Drug-drug Interaction Study of Lemborexant as an Adjunctive Treatment for Buprenorphine/Naloxone for Opioid Use Disorder

Study Overview
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Brief Summary
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The purpose of this research study is to test the safety, tolerability, drug interactions with buprenorphine-naloxone, and effectiveness lemborexant when used to treat Opioid Use Disorder.

Detailed Description
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The purpose of this study is to test the effects of lemborexant when used in combination with opioids (including buprenorphine). We are also interested in learning lemborexant might help improve sleep problems and problems related to opioid use (e.g., cravings, withdrawal), in people with opioid use disorder. Study participants will be randomly assigned in a two to one ratio to receive either lemborexant or placebo. Lemborexant (DAYVIGO®) is approved by the U. S. Food and Drug Administration (FDA) for treatment of insomnia. In this study, Participants will be asked to do the following things: Visit the CARI clinic and/or Motivate clinic at Jackson Center to complete study screening. Visit the VCUHS Clinical Research Unit to complete an outpatient blood draw/testing visit. Take either lemborexant or the placebo, depending upon which group subjects are assigned to. Complete two (2) overnight study visits at the VCUHS Clinical Research Unit. Complete 8 outpatient follow-up visits (broken into 2 four day visit groupings) Have an EKG during screening and at each study visit (outpatient and inpatient) Have an IV inserted into your arm for blood draws at the outpatient blood draw visit and each inpatient visit. Record sleep in a sleep diary. Take surveys and answer questions about health, mental health, medications used, drug use, and cravings. Complete tasks on the computer. Complete physical exams during screening, outpatient and inpatient visits. Give permission for the researchers to collect information about opioid treatment, medical status, and other information from your medical record. Participation in this study will last approximately 4 weeks. Approximately 18 people will participate in the drug interaction phase of this study.

Official Title
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Phase Ib/2a Drug-drug Interaction Study of Lemborexant as an Adjunctive Treatment for Buprenorphine/Naloxone for Opioid Use Disorder

Conditions
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Drug Interaction, Analgesics, Opioid

Intervention / Treatment
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* Drug: Lemborexant
* Drug: Placebo
* Drug: Buprenorphine-naloxone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between 18 - 65 years-of-age; Understand the study procedures and provide written informed consent in English language; Meet current DSM-5 criteria for opioid use disorder, of at least moderate severity, currently engaged medication assisted treatment at a buprenorphine-naloxone sublingual film daily dose ranging from 8mg/2mg to 24mg/6mg or buprenorphine sublingual tablet 5.7mg/1.4mg to 17.1/4.3 once daily for at least last 2 weeks; Have a positive urine drug screen for buprenorphine during screening and on admission to the clinical research unit to document buprenorphine use; Have a Pittsburgh Sleep Quality Index (PSQI) Total Score of 6 or higher. Exclusion Criteria: Contraindications for participation as determined by medical history and physical exam performed by study NP or study physician; Pregnant or nursing women; Baseline ECG with clinically significant abnormal conduction; Uncontrolled serious psychiatric or major medical disorder, including COPD. Narcolepsy is also considered exclusionary; Taking prescription or over-the counter drugs or dietary supplements known to significantly inhibit CYP3A4 (such as Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), or CYP3A4 inducers (such as phenobarbital, phenytoin, rifampicin, St. John's Wort, and glucocorticoids); Prescribed medications for insomnia, or unable to discontinue over the counter drugs or dietary supplements used to treat insomnia on study days. Current severe alcohol use disorder or current benzodiazepine use disorder Current DSM-5 diagnosis of any psychoactive substance use disorder other than opioids, cocaine, marijuana, or nicotine, or mild or moderate alcohol use disorder. Diagnosis of mild to moderate use disorder for alcohol will not be considered exclusionary. Any previous medically adverse reaction to opioids or lemborexant: Significant current suicidal or homicidal ideation (C-SSRS yes answers on questions 4 or 5) or a history of suicide attempt within the past 6 months. Subjects with Suicidal Behaviors Questionnaire-Revised score ≥8 at the screening visit. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lemborexant Arm<br>Study Drug Dosage: 5 mg of lemborexant, and 10 mg of lemborexant combined with 16 mg/4 mg of buprenorphine-naloxone sublingually as a film. | Drug: Lemborexant<br>* Participants will complete 2 inpatient visits which may last up to 24 hours. The two visits will be approximately 14 days apart. During the inpatient visit they will receive 5 mg of lemborexant (first visit) and 10 mg of lemborexant (second visit).<br>* Other names: Dayvigo;Drug: Buprenorphine-naloxone<br>* Participants will receive 16 mg/4 mg of buprenorphine-naloxone sublingually as a film.<br>|
| Placebo Comparator: Placebo Arm<br>Comparative placebo combined with 16 mg/4 mg of buprenorphine-naloxone sublingually as a film. | Drug: Placebo<br>* Participants will complete 2 inpatient visits which may last up to 24 hours. The two visits will be approximately 14 days apart. During the inpatient visit they will receive a placebo which matches the intervention drug.<br>Drug: Buprenorphine-naloxone<br>* Participants will receive 16 mg/4 mg of buprenorphine-naloxone sublingually as a film.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pulse oximetry | A finger pulse oximeter will be used to asses pulse oximetry. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in Blood Pressure | Blood Pressure measured with an automatic BP cuff. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in patient consciousness | The Richmond Agitation Sedation Scale (RASS) measures level of patient consciousness on a 10 point scale raging from plus 1 (combative/agitated) to minus 5 (unarousable/sedated). | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in Buprenorphine Plasma Concentration (PK) | Blood will be drawn pre-dose and at specific time points to determine the area under the plasma concentration-time curve for buprenorphine. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in Lemborexant PK | Blood will be drawn pre-dose and at specific time points to determine the area under the plasma concentration-time curve for Lemborexant. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in respiration | Respiration will be measuring with End Title CO2( EtC02) which is a measure of CO2 (measured in millimeters of mercury, mmHg) plotted against time. Participants will wear a mask which will be connected to a Capnographer. End Title CO2 should be between 35-45 mmHg with box wave form | During each inpatient visit from admission to discharge, up to 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in drug effects | Drug effects will be assessed using the Drug Effects Questionnaire (DEQ). The DEQ is comprised of 11 items which assess physical effects of the drug. Participants rate each physical effect on a visual analog scale from not at all to extremely. A higher score indicates greater drug effect. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in opioid craving | Opioid craving will be measured by a Brief Substance craving scale (BSCS). The BSCS asks about the drug craving on a 5 point scale. A higher score indicates greater craving | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in opioid withdrawal effects | Opioid withdrawal symptoms will be measured with the Subjective Opioid Withdrawal Scale (SOWS). The SOWS contains 16 likert scaled items with participant rate from 0 (not at all) to 4 (Extremely). A higher score indicates higher opioid withdrawal effects | During each inpatient visit from admission to discharge, up to 24 hours | 
| Change in objective opioid withdrawal | Participants will be assessed by research staff using the Clinical Opioid Withdrawal Scale (COWS) which consists of 11 items. A higher score indicates greater withdrawal effects. | During each inpatient visit from admission to discharge, up to 24 hours | 
| Impulsivity | Impulsivity is measured by a delayed discounting task (DDT). Participants are presented with a series of choices and will choose to receive pretend money now or after a delay. The task yields a discounting rate. Higher discounting rates indicate higher impulsivity. | During each inpatient visit from admission to discharge, up to 24 hours |