AXS-05 Phase II Trial on Smoking Behavior

Study Overview
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Brief Summary
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This research study is designed with the purpose of evaluating a new drug, combination Dextromethorphan-Bupropion (AXS-05), for its effects on smoking behavior.

Detailed Description
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This study aims to investigate the potential efficacy of a combination of two FDA-approved agents, sustained release (SR) Bupropion (BUP) and immediate release (IR) Dextromethorphan (DXM), for the purpose of smoking cessation treatment. DXM, a widely used over-the-counter cough suppressant, is a nicotine receptor antagonist. In fact, studies by Duke's Center for Smoking Cessation (CSC) have shown that administration of DXM leads to a decrease in self-administration of nicotine in nicotine-dependent rats. DXM, however, has not been studied in humans. DXM, when taken alone, is not expected to be useful for treating nicotine dependence in humans given DXM rapidly metabolizes in humans via CYP2D6. As a result, therapeutic concentrations needed to bind to nicotine receptors are not obtained. Therapeutic concentrations of DXM are required, therefore, to allow DXM to bind to nicotine receptors and act as a nicotine antagonist. In order to attain therapeutic concentrations of DXM a metabolism inhibitor must be introduced. BUP is a well-known FDA approved smoking cessation medication that has been shown to inhibit the metabolism of DXM. When BUP is co-administered with DXM to healthy volunteers, a significant increase in DXM plasma levels is observed. Currently, Axsome Therapeutics Inc. (Axsome) is developing and testing an oral fixed-dose combination of IR DXM with SR BUP to achieve therapeutic concentrations of DXM. This investigational drug has been named AXS-05. Axsome has found AXS-05 to be generally safe and well-tolerated in three Phase 1 studies. The adverse event profile of AXS-05 was similar to that of BUP alone. Given the distinct mechanisms by which BUP and DXM interact, it is hoped that combining DXM and BUP will prove more efficacious than either drug administered alone for the purpose of tobacco use treatment in humans.

Official Title
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A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior

Conditions
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Smoking Cessation, Smoking, Cigarette, Nicotine Dependence

Intervention / Treatment
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* Drug: AXS-05
* Drug: Bupropion SR


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age 18 years or above Daily smoker using 10 or more cigarettes per day Willing to be smoke-free for 7 days Is able to provide written informed consent (in English) to participate in the study and able to understand the procedures and study requirements. Is willing to voluntarily sign and date an informed consent form that is approved by an institutional review board before the conduct of any study procedure. Key Exclusion Criteria: Current use of a smoking cessation medication (e.g. nicotine replacement, Varenicline, bupropion) Current use of tobacco product other than cigarettes (e.g. e-cigarettes, smokeless tobacco) Not pregnant or breastfeeding Contraindication to the use of bupropion. Additional criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Participants are randomized to either take AXS-05 or BUP SR in parallel for the duration of the study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AXS-05<br>Participants will receive AXS-05 (Dextromethorphan Immediate Release + Bupropion Sustained Release) for 4 weeks and will be instructed to take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal. | Drug: AXS-05<br>* Dextromethorphan Immediate Release + Bupropion Sustained Release: Take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal.<br>* Other names: Bupropion/dextromethorphan;|
| Active Comparator: Bupropion SR<br>Participants will receive Bupropion SR (Bupropion Sustained Release) for 4 weeks and will be instructed to take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal. | Drug: Bupropion SR<br>* Bupropion Sustained Release: Take 1 tablet two times per day, at least 8 hours apart and 1 hour prior to a meal, and 2 hours after a meal.<br>* Other names: Zyban SR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Smoking Intensity | Smoking intensity refers to the number of cigarettes smoked per day. | Baseline (V1), 3-Week Follow-Up Visit (V4) | 
| Percentage of Participants Who Experienced a More Than 50% Reduction in Expired Carbon Monoxide (CO) Levels | A biochemical marker of smoking intensity. | Baseline (V1), 3-Week Follow-Up Visit (V4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Smoking Behavior | 7-day point prevalence smoking abstinence. Measured by composite self-report diaries and biochemically confirmed via expired CO and salivary cotinine. | 3-Week Follow-Up Visit (V4), 4-Week Follow-Up Visit (V5) | 
| Medication Adherence | Medication adherence is measured by composite self-reported diaries. | Baseline (V1), 3-Week Follow-Up Visit (V4) | 
| Medication Tolerance by Self-Reported Side Effects | Number of participants who scored 3 or higher on a 7-point Likert scale ranking severity of side effects (1-2 mild; 3-5 moderate; 6-7 severe). | Baseline (V1), 3-Week Follow-Up Visit (V4) | 
| Medication Tolerance by Serious Adverse Events | Measured by FDA reporting guidelines on adverse event or serious adverse event designation. | Baseline (V1), 4-Week Follow-Up Visit (V5) | 
| Urinary Levels of Dextromethorphan | Measured via Urinary Dextromethorphan testing. | 3-Week Follow-Up Visit (V4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoking cessation, Nicotine dependence, Bupropion, DXM, Nicotine addiction, Cigarette smoking, Dextromethorphan