice to 
record lot number, expiration date, breakage, storage condition, and total 
quantities. The shipping invoice will be signed and dated. The shipment will 
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be refrigerated during shipment, and recorded on the study drug 
accountability log. The shipping invoice will be filed in the shipping file and 
the study medication will be placed into appropriate storage conditions. 
7.4.6.2
Storage
The storage of the medication will be at the medical detox unit at the 
CaronTC. In this unit is a locked room (nurses’ clinic) that contains a locked 
refrigerator where the medication will be stored. Therefore, the medication 
will be double locked. Only Caron nurses will have access to the medication. 
The study drugs will be refrigerated at 2°C to 8°C during storage. Caron 
nurses will check and record temperature daily.
7.4.6.3
Preparation and Dispensing
Synergy Pharmacy will prepare and deliver the medication after receiving a 
scanned signed informed consent from Caron. Synergy Pharmacy will use 
the randomization log to prepare the study medications for each 
participant. The study medications will be pre-filled injectable pens that are 
identically labeled for double blinding. Dispensed study medications will be 
labeled with the label from the Synergy Pharmacy’s Computer System, 
conforming to state and federal law. The study’s required labeling will be 
attached to the dispensed product in addition to the pharmacy label. No 
parts of the study’s label will be obliterated by the pharmacy label. All study 
medications will be labeled with the caution, “New Drug- Limited by Federal 
(or United States) law to investigational use.”
The study drug (liraglutide or placebo) will be ordered by the medical staff 
at Caron, stored in the medical unit, and dispensed using the supplied, pre-
filled, multi-dose pens that deliver doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 
or 3 mg of liraglutide as a subcutaneous injection. Study staff will maintain 
medication logs including information on time of administration, batch 
number, and expiration date. Study drugs will not be used after the 
expiration or use-by date. 
Study treatment injection pens (liraglutide or placebo) will look identical. 
The study drug will be obtained from the study nurse and self-administered 
by the participant under the observation of the study staff or study nurse.
7.4.6.4
Return or Destruction of the Test Article
Once the study drug is prepared for the subject, it can only be administered 
to that subject. Final reconciliation of the medication will take place at the 
CaronTC, if appropriate. The CaronTC 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. Patients who do not complete the entire study will have their 
medication destroyed via Caron’s established medication disposal protocols. 
7.4.6.5
Prior and Concomitant Therapy
A concomitant therapy is any medication which is administered between 
study enrollment and the end of the study drug treatment phase. All 
concomitant therapies will be monitored daily and recorded at minimum 
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once weekly by study team members during the duration of the treatment 
phase with the study drug. 
The subjects recruited will be current patients in a residential facility for the 
treatment of opioid dependence. Since the physicians 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.
Precautions: Saxenda is contraindicated with the use of insulin or any other 
GLP-1R agonist; the use of these medications are identified in the exclusion 
criteria. 
Respiration and heart rate will be monitored at baseline and following all 
dosage increases. 
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
This study will enroll 50 opioid use disordered patients in residential treatment.
8.2
Sample size determination
This is an exploratory study to accumulate pilot data. The primary endpoint of this study is cue-elicited 
self-reported craving VAS scores. A sample size of N=20 per group will give 80% power to detect an 
effect size of 0.91 based on a two-sided two-sample t-test with a significance level of alpha=0.05. 
Accounting for an estimated 20% attrition rate, we plan to randomize a total of 20*2/0.8=50 patients in 
the study. To preserve statistical power, the sample will not be balanced with regard to MAT and non-
MAT participants. 
8.3
Statistical methods
The primary aim is to test whether liraglutide reduces craving in patients recovering from OUD in 
residential treatment. Analysis of covariance (ANCOVA) will be used to compare liraglutide versus 
placebo treatment groups controlling for baseline values of craving. Linear mixed effects models for 
repeated measurements will also be used to evaluate the difference in changes in these primary 
outcomes between treatment groups. The baseline and post-treatment outcomes are treated as 
dependent variables in the mixed model. Subjects with missing values can be incorporated in the mixed 
model analysis when data are missing at random. The moderating effect will be assessed by adding the 
interaction term between moderator and treatment group in the models.
SAS (version 9.4) and R (version 3.2.5) software will be used for analyses with a significance level of 0.05. 
Summary statistics including means, medians, ranges, and standard deviations will be computed for 
each continuous variable and frequencies with percentages for categorical variables. Identified data 
outliers will be further examined to determine if they are data entry errors, in which case they will be 
modified when possible; otherwise, values will be kept for final analysis. 
Primary outcomes to assess efficacy are: (1) cue-elicited drug craving rated on a 100-pt VAS; and (2) 
ambient drug craving, derived from EMA of daily craving throughout the study period. Data analyses for 
cue-elicited craving will consist of a 2 x 2 ANOVA with medication status (pre- vs post-medication) as a 
within-group variable and medication type (liraglutide vs placebo) as a between-group variable. 
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Secondary analyses of self-reported craving measures will evaluate the role of MAT, specifically BUP/NA, 
in these results. 
EMA and Wearable Assessment: Ambient drug craving derived from the EMA will be analyzed as a 
multilevel model in the regression framework and will test effects of medication status within-person 
and medication type between-person. Secondary analyses of EMA will examine the effect of time (e.g. 
study day) to identify differences across condition in the rate of decline in craving across time.  
Data reduction including derivation of summary features for continuously collected data (e.g., sleep 
data, physiological data) will be performed before formal statistical analysis. Descriptive analysis will be 
performed to explore distributions of data and identify potential outliers. Assumptions and goodness of 
fit of statistical models will be assessed. Missing data, including mobile and ambulatory attrition and 
drop-out will be examined to ensure the validity of statistical models used.  Because ambulatory and 
mobile monitoring will continue during laboratory assessment days, correlation analyses will be used to 
confirm the agreement between corresponding measures from the two approaches; this will both speed 
harmonization for follow-up analyses, and provide additional validation of the measures used in the 
both cases.
The primary endpoints of the EMA assessment will be the rate of reduction of craving across the 
approximately 21 day study period in the treatment condition compared to the control condition while 
controlling for the traditional craving triggers of sleep, stress, hunger, affect, and pain and discomfort. 
Sleep and activity will be measured using a multimodal approach with self-report via the morning EMA 
survey and wearable actigraphy to measure and account for subjective biases in sleep timing. Craving 
reduction will be primarily measured using EMA assessment, and will be modeled using linear mixed 
models in the multilevel modeling (MLM) framework. In MLM, subject-specific random effects are 
combined with population-level fixed effects to account for variability both within each individual and 
between individuals in a manner that allows participants with incomplete data to be included in the 
model. Craving reduction will be modeled as an effect of time in treatment, and differences in rate of 
craving reduction will be tested as an interaction between treatment state and time. Drs. Brick, 
Cleveland, and Kong each have extensive experience analyzing similar data in the multilevel modeling 
framework.
For secondary safety outcomes, intensive longitudinal methods such as time-varying effect models will 
be used to assess for changes in continuously measured outcomes (e.g. blood pressure, heart rate, 
respiratory rate, body weight) to account for repeated measures. The proportion of participants 
experiencing AE and SAE will be compared between treatments using chi-square analysis. 
For exploratory outcomes, analysis of fNIRs-based neuroimaging will utilize a 2 (Medication Status) x 2 
(Medication Type) ANOVA to evaluate the change in oxygenation in prefrontal cortex in response to 
opioid drug cues vs neutral cues, with a region of interest in left middle frontal gyrus. Analysis of safety 
outcomes from baseline to the end of target dose and to end of rebound follow-up will be analyzed 
using intensive longitudinal methods similar to the analysis of secondary outcomes. Changes in indices 
of glycemic control measured at baseline and at end of the target dose (e.g. HgA1c, fructosamine) will 
be calculated as deltas, with comparisons made between treatments using unpaired t-tests or Mann 
Whitney U tests as appropriate. 
Interim Power Analysis: one or more interim power analyses may be conducted during the study to 
assess the effect size needed to observe a significant drug effect for primary, secondary, and/or 
exploratory endpoints based on the data collected at that time. These analyses would not bias type 1 
error rates and the study team will use this information to determine whether and when to perform an 
interim data analysis to justify advancement to the second phase of the funding award (UH phase).  In 
particular, the confidence intervals around the parameters representing the primary endpoint will be 
used as an approximation of the power available for our primary endpoints using the current data.  This 
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will be weighed against the original proposed power and the PI’s estimates of likely power after 
completion of the grant period to determine whether an interim analysis is warranted.
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
To monitor safety throughout the course of the study, every effort will be made to remain alert to 
possible Aes/SAEs. If an AE/SAE occurs, the first concern should be for the safety of the subject; 
CaronTC’s medical staff is available 24/7 and will be immediately alerted in the event of a SAE. If 
necessary, appropriate medical intervention will be provided. At the signing of the written consent form, 
each subject will have been given the names and telephone numbers of study site staff for reporting 
Aes/SAEs and medical emergencies.
In this study, any AE/SAE experienced by the subject between the time of first dose of study treatment 
and 24 hours after the last dose will be recorded on the case report form, regardless of the severity of 
the event or its relationship to study treatment. During study treatment, the research team will assess 
the subject for Aes and will record any new Aes/SAEs or updates to previously reported Aes on the 
electronic case report form.
9.2
Data that are reviewed
Data collected as primary outcomes, secondary outcomes, exploratory outcomes, and safety profile for 
the study will be reviewed. Primary outcomes include cue-elicited drug craving and ambient drug 
craving. Secondary outcomes include blood pressure, heart rate, respiration, body weight, and AE. 
Exploratory outcomes include prefrontal cortical response to drug cues, markers of long-term glycemic 
control and rebound in ambient drug craving, blood pressure, heart rate, and respiration.
9.3
Method of collection of safety information
Safety information will be collected in the REDCap research database throughout the study. The safety 
of the study drug will be evaluated by clinical assessments and laboratory tests.
9.4
Frequency of data collection
Primary outcome data for cue-elicited drug craving will be collected on the day before drug treatment 
(Day 1) and Day 19 (additionally Day 31for the 5-dose intervention). Ambient drug craving data will be 
collected on test days and on the first two days and last 2 days of each treatment dose (Days 1-21 [Days 
1-33 for 5-dose intervention]). Secondary outcome data for the physical/psychological screening will be 
collected on Day 1. Cardiorespiratory function data will be collected periodically throughout the study 
(Days 1, 2, 8, 14, 19, 21 [5-dose intervention: 1, 2, 8, 14, 20, 26, 31, 33]). HbA1c and fructosamine 
monitoring (blood draw) data will be collected on Days 2 and 19 [additionally Day 31 for 5-dose 
intervention]. See also table of study events, section 7.2.
9.5
Individuals reviewing the data
The DSMB will be responsible for safeguarding the interests of participants in this trial. This 
responsibility will be exercised by providing recommendations for continuation or early termination of 
the trial, based on assessment of safety. The DSMB may also formulate recommendations related to the 
selection, recruitment or retention of participants, their management and adherence to protocol-
specified interventions, and the procedures for data management and quality control. The DSMB will be 
advisory to the PI, to the medical monitor (Dr. Jessica Fournier), and to their co-investigators. The PI will 
be responsible for promptly reviewing and implementing DSMB recommendations.
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The DSMB will consist of at least 3 independent experts who have no conflicts of interest. Members of 
the DSMB will include Dr. Urs Leuenberger, a cardiologist and clinician scientist with expertise in 
mechanisms of neurocirculatory control, broad clinical experience and a track record of clinical research, 
translational research, human studies and clinical trials at Penn State University; Dr. Ayesha Siddiqui, a 
board-certified physician in internal medicine and endocrinology, currently practicing at the Penn State 
Health Cocoa Outpatient Center; and Dr. Tonya King, a professor in biostatistics in the Public Health 
Sciences department at the Penn State College of Medicine that has served on many DSMBs for the NIH- 
or industry-sponsored clinical trials. Representation from the Office of Patient Oriented Research 
(OPOR) also will participate. The approval of the DSMB will be required for any significant changes in 
protocol recommended by the clinical Project PI, on consultation with Study Physicians, during the 
course of the study.
The DSMB membership will be restricted to individuals who have no apparent financial, scientific or 
regulatory conflicts of interest. DSMB members are expected to declare any other potential conflicts of 
interest so that other members can judge whether any such conflicts might affect objectivity. Members 
who develop significant conflicts of interest during the course of the trial are expected to resign from 
the DSMB. DSMB members are otherwise expected to continue their participation until the trial is 
closed. If necessary, the PI will appoint replacements for any DSMB members who resign, subject to 
concurrence of the remaining DSMB members.
9.6
Frequency of review of cumulative data
Safety is constantly monitored during the study and any concerns are brought to the attention of the PI 
immediately. Summary data will be provided at least once per month to the medical monitor to review 
recruitment and enrollment, protocol adherence, data quality, and Aes. The Aes will be documented and 
reported appropriately according to the Human Subjects Protection Office (HSPO) policies and 
procedures.
The DSMB will meet every 6 months with the PI, or more often if needed. In preparation for these 
meetings, the PI will provide information by email regarding enrollment, protocol adherence, and data 
quality. The DSMB will also assess safety data including common and serious AE. In the case of an 
unanticipated or serious AE, the DSMB will be notified within 24 hours of the PI’s notification of the 
event. The PI will provide the DSMB with a list of non-serious AE during regularly scheduled meetings.
9.7
Statistical tests
For details, see the statistical section under 8.3.
9.8
Suspension of research
After periodic evaluation of study result and safety profile, the PI can terminate the research anytime 
based on outcomes of periodic safety monitoring and benefit/risk outcomes and would be assessed with 
the IRB and DSMB.
10.0
Risks
The following risks are associated with the GLP-1R agonist liraglutide during study treatment 
Potential risks associated with the study drug: There is a potential risk of experiencing side effects from the 
investigational drug. Common side effects of liraglutide include: nausea, diarrhea, vomiting, and decreased 
appetite. These side effects dissipate over time and are minimized with appropriate dose titration. Other 
potential side effects, though expected to be rare, include: hypoglycemia, constipation, headache, dyspepsia, 
fatigue, dizziness, abdominal pain, increased lipase, and vaso-vagal response if there is a history of vaso-vagal 
response. Serious side effects include: risk of thyroid c-cell tumors, acute pancreatitis, acute gallbladder disease, 
risk of hypoglycemia with concomitant use of anti-diabetic therapy, heart rate increase, renal impairment, and 
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suicidal behavior and thoughts. There is also potential risk of irritation at the injection site, and increased drug 
craving in response to needle use.
An allergic reaction to liraglutide can include hives; fast heartbeat, dizziness, trouble breathing or swallowing, 
and swelling of face, lips, tongue, or throat. There is also potential risk of irritation at the injection site, and 
increased drug craving in response to needle use. The side effects of acute withdrawal from liraglutide include 
nausea and vomiting. With a half-life of 13 hours, liraglutide should be completely eliminated in 65 hours, within 
the 4-day rebound follow-up observation period. Since liraglutide has not been previously used in patients with 
OUD, it is considered an investigational drug. Since this drug has not been previously given in OUD, there may be 
risks that are not known at this time.
Overdose of the study drug, according to the literature, is limited to severe nausea and vomiting and occasional 
abdominal pain and diarrhea. None of the reported cases resulted in hypoglycemia.
Hypoglycemia signs and symptoms
•
Feeling shaky
•
Being nervous or anxious
•
Sweating, chills and clamminess
•
Irritability or impatience
•
Confusion
•
Fast heartbeat
•
Feeling lightheaded or dizzy
•
Hunger
•
Nausea
•
Color draining from the skin (pallor)
•
Feeling Sleepy
•
Feeling weak or having no energy
•
Blurred/impaired vision
•
Tingling or numbness in the lips, tongue, or cheeks
•
Headaches
•
Coordination problems, clumsiness
•
Difficulty concentrating
•
Slurred speech
•
Nightmares or crying out during sleep
•
Seizures
•
Loss of consciousness
 
Blood Pressure and Heart Rate: Frequent blood pressure measurements with the cuff around the arm or finger 
may be inconvenient and may produce some discomfort and occasional bruising of the upper arm. There is a 
minimal risk of skin irritation from the EKG patches.
 
Blood Sampling: There are minor risks and discomforts associated with blood sampling. We will draw blood 
from the antecubital veins which may cause a brief period of pain and possibly a small bruise at the site. 
Occasionally, a person feels faint when their blood is drawn. There is a small risk of bleeding after removal of the 
needle, which can be prevented by tight compression. Rarely, an infection develops which can be treated. 
Rarely, a clot could form. It is possible that exposure to needles during blood sampling may serve as a trigger for 
opioid use for some participants.
 
Pregnancy: This treatment may hurt an unborn child. Subjects will be advised to use approved birth control such 
as birth control pills, birth control shots, IUD, diaphragm, or condoms while in this study. Subjects will be 
instructed to inform us if they become pregnant or father a child while in this study. Women able to become 
pregnant will have a urine test to make sure they are not pregnant before receiving treatment in this study and 
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at Day 19 [an additional pregnancy test will be given at Day 31 for the 5-dose intervention]. They will be 
encouraged to use birth control or refrain from intercourse throughout the study. Study drug will be 
discontinued in case of pregnancy.
 
Potential risks associated with exposure to drug-related cues: There is a risk of relapse to those in recovery 
when they are exposed to drug cues in the cue reactivity task. Participants may experience an increase in craving 
in response to opioid-related images.  
 
Risks related to exposure to fNIRs: There are no known discomforts or risks associated with the brain imaging 
study. Risks of fNIRs were previously found to be minimal. FDA approval has been granted for research purposes 
for the technology that is used in this specific device (FDA 510(K) Numbers K011320; K042501). In this fNIRs 
Devices system: 1) No voltage in excess of 12.2 volts is available; 2) The sensor pads can be washed, disinfected 
and autoclaved; 3) The safety of fNIRs for use on brain tissue can be demonstrated by comparing the risks 
associated with experimental exposure to everyday risks. The instrument used in the current research employs 
light emitting diodes (LEDs) to generate the near infrared light for measuring changes in hemoglobin. LEDs are 
electronic devices that are illuminated when electricity is passed through them. LEDs use a semiconductor diode 
that emits light when charged. There currently exists no specific safety regulations applied to LEDs, although 
they fall within the Class I standards for safety. In other words, the risks associated with spending 20-30 minutes 
in a protocol utilizing fNIRs are less than the risks associated with spending an equivalent amount of time in the 
sunlight in the US without a hat. In summary, exposing the brain to the infrared light generated by these LEDs 
poses no greater risk than spending an equivalent amount of time (about 1 hour) exposed to sunlight.  There is 
minimal risk of headache from the use of sensors.
 
Actigraphy/Wearables: 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 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.
Other risks
There is a risk that blood tests will reveal that patients are positive for hepatitis or HIV. These infections are 
required by law to be reported to the Pennsylvania Department of Health.
There is a risk of loss of confidentiality if a patient’s information or identity is obtained by someone other than 
the investigators, but precautions will be taken to prevent this from happening. The confidentiality of the 
patients’ electronic data will be maintained as required by applicable law and to the degree permitted by the 
technology used. Absolute confidentiality cannot be guaranteed.
There is a risk from randomization as patients will be assigned to a treatment program by chance. The treatment 
a patient receives may prove to be less effective or to have more side effects than the other research treatment 
or other available treatments.
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
It is unclear whether liraglutide treatment will lead to any benefits in study subjects as no data are 
currently available. However, possible benefits the subject may experience from this research study 
include the possible reduction of opioid craving, which might improve their day-to-day function, and/or 
reduce near-term relapse to opioid abuse.
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11.2
Potential Benefits to Others
The potential benefit to society and others includes increasing knowledge regarding the effects of 
liraglutide on clinical outcomes and its effect on the stress-immune response in acute hyperglycemic 
patients. New knowledge gained from this study could give way to novel treatments to help OUD 
recovery for a high-risk population.
12.0
Sharing Results with Subjects
Any clinically relevant study results (including, but not limited to, EKG and blood tests) will be shared with 
subjects and their treating physicians. No other study results of an individual subject’s result will be shared with 
subjects or any treating physician.
13.0
Subject Payment and/or Travel Reimbursements
Participants will be reimbursement for their time in the amount of $25 for the initial evaluation, $50 for the first 
test day (Day 1, when fNIRs tasks and Cued response assessments are performed), $50 for the 3-5 weeks 
(approximately 21-33 days) of EMA and physiological measures, $75 for the second test day (Day 19) and $50 for 
the third test day (Day 31) [5-dose intervention only]; when fNIRs tasks and Cued response assessments are 
performed), $20 for the rebound follow-up, and $30 for the follow-up phone call, for a total of $250 ($300 for 5-
dose intervention). Payments will be titrated relative to the tasks accomplished. Reimbursements will be paid 
using Target gift cards because neither alcohol nor tobacco products can be purchased at Target.
14.0
Economic Burden to Subjects
14.1
Costs
There will be no added costs to the participants enrolled in this study. Any research-only laboratory tests 
and data collection procedures completed will be paid for by the research study.
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
15.0
Resources Available 
15.1
Facilities and locations
All recruitment and study procedures will be performed at the CaronTC, a treatment facility in 
Wernersville, PA. 
15.2
Feasibility of recruiting the required number of subjects
We have previously conducted three successful studies (two involving prescription opioids) at the 
CaronTC [50-55]. The professionals unit has 12 beds, and has typically had 30%-40% of those beds filled 
with patients with OUD. In addition, a recent census at CaronTC indicates a total of about 30 patients 
with OUD per month could be available for recruitment into the study from other units, which should be 
more than adequate to recruit the required sample size.
15.3
PI Time devoted to conducting the research
The PI has allocated sufficient time to work closely with the study team members. There will be regular 
meetings with study co-investigators to allow ongoing discussions, interim analyses and to address any 
operational issues.
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15.4
Availability of medical or psychological resources
The CaronTC’s Medical staff is available on a 24/7 basis.
15.5
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, and instruct participants on how to use 
the equipment required for the study (actigraphs, smartphones). Staff members and nurses at Caron will 
be instructed on medication distribution and administration procedures. The PI and/or study 
coordinator will communicate updates to all team members as they become aware of any changes or 
updates.
16.0
Other Approvals
16.1
Other Approvals from External Entities
National Institute of Health (completed and approved)
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 – Human Tissue For Research Form” in CATS IRB. 
  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 – Penn State Health 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 – Human Body Fluids for Research Form” in CATS IRB. 
  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 – Penn State Health 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” in CATS IRB. 
  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 – Penn State Health 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 
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the Clinical Research Center Advisory committee.  NOTE: Review by the Penn State Health Cancer 
Institute (PSCI) Protocol Review Committee or the PSCI Disease Team 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.
17.0
Multi-Site Study
17.1
Other sites 
Not applicable
17.2
Communication Plans
17.3
Data Submission and Security Plan
17.4
Subject Enrollment
17.5
Reporting of Adverse Events and New Information
17.6
Audit and Monitoring Plans
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
An Adverse Reaction is an adverse event for which the causal relationship 
between the drug and the adverse event is suspected.
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, 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-
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. Suspicion of transmission of infectious 
agents must always be considered a serious adverse event.
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 
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, not listed as per the reference 
safety information (Prescribing information), or elsewhere in the current IND 
application; or is not listed at the specificity or severity that has been 
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suspected adverse 
reaction.  
previously observed and/or specified. For the assessment of expectedness, a 
current version of the Prescribing information, or any updates thereof, would 
be used.
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.
18.2
Recording of Adverse Events
All Aes (serious or non-serious) and abnormal test findings observed or reported to study team which 
are believed to be associated with the study drug will be followed until the event (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator.
Pregnancy: Pregnancy complications will be recorded as AE. Outcome of the pregnancy will be followed 
up. If the infant has a congenital anomaly/birth defect this must be reported and followed up as an SAE. 
Any pregnancy occurring during the trial period will be reported to the IRB, NIDA, and Novo Nordisk 
within the same timelines described for reporting of AE.
18.3
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.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
18.4.1 Written IND/IDE Safety Reports
Not applicable
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
Not applicable
18.5
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) possibly or probably related to the research procedures. Harms (adverse events) 
will be submitted to the IRB in accordance with the IRB policies and procedures.
In the event of an SAE or life-threatening adverse reaction, Caron medical staff will be immediately 
informed and address the situation. Dr. Bunce and the medical monitor will be contacted within 12 
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hours. SAEs will be reported to the DSMB within 24 hours, and to the IRB within 10 days, of the PI’s 
notification of the event. The need to suspend or modify the study procedures will be assessed with the 
IRB and DSMB. All non-serious Aes will be summarized and included in regular reports to the IRB and 
DSMB.
Reporting Adverse Reactions and Unanticipated Problems to NIDA 
SAEs will be systematically evaluated at each clinic visit. Any SAE, whether or not related to study 
medication, will be reported to NIDA. SAEs that are “unexpected” and “possibly or probably related” to 
the research procedures will be reported to the IRB. The clinical PI, Dr. Bunce, will report any SAEs to 
NIDA within 72 hours of first becoming aware of the event. The initial SAE report will be followed by 
submission of a completed SAE report to NIDA. All SAEs will be followed until satisfactory resolution or 
until the site investigator deems the event to be chronic or the participant is stable. 
Reporting of IRB actions to NIDA
Any actions recommended by the IRB will be reported to NIDA within 5 calendar days of the PI’s 
notification.  
Report of Changes or Amendments to the Protocol 
Planned changes to the study will be reported and must receive approval from the Penn State IRB and 
NIDA prior to implementing these changes, except where necessary to eliminate apparent immediate 
hazards to the participants. In the case of changes implemented to eliminate immediate hazards to the 
participants, the emergency protocol changes will be reported to the IRB using a Reportable New 
Information submission. Electronic copies of all documents submitted to the IRB and NIDA will be 
maintained in the records. All research will continue to be conducted without inclusion of the 
modification until IRB and NIDA approval have been received.  
Novo Nordisk safety reporting
The safety reporting requirement from Novo Nordisk states that, at minimum, all serious adverse 
reactions (SARs) and pregnancies occurring during the use of a Novo Nordisk product must be reported 
to Novo Nordisk. In addition to SARs, any other events that have been submitted to the health 
authorities according to local regulatory requirement must also be reported to Novo Nordisk at the time 
of submission to health authorities at the latest. 
18.6
Unblinding Procedures
In case of a medical emergency, when the knowledge of the subject’s treatment assignment may 
influence the subject’s clinical care, the treating physician may contact Synergy Pharmacy to access the 
subject’s treatment assignment. The research team members will document the reasons for unblinding 
in the subject’s source documentation. Study team members will not share the information with 
personnel involved with the analysis and conduct of the study.
18.7
Stopping Rules
Blood pressure, heart rate, and respiratory rate will be measured on Days 1, 2, 8, 14, 19, and 21. On 
each day, each measure will be recorded 3-4 times and then averaged. Participants will be withdrawn if 
they experience an average daily value for any measure on Day 1, 2, 8, 14, or 19:

Systolic blood pressure (SBP) changes >40 mmHg, or <90 mmHg or >200 mmHg, or clinical 
symptoms of hypertension (e.g. headache, dizziness, blurred vision, nausea edema) or 
hypotension (e.g. dizziness, nausea, fainting) develop 

Heart rate reaches levels <40 beats/min or >120 beats/min

Respiratory rate changes by >5 breaths/minute or reaches levels <10 breaths/minute or >24 
breaths/minute
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The medical monitor will be alerted and immediate medical assistance will be sought from the 
medical staff at Caron if participants experience any of these events, or more serious AEs. The 
investigators will also exercise discretion to end an individual’s study participation if they should 
engage in behavior that could jeopardize their own health and well-being or that of others.
Participants who develop any new conditions described in the exclusion criteria during the 
treatment phase of clinical trial will be removed from the study.
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 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.
19.1.2 Safety Monitoring
The PI will confirm that all 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 and/or DSMB of all applicable AEs as appropriate. All AE assessments 
will be made by the PI AND one of the following: Dr A Scioli (physician and study team member), 
the medical monitor, or Dr N Raja-Khan (physician and study team member).
The Research Coordinator will complete the appropriate report form and logs; assist the PI to 
prepare reports and notify the IRB 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.
20.0
Future Undetermined Research: Data and Specimen Banking
Not applicable
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20.1
Data and/or specimens being stored
20.2
Location of storage
20.3
Duration of storage
20.4
Access to data and/or specimens
20.5
Procedures to release data or specimens
20.6
Process for returning results
21.0
References
1.
United Nations Office on Drugs and Crime, World Drug Report 2018. 2018: ISBN: 978-92-1-148304-8, eISBN: 
978-92-1-045058-4,United Nations publication, Sales No. E.18.XI.9.
2.
Center for Behavioral Health Statistics and Quality, 2017 National Survey on Drug Use and Health: Detailed 
Tables., Substance Abuse and Mental Health Services Administration, Editor. 2018: Rockville, MD.
3.
Centers for Disease Control and Prevention. Opioid Overdoses Treated in Emergency Departments. Vital 
Signs 2018 [8/5/18]; Available from: https://www.cdc.gov/vitalsigns/opioid-
overdoses/infographic.html#graphic2.
4.
Centers for Disease Control and Prevention. Drug Overdose Deaths. 2018 December 2018 3/19/19]; 
Available from: https://www.cdc.gov/drugoverdose/data/statedeaths.html.
5.
Jiang, R., et al., The societal cost of heroin use disorder in the United States. PLoS One, 2017. 12(5): p. 
e0177323.
6.
The Council of Economic Advisors. The Underestimated Cost of the Opioid Crisis. 2017  [cited 2018 5/25/18]; 
Available from: https://www.whitehouse.gov/sites/whitehouse.gov/files/images/
The%20Underestimated%20Cost%20of%20the%20Opioid%20Crisis.pdf.
7.
Koob, G.F. and F.E. Bloom, Cellular and molecular mechanisms of drug dependence. Science, 1988. 
242(4879): p. 715-23.
8.
Bejerot, N., [Addiction as an artificially induced instinct. A theory]. Nordisk medicine, 1971. 85(1): p. 20-7.
9.
Grigson, P.S., Reward Comparison: The Achilles' heel and hope for addiction. Drug Discov Today Dis Models, 
2008. 5(4): p. 227-233.
10. Prasad-Reddy, L. and D. Isaacs, A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes 
and beyond. Drugs in context, 2015. 4: p. 212283.
11. Alhadeff, A.L., L.E. Rupprecht, and M.R. Hayes, GLP-1 neurons in the nucleus of the solitary tract project 
directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology, 
2012. 153(2): p. 647-58.
12. Merchenthaler, I., M. Lane, and P. Shughrue, Distribution of pre-pro-glucagon and glucagon-like peptide-1 
receptor messenger RNAs in the rat central nervous system. The Journal of comparative neurology, 1999. 
403(2): p. 261-80.
13. Lopez-Ferreras, L., et al., Lateral hypothalamic GLP-1 receptors are critical for the control of food 
reinforcement, ingestive behavior and body weight. Molecular psychiatry, 2018. 23(5): p. 1157-1168.
14. Turton, M.D., et al., A role for glucagon-like peptide-1 in the central regulation of feeding. Nature, 1996. 
379(6560): p. 69-72.
15. Egecioglu, E., J.A. Engel, and E. Jerlhag, The glucagon-like peptide 1 analogue, exendin-4, attenuates the 
rewarding properties of psychostimulant drugs in mice. PLoS One, 2013. 8(7): p. e69010.
16. Sorensen, G., et al., The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-
administration in mice. Physiology & Behavior, 2015. 149: p. 262-8.
17. Reddy, I.A., et al., Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine 
homeostasis in the lateral septum by decreasing arachidonic acid levels. Translational psychiatry, 2016. 6: p. 
e809.
18. Schmidt, H.D., et al., Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases 
the Reinforcing Efficacy of Cocaine. Neuropsychopharmacology : official publication of the American College 
of Neuropsychopharmacology, 2016. 41(7): p. 1917-28.
19. McKay, N.J. and D. Daniels, Glucagon-like peptide-1 receptor agonist administration suppresses both water 
and saline intake in rats. Journal of neuroendocrinology, 2013. 25(10): p. 929-38.
20. Graham, D.L., et al., GLP-1 analog attenuates cocaine reward. Molecular psychiatry, 2013. 18(9): p. 961-2.
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Page 40 of 46 (V.01/21/2019) 
21. Egecioglu, E., J.A. Engel, and E. Jerlhag, The glucagon-like peptide 1 analogue Exendin-4 attenuates the 
nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well 
as the expression of locomotor sensitization in mice. PLoS One, 2013. 8(10): p. e77284.
22. Hernandez, N.S., et al., Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates 
cocaine seeking in rats. Neuropsychopharmacology : official publication of the American College of 
Neuropsychopharmacology, 2018. 43(10): p. 2000-2008.
23. Baggio, L.L. and D.J. Drucker, Biology of Incretins: GLP-1 and GIP. Gastroenterology, 2007. 132(6): p. 2131-
2157.
24. Nauck, M.A., et al., Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 
amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia, 1993. 36(8): p. 741-4.
25. Astrup, A., et al., Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-
controlled study. The Lancet, 2009. 374(9701): p. 1606-1616.
26. Rosenstock, J., et al., Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance 
in Obese Subjects With and Without Pre-Diabetes. Diabetes Care, 2010. 33(6): p. 1173-1175.
27. Wadden, T.A., et al., Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-
induced weight loss: the SCALE Maintenance randomized study. International journal of obesity, 2013. 
37(11): p. 1443-51.
28. Blonde, L., J. Rosenstock, and C. Triplitt, What are incretins, and how will they influence the management of 
type 2 diabetes? Journal of managed care pharmacy : JMCP, 2006. 12(7 Suppl A): p. S2-12; quiz S14-6.
29. Fink-Jensen, A., Does treatment with GLP-1 reduce alcohol intake in patients with alcohol depence? (EXALT) 
in NCT03232112. 2017, National Institutes of Health: U.S. National Library of Medicine: ClinicalTrials.gov.
30. Boston Medical Center, The effects of exenatide, a GLP-1agonist, on alcohol self-administration in heavy 
drinkers, in NCT03645408. 2018, National Institutes of Health: U.S. National Library of Medicine: 
ClinicalTrials.gov.
31. Imperial College of London, Gut hormones in obesity, nicotine and alcohol dependence (GHADD), in 
NCT02690987. 2015, National Institutes of Health: U.S. National Library of Medicine: ClinicalTrials.gov.
32. Ashare, R., Daily liraglutide for nicotine dependence (DAL), in NCT03712098. 2018, National Institutes of 
Health: U.S. National Library of Medicine: ClinicalTrials.gov.
33. University Hospital, B., Switzerland, Smoking cessation facilitated by glucagon-like peptide-1 (GLP-1) 
Analogues (SKIP), in NCT03204396. 2017, National Institutes of Health: U.S. National Library of Medicine: 
ClinicalTrials.gov.
34. The University of Texas Health Science Center, H., Exenatide once weekly for smoking cessation, in 
NCT02975297. 2016, National Institutes of Health: U.S. National Library of Medicine: ClinicalTrials.gov.
35. Dong, S., et al., Determination of liraglutide in rat plasma by a selective liquid chromatography-tandem mass 
spectrometry method: Application to a pharmacokinetics study. Journal of chromatography. B, Analytical 
technologies in the biomedical and life sciences, 2018. 1091: p. 29-35.
36. Zaccardi, F., et al., Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist 
Treatments: A Systematic Review and Network Meta-analysis. Annals of internal medicine, 2016. 164(2): p. 
102-13.
37. Andersen, A., et al., Glucagon-like peptide 1 in health and disease. Nature reviews. Endocrinology, 2018. 
14(7): p. 390-403.
38. Hemmer, A., et al., Long-term effects of GLP-1 receptor agonists in type 2 diabetic patients: A retrospective 
real-life study in 131 patients. Diabetes & metabolic syndrome, 2019. 13(1): p. 332-336.
39. van Bloemendaal, L., et al., GLP-1 receptor activation modulates appetite- and reward-related brain areas in 
humans. Diabetes, 2014. 63(12): p. 4186-4196.
40. Sun, F., et al., Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among 
patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes research and clinical 
practice, 2015. 110(1): p. 26-37.
41. Hussein, H., et al., Efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-
like peptide-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes: a systematic review and 
network meta-analysis study protocol. BMJ open, 2018. 8(11): p. e023206.
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Page 41 of 46 (V.01/21/2019) 
42. Hussein, H., et al., Cardiovascular efficacy and safety of sodium-glucose co-transporter-2 inhibitors and 
glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis. Diabetic 
medicine : a journal of the British Diabetic Association, 2019. 36(4): p. 444-452.
43. Bhavsar, S., S. Mudaliar, and A. Cherrington, Evolution of exenatide as a diabetes therapeutic. Current 
diabetes reviews, 2013. 9(2): p. 161-93.
44. Jacobsen, L.V., et al., Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and 
Pharmacodynamics. Clinical pharmacokinetics, 2016. 55(6): p. 657-72.
45. Wadden, T.A., et al., Intensive Behavioral Therapy for Obesity Combined with Liraglutide 3.0 mg: A 
Randomized Controlled Trial. Obesity, 2019. 27(1): p. 75-86.
46. Buse, J.B., et al., Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes 
(DURATION-6): a randomised, open-label study. Lancet, 2013. 381(9861): p. 117-24.
47. Pratley, R.E., et al., Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes 
inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority 
phase 3 study. The lancet. Diabetes & endocrinology, 2014. 2(4): p. 289-97.
48. O'Neil, P.M., et al., Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from 
randomized controlled phase 2 and 3a trials. Diabetes, obesity & metabolism, 2017. 19(11): p. 1529-1536.
49. Pickens, R.W. and C.E. Johanson, Craving: consensus of status and agenda for future research. Drug and 
alcohol dependence, 1992. 30(2): p. 127-31.
50. Huhn, A.S., et al., Ecological momentary assessment of affect and craving in patients in treatment for 
prescription opioid dependence. Brain Research Bulletin, 2016. 123: p. 94-101.
51. Lydon-Staley, D.M., et al., Daily sleep quality affects drug craving, partially through indirect associations with 
positive affect, in patients in treatment for nonmedical use of prescription drugs. Addictive behaviors, 2017. 
65: p. 275-282.
52. Bunce, S.C., et al., Possible evidence for re-regulation of HPA axis and brain reward systems over time in 
treatment in prescription opioid-dependent patients. Journal of addiction medicine, 2015. 9(1): p. 53-60.
53. Harris, J.D., Prefrontal Cortical Function as an Objective Marker of Early Relapse Risk in Alcohol-Dependent 
Patients Following Residential Treatment: A Functional Near-Infrared Spectroscopy Study (Doctoral 
Dissertation), in Department of Psychiatry. 2016, Penn State University College of Medicine: Hershey, PA.
54. Huhn, A.S., et al., Evidence of anhedonia and differential reward processing in prefrontal cortex among post-
withdrawal patients with prescription opiate dependence. Brain Research Bulletin, 2016. 123: p. 102-9.
55. Huhn, A.S., Predicting Treatment Outcome from Prescription Opiate Abuse (Doctoral Dissertation), in 
Department of Psychiatry. 2016, Penn State University College of Medicine: Hershey, PA.
56. Nordmann, S., et al., A prospective, longitudinal study of sleep disturbance and comorbidity in opiate 
dependence (the ANRS Methaville study). Psychopharmacology (Berl), 2016. 233(7): p. 1203-1213.
57. Kay, D.C., Human sleep during chronic morphine intoxication. Psychopharmacologia, 1975. 44(2): p. 117-24.
58. Kay, D.C., R.B. Eisenstein, and D.R. Jasinski, Morphine effects on human REM state, waking state and NREM 
sleep. Psychopharmacologia, 1969. 14(5): p. 404-416.
59. Mehtry, V., et al., Sleep Profile in Opioid Dependence: A Polysomnographic Case-Control Study. Journal of 
clinical neurophysiology : official publication of the American Electroencephalographic Society, 2014. 31(6): 
p. 517-522.
60. Asaad, T.A., et al., Sleep Profile in Patients With Chronic Opioid Abuse: A Polysomnographic Evaluation in an 
Egyptian Sample. Addictive Disorders & Their Treatment, 2011. 10(1): p. 21-28.
61. Hartwell, E.E., et al., Sleep disturbances and pain among individuals with prescription opioid dependence. 
Addict Behav, 2014. 39(10): p. 1537-1542.
62. Peles, E., S. Schreiber, and M. Adelson, Variables associated with perceived sleep disorders in methadone 
maintenance treatment (MMT) patients. Drug Alcohol Depend, 2006. 82(2): p. 103-110.
63. Xiao, L., et al., Nocturnal Sleep Architecture Disturbances in Early Methadone Treatment Patients. Psychiatry 
research, 2010. 179(1): p. 91-95.
64. Burke, C.K., et al., Sleep Problems Reported by Patients Entering Opioid Agonist Treatment. Journal of 
substance abuse treatment, 2008. 35(3): p. 328-333.
65. Howe, R.C., F.W. Hegge, and J.L. Phillips, Acute Heroin Abstinence in Man: I. Changes in Behavior and Sleep. 
Drug and alcohol dependence, 1980. 5(5): p. 341-356.
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66. Peles, E., et al., No Change of Sleep After 6 and 12 Months of Methadone Maintenance Treatment. Journal 
of addiction medicine, 2011. 5(2): p. 141-147.
67. Dunn, K.E., et al., Frequency and Correlates of Sleep Disturbance in Methadone and Buprenorphine-
Maintained Patients. Addictive behaviors, 2018. 76: p. 8-14.
68. Dimsdale, J.E., et al., The Effect of Opioids on Sleep Architecture. Journal of clinical sleep medicine: JCSM: 
official publication of the American Academy of Sleep Medicine, 2007. 3(1): p. 33-36.
69. Lewis, S.A., et al., Heroin and Human Sleep. Electroencephalography and clinical neurophysiology, 1970. 
28(4): p. 374-381.
70. Shaw, I.R., et al., Acute Intravenous Administration of Morphine Perturbs Sleep Architecture in Healthy Pain-
Free Young Adults: A Preliminary Study. Sleep, 2005. 28(6): p. 677-682.
71. Kay, D.C., Human sleep and EEG through a cycle of methadone dependence. Electroencephalogr Clin 
Neurophysiol, 1975. 38(1): p. 35-43.
72. Kay, D.C., W.B. Pickworth, and G.L. Neider, Morphine-like Insomnia From Heroin in Nondependent Human 
Addicts. British journal of clinical pharmacology, 1981. 11(2): p. 159-169.
73. Pickworth, W.B., G.L. Neidert, and D.C. Kay, Morphinelike Arousal by Methadone During Sleep. Clinical 
pharmacology and therapeutics, 1981. 30(6): p. 796-804.
74. 74. Kay, D.C., et al., Opioid Effects on Computer-Derived Sleep and EEG Parameters in Nondependent 
Human Addicts. Sleep, 1979. 2(2): p. 175-191.
75. Peles, E., S. Schreiber, and M. Adelson, Documented poor sleep among methadone-maintained patients is 
associated with chronic pain and benzodiazepine abuse, but not with methadone dose. European 
Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 2009. 
19(8): p. 581-588.
76. Brower, K.J. and P.B. E, Sleep Disturbance as a Universal Risk Factor for Relapse in Addictions to 
Psychoactive Substances. Medical hypotheses, 2010. 74(5): p. 928-933.
77. Wang, D. and H. Teichtahl, Opioids, Sleep Architecture and Sleep-Disordered Breathing. Sleep medicine 
reviews, 2007. 11(1): p. 35-46.
78. Dijkstra, B.A.G., et al., Prediction of Abstinence in Opioid-Dependent Patients. Journal of addiction medicine, 
2008. 2(4): p. 194-201.
79. Al-Yassiri, M.M., S.I. Ankier, and P.K. Bridges, Trazodone--a new antidepressant. Life Sci, 1981. 28(22): p. 
2449-58.
80. Atkin, T., S. Comai, and G. Gobbi, Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical 
Applications, and Discovery. Pharmacol Rev, 2018. 70(2): p. 197-245.
81. Khouzam, H.R., A review of trazodone use in psychiatric and medical conditions. Postgrad Med, 2017. 
129(1): p. 140-148.
82. Friedmann, P.D., et al., Trazodone for sleep disturbance after alcohol detoxification: a double-blind, placebo-
controlled trial. Alcohol Clin Exp Res, 2008. 32(9): p. 1652-60.
83. Le Bon, O., et al., Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-
withdrawal syndrome: polysomnographic and clinical evaluations. J Clin Psychopharmacol, 2003. 23(4): p. 
377-83.
84. Bass, J.T., A.D. Laposky, and F.W. Turek, GLP-1 Receptor Agonist Compounds for Sleep Enhancement., 
D.U.S.P.a.T.O. Washington, Editor. 2012: U.S.
85. Douton, J. E., Augusto, C., Stoltzfus, B. A., Carkaci-Salli, N., Vrana, K. E., & Grigson, P. S. (2019). Glucagon-like 
peptide-1 receptor agonist, exendin-4, reduces reinstatement of heroin seeking behavior in rats. bioRxiv, 
730408.
22.0
Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form.
23.0
Optional Sub-study: Polysomnography Assessment
In addition to the main part of the research study as explained above, there is a supplemental part to the 
research study. Participants can be in the main part of the research without agreeing to be in this supplemental 
part of the study.
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Study Objectives
Preliminary data suggest that the study medication, liraglutide, may help to improve sleep. Liraglutide decreases 
orexin transmission, which, in turn, reduces arousal, leading to improved total sleep time and increases 
percentage of slow wave (Stage III) sleep. The supplemental part of the study will evaluate the effect of 
liraglutide on objective measures of sleep, assessed with overnight polysomnography (PSG). 
1.
To evaluate the efficacy of liraglutide (vs placebo), administered daily, in improving objective total 
sleep time (TST) as measured by PSG in opioid use disorder patients in residential treatment. 
Specifically, we hypothesize that: liraglutide will be more effective than placebo in increasing objective 
TST in OUD patients undergoing residential treatment for OUD. 
2.
To evaluate the efficacy of liraglutide (vs placebo), administered daily, on the objective measures of 
%slow wave sleep (%SWS), as measured by PSG, in opioid use disordered patients in residential 
treatment. Specifically, we hypothesize that liraglutide, relative to placebo, will increase the %SWS, 
which will contribute to overall sleep quality. 
Primary end point
The primary objectives of the supplemental study is to determine whether liraglutide can improve objective TST 
measured by PSG over 3-5 weeks while participants are in residential treatment for OUD. For the 3-dose 
intervention, change in TST will be measured by performing PSG at baseline, prior to receiving the first dose of 
liraglutide (Night 1) and the night after receiving the final target drug dose (Night 19). For the 5-dose 
intervention, change in TST will be measured by performing PSG at baseline (prior to receiving the first dose of 
liraglutide, Night 1), the night after receiving the final 1.8 mg (third) drug dose (Night 19), and the night after 
receiving the final 3.0 mg (fifth) drug dose (Night 31).
Secondary end point
The secondary end point of the study is to determine whether liraglutide improves %SWS measured by PSG over 
a 3-5 week period while participants are in residential treatment for OUD. For the 3-dose intervention, change in 
%SWS will be measured by performing PSG at baseline, i.e., prior to receiving the first dose of liraglutide (Night 
1) and the night after receiving the final target drug dose (Night 19). For the 5-dose intervention, change in 
%SWS will be measured by performing PSG at baseline, i.e., prior to receiving the first dose of liraglutide (Night 
1), the night after receiving the final 1.8 mg (third) drug dose (Night 19), and the night after receiving the final 
3.0 mg (fifth) drug dose (Night 31).
Exploratory end point
The exploratory end point is to determine if the improvement in TST and %SWS is accompanied by decreased 
craving, insomnia severity, and prefrontal cortical brain response to visual drug cues following 18-30 days of 
treatment with liraglutide in OUD patients in residential treatment. We will examine the correlation between 
improvements in TST, %SWS, and craving and insomnia severity as measured by self-report and prefrontal 
response to drug cues. 
Background
Scientific Background and Gaps
Sleep problems are common – and undertreated – symptoms in most substance use disorder syndromes, 
including OUD [56-62]. Sleep problems are 8-9 times more prevalent among patients in early treatment for 
opioid use disorders (OUD) than the general population [63-67]. Aside from misuse, or abuse, even regular, 
chronic use of opioids is known to interfere with sleep via several mechanisms, leading to increased Stage I [68-
70] and Stage II sleep [70], reduced levels of sleep efficiency, rapid eye movement (REM) sleep [57, 58, 69-74], 
and percentage of non-rapid eye movement (NREM) slow wave sleep (%SWS) [57, 58, 71-74]. Peles et al. [75] 
also found that the %SWS was correlated with of the severity of OUD. Thus, the persistence of insomnia, 
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especially when associated with decreased SWS, is a predictor of relapse following discharge from residential 
treatment with an OUD. Sleep problems may persist for months following withdrawal, contributing to high rates 
of relapse [76-78]. To date, there are no approved medications for insomnia in patients with OUD. The standard 
hypnotic medications used to treat sleep disorders cannot be used in OUD patients because of their addictive 
properties. The two most commonly used FDA-approved medications for OUD treatment, methadone and 
buprenorphine, do not improve sleep for the majority of patients [67], and indeed, may make is worse due to 
their agonism or partial agonism on the opioid receptors. Trazodone and other antidepressants like 
doxepin/mirtazepine, are commonly prescribed off-label for the treatment of insomnia in the general 
population [79, 80], and are the standard of care for the treatment of insomnia in SUDs [80, 81]. However, 
previous studies with trazodone and other antidepressants in post-withdrawal SUD participants have shown 
mixed efficacy, with little to no relief for a large percentage of the population [82, 83]. Collectively, these 
findings suggest that there is a significant need to develop more efficacious treatments for insomnia in patients 
with SUDs in general, and OUD in particular.
Glucagon-Like Peptide-1 (GLP-1), Orexins and Sleep
In addition to its potential to reduce craving in OUD patients, there is evidence that the study drug, a GLP-1r 
agonist, may also improve sleep. In a mouse model, the GLP- 1R agonist Exendin-4 was shown to increase NREM 
sleep time (Stage III %SWS sleep) by 93% over the first 6 hours of the dark cycle in mice [84]. We are unaware of 
any study of the effects of a GLP-1r agonist on sleep architecture in humans. We believe its effect on sleep may 
due to the effect of GLP- 1R agonism on orexin transmission.
Orexin is one of the wake neurotransmitters that play a role in the wake-sleep cycle. It is believed that orexin is 
involved with sending wake signals to other parts of the brain. Inhibiting the action of orexin by blocking 
transmission is expected to result in decreased arousal and increased sleep. The orexin type-2 receptor, in 
particular, has been shown to be associate with arousal, whereas the orexin type-1 receptor has been associated 
with positive mood.  In a preclinical study by our group, the administration of the GLP1 agonist, Ex-4 has been 
shown to increase both orexin 1 [85] and orexin 2 (unpublished) receptor mRNA expression in the nucleus 
accumbens shell. This effect suggests that GLP1 agonism decreases orexin transmission, leading to a 
compensatory increase in orexin receptors in the nucleus accumbens. The orexin receptor antagonist, 
suvorexant, decreases arousal and improves sleep in humans (marketed as Belsomra) and is FDA approved for 
the treatment of primary Insomnia. Given that a GLP1 agonist can decrease orexin neurotransmission, and 
thereby dampen arousal, treatment with a GLP-1r agonist may improve sleep - in addition to decreasing craving. 
As such, we hypothesize that the GLP-1r agonist, liraglutide, is a novel and promising therapeutic to improve 
sleep in patients with OUD, as it may not only decrease craving, but also improve sleep by acting on the orexin-
mediated arousal and reward pathways.
Study Rationale
The rationale for the proposed research is to develop an intervention that can improve sleep outcomes in 
addition to reducing craving in OUD patients, a combination of factors which contribute to early relapse. 
Although liraglutide was approved for human use in 2010, there are no data testing the effectiveness in craving 
and sleep in patients with an OUD. Because of its importance to health and well-being, and its role in relapse, 
both objective (wrist actigraphy) and intensive subjective (Ecological Momentary Assessment, EMA) measures of 
sleep were included in the parent UG3 grant study, in addition to well-validated self-reported sleep inventories. 
However, the existing animal research model shows that GLP-1r agonism improved the percentage of slow wave 
sleep (%SWS), an important aspect of sleep architecture that cannot be measured with self-report or wrist 
actigraphy. 
The objective of the proposed supplemental research is to use the gold-standard, polysomnography, to evaluate 
the hypothesis that treatment with a GLP-1R agonist can improve sleep in humans with OUD. If liraglutide shows 
a trend towards efficacy in improving sleep, and safety of the GLP-1R agonist is demonstrated in this population, 
it would provide an indication to run a multi-center clinical trial of GLP-1R agonist in OUD patients. 
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The inclusion, exclusion criteria, recruitment methods and consent process for the polysomnography studies are 
the same as those described above for the primary study. 
Study Design and Procedure
Study Design
The polysomnography portions will be inserted into the study design (described above) on Nights 1, 19, and 31, 
as described below.
Study procedures
Following randomization and full screening, the first PSG recording will be collected on baseline night (Night 1) 
before starting liraglutide/placebo. A second PSG study will be conducted 6 days after reaching the 1.8 mg dose 
of liraglutide, on Night 19. For the 5-dose intervention only, a third PSG study will be conducted 6 days after 
reaching the 3.0 mg dose of liraglutide, on Night 31. PSG studies will be performed at Caron treatment center in 
the patients’ own rooms. An appropriately trained study team member (Project Coordinator or Research 
Support team member) will set-up the sleep recording. Training for the Sleep Project Coordinator will be 
provided by registered polysomnography technicians from the Sleep Research & Treatment Center involved in 
research and/or clinical care and supervised by the sleep co-investigators (Krishnamurthy, Fernandez-Mendoza) 
in this study. Training will include all aspects necessary for a gold-standard, ambulatory PSG recording, including 
1) application and removal of electrodes, 2) set-up of PSG equipment, 3) calibration of signals, 4) software and 
hardware management, 5) disposal and/or clean-up of supplies for research purposes, and 6) secure transfer of 
the sleep data files to the PSHealth network using Kiteworks. Data transferred via Kiteworks will be scored by an 
independent technician (sleep scorer) not involved in data acquisition. 
The polysomnography (PSG) assessments will only be set up and taken down (patient unhooked from 
equipment and electrodes) by appropriately trained Penn State study team members (Project Coordinators). 
The use of portable PSG units (not in-lab PSG) requires a trained technician to get good signal, but does not 
require a Registered Polysomnographic Technologist (RPSGT) to successfully gather good-quality data. RPSGTs 
are required for accreditation of clinical sleep centers, but not for research studies as long as the investigator 
team includes sleep specialists with demonstrated experience who assure appropriate training and skills with 
adequate expertise and resources. The study team includes two board-certified sleep specialists and sleep 
researchers who have demonstrated experience in PSG and in training research technicians for successful 
outcomes. The Penn State Project coordinator will be trained by the two board-certified sleep specialists, 
including hands-on training with other human research technicians trained in PSG and/or RPSGTs currently 
working in the clinical sleep center and within the sleep research division 
The appropriately trained study team member will be using a Natus Trex HD ambulatory PSG system, and 
standard PSG methodology. The PSGs will include two central, frontal, and occipital electroencephalogram 
channels, two electrooculograms, chin and limb electromyograms, and an electrocardiogram during the baseline 
and follow up. Additional sensors to detect sleep disordered breathing events, including chest and abdominal 
bands, a thermocouple, a nasal cannula, and a pulse oximeter, all of which are standard in PSG studies, will be 
included. Application of the PSG sensors will begin around 9:15, and participants will be instructed to go to bed 
at the time closest to their habitual bedtime, within a time range of 10pm to 11pm, and to get up at 6am (which 
is within their Caron-scheduled wake time.  (All morning patient medication at Caron is provide at the Neag 
Medical Center from 6:15am to 6:50am, so this time is consistent with their typical schedules.)
Data from the PSG study will be collected on a study-dedicated laptop. The data will be securely transferred to 
the Sleep Research and Treatment Center (SRTC), Penn State Health and Penn State College of Medicine via 
https://kiteworks.pennstatehealth.net for further storage, scoring, interpretation and analysis using Cerner’s 
environment within Penn State Health secure network. Data sent to the SRTC from the study team will be 
identified by the participant’s random ID number only. This will allow investigators to pair the polysomnographic 
sleep study data with the clinical data collected in the primary study, described above. 
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Sleep records will be manually scored by a trained technologist following the current version of American 
Academy of Sleep Medicine (AASM) Manual. Standard PSG sleep parameters, including total sleep time, wake 
after sleep onset, and the percentage and duration of each sleep stage will be calculated using Sleepworks 
(Natus) software.
Participants will be allowed to request a sleep physician report of their sleep stages, breathing patterns (e.g., 
sleep apnea) or other physiologic measures that they may share with their primary care provider, if desired, for 
further clinical care outside of the study.
All other aspects of the study (e.g., drug and placebo administration, adverse event monitoring, enollment and 
randomization, duration of the study procedure, etc), including self-reported craving (0-100 VAS) will be 
conducted as described in the primary study above. Subjects will also complete the 7-item self-reported 
Insomnia Severity Index (ISI), the gold-standard subjective measure of insomnia severity in clinical trials (PMID: 
21532953; PMID: 33164741). The ISI  is already embedded into REDCap from our previous studies and will be 
added to this optional sleep study to measure the potential improvement in subjective insomnia severity from 
baseline (initial evaluation, Night 1) to post intervention (Nights 19 and 31), as mentioned in the exploratory 
endpoints above.
Risks
There are no known risks associated with the polysomnographic recordings of sleep. On rare occasions, some 
individuals can have mild allergic reactions to the tape applied over the electrodes, or allergies to latex. We will 
minimize this risk by using hypoallergenic tapes. There can be some mild discomfort in applying the skin 
electrodes as the skin is cleaned, or while wearing the electrodes at night.
Subject payment and travel information
In addition to the reimbursement for participating in the main parts of the study, participants will receive an 
additional reimbursement of $90 for the first PSG, $90 for the second PSG, and $90 for the third PSG [5-dose 
intervention only] for a total of $180 [$270 for three nights] for participating in the supplemental 
polysomnographic sleep recordings. Reimbursements will be paid using Target gift cards as neither alcohol nor 
tobacco products can be purchased at Target.
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