AXS-05 Phase II Trial on Smoking Behavior

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

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

Study Overview

• Status: Completed
• Conditions: Smoking Cessation; Nicotine Dependence; Smoking, Cigarette
• Intervention / Treatment: Drug: AXS-05; Drug: Bupropion SR

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 Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Center for Smoking Cessation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: James Davis
• Collaborators: Axsome Therapeutics, Inc.
• Investigators: Principal Investigator: James M Davis, MD, Duke Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2018
• Primary Completion (Actual): March 31, 2019
• Study Completion (Actual): March 31, 2019

Study Registration Dates

• First Submitted: March 19, 2018
• First Submitted That Met QC Criteria: March 19, 2018
• First Posted (Actual): March 21, 2018

Study Record Updates

• Last Update Posted (Actual): December 19, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Smoking cessation; Bupropion; Nicotine addiction; Cigarette smoking; Dextromethorphan; Nicotine dependence; DXM
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Dopamine Uptake Inhibitors; Antitussive Agents; Bupropion; Dextromethorphan
• Other Study ID Numbers: Pro00089413

Drug and device information, study documents

• 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