AXS-05 Phase II Trial on Smoking Behavior

• ClinicalTrials.gov Identifier: NCT03471767
• Recruitment Status: Completed
• First Posted: March 21, 2018
• Last Update Posted: March 19, 2020
• Sponsor: James Davis
• Collaborator: Axsome Therapeutics, Inc.
• Information provided by (Responsible Party): James Davis, Duke University

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Smoking Cessation; Smoking, Cigarette; Nicotine Dependence	Drug: AXS-05; Drug: Bupropion SR	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants are randomized to either take AXS-05 or BUP SR in parallel for the duration of the study.
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind 4-Week Study to Evaluate the Impact of AXS-05 on Smoking Behavior
• Actual Study Start Date: March 25, 2018
• Actual Primary Completion Date: March 31, 2019
• Actual Study Completion Date: March 31, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: AXS-05; 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; 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.; Other Name: Bupropion/dextromethorphan
Active Comparator: Bupropion SR; 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; 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.; Other Names: Wellbutrin SR; Zyban SR

Outcome Measures

Primary Outcome Measures :

1. Change in Smoking Intensity [ Time Frame: Baseline (V1), 3-Week Follow-Up Visit (V4) ]
   Smoking intensity refers to the total amount of smoke inhaled by the smoker and includes the number of cigarettes smoked per day. Measured through salivary cotinine, expired carbon monoxide (CO) breath testing, and the number of cigarettes smoked per day by composite self-report smoking diaries.

Secondary Outcome Measures :

1. Change in Smoking Behavior [ Time Frame: 3-Week Follow-Up Visit (V4), 4-Week Follow-Up Visit (V5) ]
   7-day point prevalence smoking abstinence. Measured by composite self-report diaries and biochemically confirmed via expired CO and salivary cotinine.
2. Medication Adherence [ Time Frame: Baseline (V1), 3-Week Follow-Up Visit (V4) ]
   Medication adherence is measured by composite self-reported diaries.
3. Medication Tolerance by Self-Reported Side Effects [ Time Frame: Baseline (V1), 3-Week Follow-Up Visit (V4) ]
   Self-reported side effects (open-ended survey questions) with a ranking scale of 1-2 (mild), 3-5 (moderate), 6-7 (severe). Any side effects of 4 or greater will be reviewed by a study medical provider.
4. Medication Tolerance by Serious Adverse Events [ Time Frame: Baseline (V1), 4-Week Follow-Up Visit (V5) ]
   Measured by FDA reporting guidelines on adverse event or serious adverse event designation.
5. Urinary Levels of Dextromethorphan [ Time Frame: Baseline (V1), 3-Week Follow-Up Visit (V4) ]
   Measured via Urinary Dextromethorphan testing.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Key Inclusion Criteria:

1. Age 18 years or above
2. Daily smoker using 10 or more cigarettes per day
3. Willing to be smoke-free for 7 days
4. Is able to provide written informed consent (in English) to participate in the study and able to understand the procedures and study requirements.
5. 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:

1. Current use of a smoking cessation medication (e.g. nicotine replacement, Varenicline, bupropion)
2. Current use of tobacco product other than cigarettes (e.g. e-cigarettes, smokeless tobacco)
3. Not pregnant or breastfeeding
4. Contraindication to the use of bupropion.
5. Additional criteria may apply.

Contacts and Locations

Locations

United States, North Carolina

Duke Center for Smoking Cessation

Durham, North Carolina, United States, 27705

Sponsors and Collaborators

James Davis

Axsome Therapeutics, Inc.

Investigators

• Principal Investigator: James M Davis, MD; Duke Cancer Institute

More Information

• Responsible Party: James Davis, Medical Director, Duke Center for Smoking Cessation, Duke University
• ClinicalTrials.gov Identifier: NCT03471767
• Other Study ID Numbers: Pro00089413
• First Posted: March 21, 2018
• Last Update Posted: March 19, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by James Davis, Duke University:

Smoking cessation; Nicotine dependence; Bupropion; DXM; Nicotine addiction; Cigarette smoking; Dextromethorphan

Additional relevant MeSH terms:

Tobacco Use Disorder; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Dextromethorphan; Bupropion; Antidepressive Agents, Second-Generation; Antidepressive Agents; Psychotropic Drugs; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Antitussive Agents; Respiratory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents