Clinical trial NCT05458609: Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep
Official title: Lemborexant Augmentation of Naltrexone for Alcohol Craving and Sleep: A Randomized, Double-Blind, Placebo- Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alcohol Use Disorder
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
First posted: 2022-07-14
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized to two different arms: lemborexant plus naltrexone versus placebo plus naltrexone using a computer-generated randomization scheme.
Primary purpose: TREATMENT

Brief summary: The purpose of this study to evaluate the effects of naltrexone plus lemborexant augmentation compared to naltrexone plus placebo on cue-induced and non-cued alcohol cravings in people with alcohol use disorder and insomnia. Our secondary goals are to evaluate the effects of lemborexant plus naltrexone combination on sleep quality using self-report questionnaires and actigraph data, depression, anxiety, and suicidal ideation.

Detailed description: 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.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.

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. 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. 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. 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.

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. It has demonstrated long-term safety and effectiveness without physical dependence or rebound insomnia. 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. In addition, Lemborexant's longer half-life (17-19h) may be advantageous for reduction of cravings during the day.

In people with AUD, insomnia is a common problem that 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. Lemborexant may be able to target both alcohol craving/urges and insomnia when added to standard treatment with naltrexone.

Eligibility criteria: Inclusion Criteria:

* Admission to The Menninger clinic
* Age 18-65 years
* diagnosis of alcohol use disorder using the DSM-5 criteria confirmed with SCID-5 and
* Diagnosis of insomnia using the DSM 5 criteria, confirmed with SCID-5

Exclusion Criteria:

* unstable medical conditions (e.g. liver enzymes (ALT and AST) more than 3 times normal)
* acute alcohol withdrawal
* another drug use disorder other than nicotine and cannabis
* use of either of the study medications, naltrexone or lemborexant, within the last 30 days
* Use of any opioid medication within the past 10 days
* Use of scheduled benzodiazepines and hypnotics
* Breathalyzer positive for alcohol
* Known sensitivity to naltrexone or lemborexant
* Pregnant or breastfeeding
* Diagnosis of narcolepsy. The presence of other psychiatric illnesses, use of other psychotropic medications, and stable medical conditions will not be excluded.

Primary outcomes:
measure: Cue-induced Alcohol Cravings using the Alcohol Urge Questionnaire
timeFrame: 4 Weeks after Randomization
measure: Non-Cued Alcohol Cravings using the Penn Alcohol Craving Scale
timeFrame: 4 Weeks after Randomization
Secondary outcomes:
measure: Sleep Quality Using the Pittsburgh sleep quality index
timeFrame: 4 weeks after randomization
measure: Insomnia Severity using the Insomnia Severity Index
timeFrame: 4 weeks after randomization
measure: Daytime sleepiness using the Epworth Sleepiness Scale
timeFrame: 4 weeks after randomization
measure: Actigraphy to measure Total Sleep Time
timeFrame: 4 weeks after randomization
measure: Actigraphy to measure sleep latency
timeFrame: 4 weeks after randomization
measure: Actigraphy to measure wake after sleep onset
timeFrame: 4 weeks after randomization
measure: Actigraphy to measure sleep efficiency
timeFrame: 4 weeks after randomization
measure: Anxiety Using the Generalized Anxiety Disorder scale
timeFrame: 4 weeks after randomization
measure: Depression using the Patient Health Questionnaire
timeFrame: 4 weeks after randomization
measure: Suicide Risk Using the Suicide Behavior Questionnaire-Revised
timeFrame: 4 weeks after randomization
Other outcomes:
Locations:
city: Houston
country: United States
facility: The Menninger Clinic
state: Texas
Study officials:
References:
citation: Swift RM, Aston ER. Pharmacotherapy for alcohol use disorder: current and emerging therapies. Harv Rev Psychiatry. 2015 Mar-Apr;23(2):122-33. doi: 10.1097/HRP.0000000000000079.
citation: Zindel LR, Kranzler HR. Pharmacotherapy of alcohol use disorders: seventy-five years of progress. J Stud Alcohol Drugs Suppl. 2014;75(17):79-88. doi: 10.15288/jsads.2014.s17.79.
citation: Ziolkowski M, Czarnecki D, Budzynski J, Rosinska Z, Zekanowska E, Goralczyk B. Orexin in Patients with Alcohol Dependence Treated for Relapse Prevention: A Pilot Study. Alcohol Alcohol. 2016 Jul;51(4):416-21. doi: 10.1093/alcalc/agv129. Epub 2015 Nov 22.
citation: von der Goltz C, Koopmann A, Dinter C, Richter A, Rockenbach C, Grosshans M, Nakovics H, Wiedemann K, Mann K, Winterer G, Kiefer F. Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward. Psychoneuroendocrinology. 2010 May;35(4):570-7. doi: 10.1016/j.psyneuen.2009.09.005. Epub 2009 Oct 13.
citation: Moorman DE. The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders. Psychopharmacology (Berl). 2018 Jun;235(6):1663-1680. doi: 10.1007/s00213-018-4871-2. Epub 2018 Mar 6.
citation: Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, Filippov G, LoPresti A, Moline M. 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 Netw Open. 2019 Dec 2;2(12):e1918254. doi: 10.1001/jamanetworkopen.2019.18254.
citation: Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800.
citation: Yardley J, Karppa M, Inoue Y, Pinner K, Perdomo C, Ishikawa K, Filippov G, Kubota N, Moline M. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021 Apr;80:333-342. doi: 10.1016/j.sleep.2021.01.048. Epub 2021 Feb 1.