Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep: A Randomized, Double-Blind, Placebo- Controlled Study
Phase: PHASE3
Conditions: Alcohol Use Disorder
Sponsor: Baylor College of Medicine

 
Title:  
Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep: A 
Randomized, Double-Blind, Placebo- Controlled Study 
NCT number: NCT05458609 
Date: 08/01/2024 

Background 
Alcohol is one of the most popular substances used worldwide for thousands 
of years. Globally, harmful alcohol use continues to be a major public health and 
economic burden. The World Health Organization global status report attributed 
harmful alcohol use to 3 million deaths in 2016.(Global Status Report on Alcohol 
and Health 2018, n.d.) In the United States, alcohol is the most used substance by 
people over the age of 12, with alcohol use disorder (AUD) affecting 14.5 million 
people in this age group. Hazardous alcohol use is associated with emergency room 
visits, overdose, driving fatalities and chronic medical conditions such as liver 
disease, heart disease, and hypertension.(Alcohol Facts and Statistics | National 
Institute on Alcohol Abuse and Alcoholism (NIAAA), n.d.)  
Pharmacological interventions for AUD have expanded over the past few 
decades, including FDA approved and off-label medications such as naltrexone that 
have demonstrated efficacy in reducing alcohol cravings, consumption, and 
likelihood of relapse.(Swift & Aston, 2015; Zindel & Kranzler, 2014) However, the 
significant variability in response to treatment fuels ongoing interest in novel 
pharmacotherapy for AUD. A common approach involves repurposing readily 
available medications based on our understanding of AUD pathophysiology. In this 
study, we focus on the orexin system, which has been implicated in behaviors such 
as feeding, sleep-wake cycle, motivation, and reward associated with food, sex and 
substances including alcohol.(Li et al., 2016) The brain neuropeptides orexin A and 
orexin B originate in the hypothalamus and project throughout the central nervous 
system, activating G-protein-coupled receptors orexin 1 and 2 (OX1R and OX2R). 
While both orexin receptors are involved in addictive behaviors, OX1R signaling has 
a stronger association with reward processes whereas OX2R promotes arousal. 
Chronic alcohol exposure may lead to neuroadaptations in the orexin system, as 
observed in studies showing a positive correlation between orexin levels and 
severity of alcohol dependence and distress during alcohol withdrawal.(Goltz et al., 
2009; Ziółkowski et al., 2016) Moreover, multiple animal studies have 
demonstrated efficacy of orexin antagonists in reducing alcohol craving, self-
administration, and reinstatement of alcohol use induced by cues and 
stress.(Moorman, 2018)  

The orexin antagonist lemborexant is FDA approved for treatment of 
insomnia. Lemborexant acts on both OX1R and OX2R and has shown efficacy in 
sleep initiation and maintenance compared to placebo on polysomnography and 
patient-report.(Rosenberg et al., 2019) It has demonstrated long-term safety and 
effectiveness without physical dependence or rebound insomnia.(Murphy et al., 
2017; Yardley et al., 2021) Compared to suvorexant, another orexin antagonist, 
lemborexant has greater selectivity and stronger binding for orexin receptors. 
Suvorexant has secondary effects on the adenosine receptor and dopamine 
transporter whereas lemborexant only has weak binding to melatonin 1. These 
differences may increase risk of misuse for suvorexant more than 
lemborexant.(Asakura et al., 2021) In addition, Lemborexant’s longer half-life (17-
19h) may be advantageous for reduction of cravings during the day.(Landry et al., 
2021)  
In people with AUD, insomnia is a common problem that is associated with 
alcohol craving and relapse.(He et al., 2019) Standard treatment for AUD with 
naltrexone improves cravings and other AUD outcomes, but does not improve 
sleep. In some cases, naltrexone may have a detrimental effect on sleep.(Anton et 
al., 2006; Panin & Peana, 2019) Lemborexant may be able to target both alcohol 
craving/urges and insomnia when added to standard treatment with naltrexone.  
 
Aims and hypothesis 
Our primary goal is to evaluate the effects of naltrexone plus lemborexant 
augmentation compared to naltrexone plus placebo on cue-induced and non-
cued alcohol craving scores. Our secondary goals are to evaluate the effects of 
this combination on sleep quality using actigraph data.   
Hypotheses: H1: we hypothesize that the group receiving naltrexone plus 
lemborexant augmentation will have a greater decrease in cue-induced and 
non-cued alcohol craving scores than naltrexone plus placebo. H2: we 
hypothesize that the group receiving naltrexone combined with 
lemborexant will experience a greater improvement on objective sleep 
measures.   

Significance of the problem 
Alcohol use disorder (AUD) and insomnia are highly comorbid in our psychiatric 
inpatients. In people with AUD, insomnia may be persistent and is associated with 
alcohol craving and relapse. Standard treatment for AUD with naltrexone 
improves cravings and other AUD outcomes, but does not improve sleep. In some 
cases, naltrexone may have a detrimental effect on sleep. Insomnia is associated 
with higher severity of depression, anxiety, and suicidality. Adequate treatment of 
both alcohol cravings and insomnia may improve overall outcomes. 
Design and methods 
The study will be a randomized, double-blind, placebo-controlled clinical trial of 
naltrexone plus placebo versus naltrexone plus lemborexant conducted at The 
Menninger Clinic on inpatients with alcohol use disorder. Recruitment will occur on 
patients admitted to a Menninger inpatient unit over a 12-month period. Because 
the average length of stay at The Menninger Clinic is 2 to 4 weeks, the study period 
will last 2 to 4 weeks depending on the patient’s length of stay. We plan to enroll 
10 patients and randomize half to lemborexant plus naltrexone and half to placebo 
plus naltrexone using a computer-generated randomization scheme.  
All participants will receive a standard treatment program with pharmacotherapy 
for their psychiatric conditions, CBT, DBT, individual therapy, and group therapy 
during their inpatient admission. Subjects will be randomly assigned to either 
naltrexone plus placebo or naltrexone plus lemborexant. For all patients, 
naltrexone will be given at 50 mg/day. For the lemborexant augmentation group, 
lemborexant will be given at 10mg at bedtime. Dose reductions due to tolerability 
will be permitted at the discretion of the investigator. Blinding will be ensured by 
use of a matching placebo for lemborexant 10mg using over-encapsulation. 
Participants and study personnel will be blinded to the study drug. Medications will 
be administered by nursing staff. All participants will be exposed to alcohol-related 
cues using virtual reality technology at baseline, at the end of week 2 or end of 
week 4. 

Safety: Safety assessments will be collected weekly throughout the study. These 
assessments will consist of monitoring and recording of adverse events and 
periodic measurement of vital signs. 
Assessment and Outcomes Measures (Tables 1 and 2): As part of the Menninger 
Clinic inpatient evaluation, each patient will be given a medical examination, 
including physical exam and laboratory testing on admission. Assessments will 
include baseline EKG, CBC, BMP, liver profile, pregnancy test (females), and urine 
drug screen. This information is part of the health record and will be collected for 
screening and analysis.  
Clinical diagnoses including alcohol use disorder will be assessed using the 
structured clinical interview for DSM-5 (SCID-5). Alcohol use disorder severity will 
be measured using the alcohol dependence scale (ADS). We will also be using an 
actigraph to measure total sleep time and wake after sleep onset. Cue-induced 
alcohol cravings will be assessed using the Alcohol Urge Questionnaire (AUQ) and 
non-cued alcohol craving will be assessed using the Penn Alcohol Craving Scale 
(PACS). 
Table 1: Initial Assessment, Sleep, Mood, and Suicide risk 
 
Measure 
Instrument 
Screening Daily Weekly Discharge 
DSM-5 
Diagnoses 
(including 
Alcohol 
use 
disorder) 
Structured 
Interview 
for 
DSM-5 (SCID-5) 
X 
 
 
 
Alcohol 
Use 
Disorder 
Severity 
Alcohol Dependence Scale 
(ADS) 
X 
 
 
 
Total 
Sleep 
Time, 
wake 
after 
sleep 
onset 
ActiGraph wGT3X-BT 
X 
 
X 
X 

Table 2: Alcohol Craving Measures 
Measure 
Instrument 
Bas
elin
e 
We
ek 1 
We
ek 2 
We
ek 3 
Wee
k 4 
Cue-
induced 
alcohol 
craving 
Alcohol 
Urge 
Questionnaire 
(AUQ) 
X 
x 
x 
x 
x 
Non-cued 
alcohol 
Craving 
Penn 
Alcohol 
Craving 
Scale 
(PACS) 
X 
X 
X 
X 
X 
 
Statistical Analysis: Descriptive statistics and bivariate tests will be used to inspect 
distributional properties of sample demographics and clinical outcomes at 
baseline, within the sample and between participant subgroups (e.g., gender, age, 
AUD severity). All outcome measures and safety assessments will be summarized 
weekly over the study period. Additionally, variables that significantly differ 
between participants who dropped out of the study and those who did not will be 
controlled statistically in our hypothesis testing to minimize any systematic bias 
due to attrition. Hierarchical linear modeling (HLM) will be conducted to examine 
the effects of receiving naltrexone plus lemborexant augmentation versus 
naltrexone plus placebo, while properly accounting for (a) the dependency of 
observations—i.e., correlation of repeated measurements (level 1) within 
participants (level 2) and (b) any difference due to receiving the treatments in a 
different group. Appropriate covariance structures will be determined in a 
preliminary analysis (i.e., intercept-only model) based on model fit (e.g., adjusted 
Akaike Information Criterion, Bayesian Information Criterion). Statistical 
significance will be determined at 0.05 alpha level. 
Sample Size and Power: The study is a pilot trial with a purpose of obtaining 
unbiased effect sizes for naltrexone plus lemborexant augmentation prescribed to 
a small number of adult patients with AUD. No formal power calculation is 

applicable because this is a first-in-human study and relevant data is not available 
in the literature.  
References 
Alcohol Facts and Statistics | National Institute on Alcohol Abuse and Alcoholism 
(NIAAA). (n.d.). Retrieved October 14, 2021, from 
https://www.niaaa.nih.gov/publications/brochures-and-fact-
sheets/alcohol-facts-and-statistics 
Anton, R. F., O’Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D., Donovan, D. 
M., Gastfriend, D. R., Hosking, J. D., Johnson, B. A., LoCastro, J. S., 
Longabaugh, R., Mason, B. J., Mattson, M. E., Miller, W. R., Pettinati, H. M., 
Randall, C. L., Swift, R., Weiss, R. D., Williams, L. D., … COMBINE Study 
Research Group,  for the. (2006). Combined Pharmacotherapies and 
Behavioral Interventions for Alcohol DependenceThe COMBINE Study: A 
Randomized Controlled Trial. JAMA, 295(17), 2003–2017. 
https://doi.org/10.1001/jama.295.17.2003 
Asakura, S., Shiotani, M., Gauvin, D. V., Fujiwara, A., Ueno, T., Bower, N., 
Beuckmann, C. T., & Moline, M. (2021). Nonclinical evaluation of abuse 
liability of the dual orexin receptor antagonist lemborexant. Regulatory 
Toxicology and Pharmacology, 127, 105053. 
https://doi.org/10.1016/j.yrtph.2021.105053 

Global status report on alcohol and health 2018. (n.d.). Retrieved October 14, 
2021, from https://www.who.int/publications-detail-
redirect/9789241565639 
Goltz, C. von der, Grosshans, M., Koopmann, A., Fink, T., Wiedemann, K., & Kiefer, 
F. (2009). Association Between Orexin Plasma Concentration and 
Psychopathology in Alcohol Dependent Patients During Acute 
Detoxification. European Psychiatry, 24(S1), 1–1. 
https://doi.org/10.1016/S0924-9338(09)70706-0 
He, S., Brooks, A. T., Kampman, K. M., & Chakravorty, S. (2019). The Relationship 
between Alcohol Craving and Insomnia Symptoms in Alcohol-Dependent 
Individuals. Alcohol and Alcoholism (Oxford, Oxfordshire), 54(3), 287–294. 
https://doi.org/10.1093/alcalc/agz029 
Landry, I., Nakai, K., Ferry, J., Aluri, J., Hall, N., Lalovic, B., & Moline, M. L. (2021). 
Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin 
Receptor Antagonist Lemborexant: Findings From Single‐Dose and Multiple‐
Ascending‐Dose Phase 1 Studies in Healthy Adults. Clinical Pharmacology in 
Drug Development, 10(2), 153–165. https://doi.org/10.1002/cpdd.817 

Li, S.-B., Jones, J. R., & de Lecea, L. (2016). Hypocretins, Neural Systems, 
Physiology, and Psychiatric Disorders. Current Psychiatry Reports, 18(1), 7. 
https://doi.org/10.1007/s11920-015-0639-0 
Moorman, D. E. (2018). The hypocretin/orexin system as a target for excessive 
motivation in alcohol use disorders. Psychopharmacology, 235(6), 1663–
1680. https://doi.org/10.1007/s00213-018-4871-2 
Murphy, P., Moline, M., Mayleben, D., Rosenberg, R., Zammit, G., Pinner, K., 
Dhadda, S., Hong, Q., Giorgi, L., & Satlin, A. (2017). Lemborexant, A Dual 
Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia 
Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, 
Placebo-Controlled Study. Journal of Clinical Sleep Medicine : JCSM : Official 
Publication of the American Academy of Sleep Medicine, 13(11), 1289–
1299. https://doi.org/10.5664/jcsm.6800 
Panin, F., & Peana, A. T. (2019). Sleep and the Pharmacotherapy of Alcohol Use 
Disorder: Unfortunate Bedfellows. A Systematic Review With Meta-
Analysis. Frontiers in Pharmacology, 10, 1164. 
https://doi.org/10.3389/fphar.2019.01164 
Rosenberg, R., Murphy, P., Zammit, G., Mayleben, D., Kumar, D., Dhadda, S., 
Filippov, G., LoPresti, A., & Moline, M. (2019). Comparison of Lemborexant 

With Placebo and Zolpidem Tartrate Extended Release for the Treatment of 
Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. 
JAMA Network Open, 2(12), e1918254. 
https://doi.org/10.1001/jamanetworkopen.2019.18254 
Swift, R. M., & Aston, E. R. (2015). Pharmacotherapy for Alcohol Use Disorder: 
Current and Emerging Therapies. Harvard Review of Psychiatry, 23(2), 122–
133. https://doi.org/10.1097/HRP.0000000000000079 
Yardley, J., Kärppä, M., Inoue, Y., Pinner, K., Perdomo, C., Ishikawa, K., Filippov, G., 
Kubota, N., & Moline, M. (2021). Long-term effectiveness and safety of 
lemborexant in adults with insomnia disorder: Results from a phase 3 
randomized clinical trial. Sleep Medicine, 80, 333–342. 
https://doi.org/10.1016/j.sleep.2021.01.048 
Zindel, L. R., & Kranzler, H. R. (2014). Pharmacotherapy of Alcohol Use Disorders: 
Seventy-Five Years of Progress. Journal of Studies on Alcohol and Drugs. 
Supplement, 75(Suppl 17), 79–88. 
Ziółkowski, M., Czarnecki, D., Budzyński, J., Rosińska, Z., Żekanowska, E., & 
Góralczyk, B. (2016). Orexin in Patients with Alcohol Dependence Treated 
for Relapse Prevention: A Pilot Study†. Alcohol and Alcoholism, 51(4), 416–
421. https://doi.org/10.1093/alcalc/agv129