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AXS-05 Phase II Trial on Smoking Behavior

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ClinicalTrials.gov Identifier: NCT03471767
Recruitment Status : Recruiting
First Posted : March 21, 2018
Last Update Posted : November 12, 2018
Sponsor:
Collaborator:
Axsome Therapeutics, Inc.
Information provided by (Responsible Party):
James Davis, Duke University

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 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
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : January 21, 2019

Resource links provided by the National Library of Medicine


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 Name: Wellbutrin SR, Zyban SR




Primary Outcome Measures :
  1. Change in Smoking Intensity [ Time Frame: Baseline to 3-Week Follow-Up Visit ]
    To evaluate the impact of AXS-05 compared to Bupropion (BUP) on smoking cessation, smoking intensity will be measured from baseline to the 3-week follow-up visit for each participant. Smoking intensity refers to the total amount of smoke inhaled by the smoker and includes the number of cigarettes smoked per day. Smoking intensity will be assessed as a latent variable modeled through three predictive factors: (1) salivary cotinine, which will be assessed at all study visits, (2) expired carbon monoxide (CO) breath testing at all study visits and (3) the number of cigarettes smoked per day assessed via daily smoking diaries.


Secondary Outcome Measures :
  1. Change in Smoking Behavior [ Time Frame: 3-Week Follow-Up Visit to 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on smoking abstinence within a 7-day Abstinence Test conducted between the 3-week follow-up and 4-week follow-up study visits. Smoking abstinence will be assessed by self-report diaries and biochemically confirmed via expired CO and salivary cotinine.

  2. Adherence [ Time Frame: 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on adherence to self-administered drug through Medication Use diaries.

  3. Side Effects [ Time Frame: 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on tolerability through weekly, open-ended survey to assess potential side effects.

  4. Tolerance [ Time Frame: 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on the incidence of adverse events or serious adverse events utilizing FDA accepted reporting guidelines on these outcomes.

  5. Urinary Levels of DXM [ Time Frame: 4-Week Follow-Up Visit ]
    To measure urine drug levels of Dextromethorphan (DXM) at weeks 1-4 and assess potential correlation of these levels with smoking behavior and side effects.

  6. Assessing Age as a Potential Covariate/Moderator [ Time Frame: Baseline ]
    To assess age (in years) as a specific baseline variable for an association with smoking behaviors. This data will be collected using a demographic intake survey during the screening visit.

  7. Assessing Gender as a Potential Covariate/Moderator [ Time Frame: Baseline ]
    To assess gender as a specific baseline variable for an association with smoking behaviors. This data will be collected using a demographic intake survey during the screening visit.

  8. Assessing Race as a Potential Covariate/Moderator [ Time Frame: Baseline ]
    To assess race as a specific baseline variable for an association with smoking behavior outcome. This data will be collected using a demographic intake survey during the screening visit.

  9. Assessing Education as a Potential Covariate/Moderator [ Time Frame: Baseline ]
    To assess education (in years) as a specific baseline variable for an association with smoking behaviors. This data will be collected using a demographic intake survey during the screening visit.

  10. Assessing Baseline Nicotine Dependence as a Potential Covariate/Moderator [ Time Frame: Baseline ]
    To assess education (in years) as a specific baseline variable for an association with smoking behaviors. This data will be collected using the Fagerstrom Test for Nicotine Dependence (FTND) survey during the screening visit.

  11. Assessing Stress as a Potential Covariate/Moderator [ Time Frame: Visit 1 ]
    To assess stress as a specific baseline variable for an association with smoking behaviors. This data will be collected using the Perceived Stress Scale-4 (PSS-4) given to participants at the screening visit.

  12. Assessing Anxiety as a Potential Covariate/Moderator [ Time Frame: Visit 1 ]
    To assess anxiety as a specific baseline variable for an association with smoking behaviors. This data will be collected using the State-Trait Anxiety Inventory (STAI) at the screening visit.

  13. Assessing Depression as a Potential Covariate/Moderator [ Time Frame: Visit 1 ]
    To assess depression as a specific baseline variable for an association with smoking behaviors. This data will be collected using the Center for Epidemiological Studies Depression Scale (CES-D).

  14. To Compare the Change in Smoking Urges as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: smoking urges. Smoking urges will be assessed using self-report diaries. Assessment of smoking urges will include the following: urge frequency, urge severity, and irritability.

  15. To Compare the Change in Withdrawal Symptoms as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow-Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: withdrawal symptoms. Withdrawal symptoms will be assessed using self-report diaries.

  16. To Compare the Change in Smoking Reward as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: smoking reward. Smoking Reward will be assessed using the Modified Cigarette Evaluation Questionnaire (mCEQ).

  17. To Compare the Change in Stress as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: Stress. Stress will be assessed across all study visits using the PSS-4.

  18. To Compare the Change in Anxiety as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: anxiety. Anxiety will be assessed across all study visits using the STAI.

  19. To Compare the Change in Depression as a Potential Mediator [ Time Frame: Baseline to 4-Week Follow Up Visit ]
    To compare AXS-05 to BUP on changes from baseline vs. weeks 1-4 Follow-up Visits on the following: depression. Depression will be assessed across all study visits using the CES-D.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03471767


Contacts
Contact: Leah C Thomas, MS, CRC, LRT/CTRS 919-668-9378 leah.thomas@duke.edu
Contact: Jillian Dirkes 919-668-5055 jillian.dirkes@duke.edu

Locations
United States, North Carolina
Duke Center for Smoking Cessation Recruiting
Durham, North Carolina, United States, 27705
Sponsors and Collaborators
James Davis
Axsome Therapeutics, Inc.
Investigators
Principal Investigator: James M Davis, MD Duke Cancer Institute

Responsible Party: James Davis, Medical Director, Duke Center for Smoking Cessation, Duke University
ClinicalTrials.gov Identifier: NCT03471767     History of Changes
Other Study ID Numbers: Pro00089413
First Posted: March 21, 2018    Key Record Dates
Last Update Posted: November 12, 2018
Last Verified: November 2018

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
Nicotine
Bupropion
Dextromethorphan
Ganglionic Stimulants
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Agents
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