Nicotine Dependence, Smoking Cessation, Smoking, Cigarette
Conditions
Keywords
Smoking cessation, Nicotine dependence, Bupropion, DXM, Nicotine addiction, Cigarette smoking, Dextromethorphan
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.
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.
Interventions
DRUGAXS-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.
DRUGBupropion 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.
Sponsors
Axsome Therapeutics, Inc.
James Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Intervention model description
Participants are randomized to either take AXS-05 or BUP SR in parallel for the duration of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Smoking Intensity | Baseline (V1), 3-Week Follow-Up Visit (V4) | Smoking intensity refers to the number of cigarettes smoked per day. |
| Percentage of Participants Who Experienced a More Than 50% Reduction in Expired Carbon Monoxide (CO) Levels | Baseline (V1), 3-Week Follow-Up Visit (V4) | A biochemical marker of smoking intensity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Medication Tolerance by Self-Reported Side Effects | Baseline (V1), 3-Week Follow-Up Visit (V4) | 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). |
| Change in Smoking Behavior | 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. |
| Urinary Levels of Dextromethorphan | 3-Week Follow-Up Visit (V4) | Measured via Urinary Dextromethorphan testing. |
| Medication Tolerance by Serious Adverse Events | Baseline (V1), 4-Week Follow-Up Visit (V5) | Measured by FDA reporting guidelines on adverse event or serious adverse event designation. |
| Medication Adherence | Baseline (V1), 3-Week Follow-Up Visit (V4) | Medication adherence is measured by composite self-reported diaries. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AXS-05 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 for 4 weeks. | 31 |
| Bupropion SR 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 for 4 weeks | 27 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | PI Withdrawal | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | AXS-05 | Bupropion SR | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 26 Participants | 53 Participants |
| Age, Continuous | 50.03 years STANDARD_DEVIATION 13.61 | 46.48 years STANDARD_DEVIATION 11.34 | 48.38 years STANDARD_DEVIATION 12.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 25 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 15 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 11 Participants | 33 Participants |
| Region of Enrollment United States | 31 Participants | 27 Participants | 58 Participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 27 |
| other Total, other adverse events | 4 / 31 | 8 / 27 |
| serious Total, serious adverse events | 2 / 31 | 1 / 27 |
Outcome results
Primary
Change in Smoking Intensity
Smoking intensity refers to the number of cigarettes smoked per day.
Time frame: Baseline (V1), 3-Week Follow-Up Visit (V4)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXS-05 | Change in Smoking Intensity | -8.49 change in cigarettes per day | Standard Error 0.37 |
| Bupropion SR | Change in Smoking Intensity | -6.79 change in cigarettes per day | Standard Error 0.39 |
p-value: 0.0595% CI: [-2.75, -0.65]t-test, 2 sided
Primary
Percentage of Participants Who Experienced a More Than 50% Reduction in Expired Carbon Monoxide (CO) Levels
A biochemical marker of smoking intensity.
Time frame: Baseline (V1), 3-Week Follow-Up Visit (V4)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AXS-05 | Percentage of Participants Who Experienced a More Than 50% Reduction in Expired Carbon Monoxide (CO) Levels | 52.0 percentage of participants |
| Bupropion SR | Percentage of Participants Who Experienced a More Than 50% Reduction in Expired Carbon Monoxide (CO) Levels | 30.4 percentage of participants |
p-value: 0.15t-test, 2 sided
Secondary
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.
Time frame: 3-Week Follow-Up Visit (V4), 4-Week Follow-Up Visit (V5)
Population: Not all participants participated in this abstinence test.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AXS-05 | Change in Smoking Behavior | 16 Participants |
| Bupropion SR | Change in Smoking Behavior | 12 Participants |
Secondary
Medication Adherence
Medication adherence is measured by composite self-reported diaries.
Time frame: Baseline (V1), 3-Week Follow-Up Visit (V4)
Population: Not all participants participated in the full reporting period (dropped out or withdrew).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXS-05 | Medication Adherence | 97.08 percentage of adherence | Standard Deviation 5.97 |
| Bupropion SR | Medication Adherence | 96.60 percentage of adherence | Standard Deviation 5.27 |
Secondary
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).
Time frame: Baseline (V1), 3-Week Follow-Up Visit (V4)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AXS-05 | Medication Tolerance by Self-Reported Side Effects | 7 Participants |
| Bupropion SR | Medication Tolerance by Self-Reported Side Effects | 5 Participants |
Secondary
Medication Tolerance by Serious Adverse Events
Measured by FDA reporting guidelines on adverse event or serious adverse event designation.
Time frame: Baseline (V1), 4-Week Follow-Up Visit (V5)
Population: There were no study-related serious adverse events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AXS-05 | Medication Tolerance by Serious Adverse Events | 0 Participants |
| Bupropion SR | Medication Tolerance by Serious Adverse Events | 0 Participants |
Secondary
Urinary Levels of Dextromethorphan
Measured via Urinary Dextromethorphan testing.
Time frame: 3-Week Follow-Up Visit (V4)
Population: Data not collected on the Bupropion SR group. Some individuals in the AXS-05 group had missing data or withdrew/dropped out early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXS-05 | Urinary Levels of Dextromethorphan | 1902.1 ng/mL | Standard Deviation 1304.4 |