Phase Ib/2a Drug-drug Interaction Study of a Combination of 45mg Dextromethorphan With 105 mg Bupropion

Study Overview
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Brief Summary
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The overall goal of this project is to collect initial human data on the effects of novel compounds on safety (interactions with an opioid drug, e.g., buprenorphine) and early efficacy signals (subjective effects on negative affect, craving, and opioid withdrawal) in OUD subjects currently in MOUD treatment with buprenorphine.

Detailed Description
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The overall goal of this project is to collect initial human data on the effects of novel compounds on safety (interactions with an opioid drug, e.g., buprenorphine) and early efficacy signals (subjective effects on negative affect, craving, and opioid withdrawal) in OUD subjects currently in MOUD treatment with buprenorphine. The compound to be studied in this protocol will be a pre-configured combination of 45mg dextromethorphan with 105 mg Bupropion (AuvelityTM, hereafter referred as Auvelity). Notably, other NMDA receptor antagonists such as ketamine have also been shown to rapidly improve mood and reduce suicidality. OUD has also been linked to histories of trauma and syndromes of negative mood, where opioid use in many individuals was initially motivated by a desire to alleviate a negative mood state. Lastly, using the NIDA Phenotyping Battery, our group has also found negative emotionality to be part of a constellation of neurofunctional domains that are associated with SUD severity. Taken together, providing AUVELITY as an adjunctive treatment to buprenorphine could be an avenue to target crucial underlying mechanisms of OUD and improve OUD treatment outcomes.

Official Title
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Phase Ib/2a Drug-drug Interaction Study of a Combination of 45mg Dextromethorphan With 105 mg Bupropion (AUVELITY) as an Adjunctive Treatment for Buprenorphine/Naloxone for Opioid Use Disorder

Conditions
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Addiction, Opioid Use, Substance Use Disorders, Opioid Use Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Auvelity


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and female subjects between 18 - 65 years of age; Understand the study procedures and provide written informed consent in the English language. Meet current DSM-5 criteria for OUD, of at least moderate severity, currently engaged in MOUD treatment at a buprenorphine-naloxone sublingual film total daily dose ranging from 8mg/2mg to 24mg/6mg or buprenorphine sublingual tablet 5.7mg/1.4mg to 17.1/4.3 daily for at least 2 weeks at screening. Or on a stable dose of depot injectable buprenorphine for at least four months, with at least one week since last depot buprenorphine injection. Have a positive urine drug screen for buprenorphine during screening and upon presenting for the first laboratory day on the clinical research unit to document buprenorphine use; Quick Inventory of Depressive Symptomatology (16-Item) (QIDS-SR16) score of mild or greater (>6) Females must be non-pregnant and non-lactating. Additionally, for females with childbearing potential (ie., have not undergone sterilization via hysterectomy, bilateral tubal ligation, or bilateral oophorectomy, or at least 1 year post-menopausal), participants must agree to use an acceptable form of contraception during study participation and to continue its use for at least 30 days after the last dose of the study drug (e.g, abstinence, intrauterine device, hormonal implant, hormonal patch/ring/pill, condoms (male or female). 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 uncontrolled hypertension, seizure disorder, anorexia nervosa or bulimia, bipolar disorder, schizoaffective disorder, or schizophrenia; Taking antidepressant medications (tricyclic antidepressants, SSRIs, SNRIs, MAOIs), antibiotic linezolid, antiepileptics, or CNS stimulants (amphetamine, methylphenidate) within the two weeks prior to initiation of study medication History of adverse reaction or allergy to dextromethorphan or bupropion Current severe alcohol use disorder or current benzodiazepine use or recent (within last 3 months) discontinuation of alcohol with severe alcohol use disorder or discontinuation of benzodiazepines with severe 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. 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. 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects who are randomized to placebo will receive identical capsules to the test product at the same time periods noted above, administered orally. | Drug: Placebo<br>* Subjects who are randomized to placebo will receive identical capsules to the test product at the same time periods noted above, administered orally.<br>|
| Experimental: Auvelity<br>Orally-administered combination of dextromethorphan with Bupropion (trade name Auvelity) | Drug: Auvelity<br>* Orally-administered combination of 45 mg dextromethorphan with 105 mg Bupropion (trade name Auvelity). Auvelity will initially be administered orally once daily for three days. After 3 days on once daily AUVELITY, the participants will begin taking AUVELITY twice daily for 4 additional days as recommended in the FDA-approved prescribing information.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety- as measured by heart rate | Heart rate (HR) | During each PK study visit from visit start to end, up to approximately 8 hours | 
| Safety- as measured by blood pressure | blood pressure | During each PK study visit from visit start to end, up to approximately 8 hours | 
| Safety- as measured by pulse oximetry | pulse oximetry | During each PK study visit from visit start to end, up to approximately 8 hours | 
| Safety- as measured by respiratory rate | respiratory rate | During each PK study visit from visit start to end, up to approximately 8 hours | 
| Safety- as measured by Adverse events | adverse events | During each PK study visit from visit start to end, up to approximately 8 hours; and from baseline to end of study participation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Buprenorphine PK | Plasma concentration-time profiles of buprenorphine and its metabolite norbuprenorphine | During each PK study visit from visit start to end, up to approximately 8 hours |