Tobacco Use Disorder
Conditions
Keywords
Ramelteon, Nicotine, Nicotine dependence, Insomnia, Tobacco Dependence
Brief summary
This is a randomized, double-blind, placebo-controlled crossover study to test whether a medication called ramelteon (Brand Name: Remeron) will help smokers quit and whether it reduces sleep problems that smokers experience during a quit attempt.
Detailed description
Ramelteon, an FDA-approved treatment for insomnia, is used to treat sleep problems (e.g., specifically sleep onset latency) by enhancing melatonin receptor function. The investigators propose a randomized double-blind placebo-controlled crossover study. Fifty chronic smokers will complete a validated procedure for screening new medications. All subjects will receive 8mg ramelteon and placebo. The order in which ramelteon and placebo is received will be randomized across participants. This is a 6-week study consisting of two 2-week medication phases separated by a 2-week washout. Each phase includes 1 week of ad libitum smoking (baseline) and 1 week of medication (ramelteon vs. placebo) plus transdermal nicotine patches while trying to abstain from smoking (quit assessment). Subjects will complete the same procedures during each study phase. Following completion of the study, participants will be offered standard smoking cessation treatment. For the duration of the study, subjects will be asked to keep sleep diaries and to wear an armband while sleeping, which provides objective indices of sleep duration and quality (SensewearPro® armband). The primary outcome will be the total number of days abstinent (out of 5) during each quit assessment period. Intermediate outcomes include sleep onset latency (self-report) and sleep efficiency (SensewearPro®). This study will provide information about the role of the melatonin system during brief abstinence and whether enhancing melatonin reduces abstinence-induced sleep problems that promote smoking relapse. Information obtained in this study may further establish the role of sleep disturbance in promoting smoking relapse.
Interventions
DRUGRamelteon
DRUGPlacebo
Sponsors
National Institute on Drug Abuse (NIDA)
National Institutes of Health (NIH)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Smokers who are between 18 and 65 years of age who self-report smoking at least 10 cigarettes per day for at least the last 6 months. 2. Interest in quitting smoking in the next 2 to 4 months. 3. Healthy as determined by the Study Physician, based on a medical evaluation including medical history and physical examination, and psychiatric evaluation. 4. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form. 5. Women of childbearing potential must consent to use a medically accepted method of birth control while participating in the study (e.g., condoms and spermicide, oral contraceptive, Depo-provera injection, contraceptive patch, tubal ligation).
Exclusion criteria
Smoking Behavior: 1. Current enrollment in a smoking cessation program, or use of other smoking cessation medications in the last month or plans to do either in the next 2 months. 2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes. 3. Provide a carbon monoxide (CO) breath sample reading less than 10 parts per million (ppm) at Intake. Alcohol/Drugs: 1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the past 6 months. Subjects will be told to limit or avoid the use of alcohol while in the study to avoid any adverse reactions to the study medication. 2. Self-reports substance use disorders (abuse or dependence involving alcohol, opiates, cocaine or other stimulants, or benzodiazepines; not nicotine) in the last 6 months. 3. Providing a breath alcohol concentration (BrAC) reading of greater than or equal to 0.01 during any session. 4. A positive urine drug screen for cocaine, amphetamines, methamphetamines, benzodiazepines, PCP, methadone, barbiturates, marijuana, ecstasy (MDMA), oxycodone, tricyclic antidepressants, and opiates (low level cut-off 300 ng/mL) during any session. Psychiatric Exclusion (as determined by self-report on phone screen and/or through MINI during Intake): 1. Current psychiatric disorders (depression, bipolar, schizophrenia, hypomanic/manic episode) as determined by self-report and/or MINI psychological interview. 2. Past history of psychiatric disorders (including suicide attempt) other than depression as determined by self-report and/or MINI psychological interview. 3. Suicide risk score on MINI greater than 1. Medical: 1. Females who are currently pregnant, planning a pregnancy during the study, or currently breastfeeding/lactating. All female subjects shall undergo a urine pregnancy test at the Intake and must agree in writing to use an approved method of contraception. Following enrollment, pregnancy tests will be conducted at the beginning of each baseline week. 2. For those with a history of jaundice/liver disease: liver function tests more than 20% outside of the normal range; Gamma-glutamyl Transpepsidase (GGT) values more than 20% outside of the normal range. If Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be evaluated for clinical significance by the Study Physician and eligibility will determined on a case-by-case basis. 3. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in the past 6 months. 4. Endocrine or metabolic disorders (e.g., Type-I diabetes). 5. Blood disorders (e.g., anemia or hemophilia). 6. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than 99)\*. 7. Clinically significant dyssomnia (except insomnia; e.g. sleep apnea syndrome, narcolepsy). * Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99 mmHg at the Intake visit will be instructed to sit quietly for 10 minutes. Then the participant will have a second blood pressure reading taken after a 10 minute period. If, after the second reading the SBP greater than 159 mmHg and the DBP greater than 99 mmHg, the individual will be instructed to sit comfortably for 10 minutes and then have a third blood pressure reading. If, after the third reading the SBP greater than 159 mmHg and the DBP greater than 99 mmHg, the individual will be ineligible to participate. Medication: 1. Current use or recent discontinuation (within the past month) of any of the following medications: 1. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam). 2. Anti-psychotic medications (e.g., thorazine, Seroquel). 3. Mood-stabilizers (e.g., Lithium, Lamictal/lamotrigine, valproic acid, Neurontin/gabapentin, Topamax/topiramate, Tegretol/carbamazepine). 4. Prescription stimulants (e.g., Provigil, Ritalin, Adderall). 5. Medications contraindicated with ramelteon (e.g., fluvoxamine, buprenorphine or other medications metabolized by certain cytochrome P450 enzymes) 2. Current use or recent discontinuation (within the past 2 weeks) of any of the following medications (subjects must agree to refrain from using any other sleep aids while enrolled in the study): 1. Sleep medications (e.g., zolpidem/Ambien, eszopiclone/Lunesta) 2. Over-the-counter sleep aids (e.g., melatonin, diphenhydramine/Benadryl) 3. Daily use of opiate-containing medications for chronic pain (Duragesic/fentanyl patches, Percocet, Oxycontin). Smokers who report taking opiate-containing medications on an as-needed basis will be instructed to refrain from use until their study participation is over and that they will be tested to ensure they have complied with this requirement. 4. Known allergy to study medication (e.g., angioedema). Subjects will be instructed to refrain from using any study prohibited drugs/medications (both recreational and prescription) throughout their participation in the study. After final eligibility is confirmed, subjects who report taking contraindicated medication(s) over the course of the study period may only remain eligible if the Study Physician and/or Principal Investigator determines that the contraindicated medication(s) do/did not impact the study design, data quality, and/or subject safety/welfare. Subjects are permitted to take necessary prescription medications not included within the exclusion list during the study. General Exclusion: 1. Current, anticipated, or pending enrollment in another research program over the next 2-3 months that could potentially affect subject safety and/or the study data/design as determined by the Principal Investigator and/or Study Physician. 2. Not planning to live in the area for the next two months. 3. Currently working night shift or rotating shift or other habitual alteration of the sleep/wake cycle. 4. Allergy to latex or adhesive tape. 5. Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator. 6. Not able to effectively communicate in English (reading, writing, speaking). 7. Missing 2 or more doses during the medication period determined by self-report.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Smoke-free Days (Biochemically Verified) During Each 5-day Quit Assessment. | Week 2 and Week 6 | The quit assessment will begin the Monday morning of each quit week and will end that Friday. The total number of days of abstinence will be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Sleep Disturbance | Week 2 and Week 6 | Sleep onset latency will be assessed via daily sleep diaries during each quit assessment. |
| Objective Sleep Disturbance | Week 2 and Week 6 | Sleep efficiency (% of time in bed spent sleeping) will be assessed via the SensewearPro armbands during each quit assessment. |
| Side Effects of Ramelteon | Baseline (weeks 1 and 5); Quit assessments (weeks 2 and 6) | Side effects will be assessed at each in-person visit using a Side Effects Checklist (SEC) that lists 21 possible side effects of ramelteon. The scale for rating each side effect is None=0, Mild=1, Moderate=2, and Severe=3. The higher the score, the more side effects reported by the participant. The minimum score is 0 and the maximum score is 3 for each possible item on the scale. The Outcome Measure is an average of the 21 listed side effects. |
Countries
United States
Participant flow
Recruitment details
697 potential participants were pre-screened over the phone for eligibility between September 2015 and August 2018. 140 potential participants attended an in-person eligibility screen at the research clinic.
Pre-assignment details
69 of 140 participants met eligibility criteria and were randomized. For participants who were not randomized: 61 did not meet inclusion criteria, 5 declined to participate, 4 missed the baseline visit, and 1 is unknown.
Participants by arm
| Arm | Count |
|---|---|
| Ramelteon Then Placebo Participants smoked ad libitum for 1 week and then received 8mg of Ramelteon once per day + transdermal nicotine for 1 week. After a washout period of 2 weeks, participants again smoked ad libitum for 1 week, then received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week. | 22 |
| Placebo Then Ramelteon Participants smoked ad libitum for 1 week and then received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week. After a washout period of 2 weeks, participants again smoked ad libitum for 1 week, then received 8mg of Ramelteon once per day + transdermal nicotine for 1 week. | 21 |
| Total | 43 |
Baseline characteristics
| Characteristic | Ramelteon Then Placebo | Placebo Then Ramelteon | Total |
|---|---|---|---|
| Age, Continuous | 49.6 years STANDARD_DEVIATION 8.9 | 52.1 years STANDARD_DEVIATION 7.4 | 50 years STANDARD_DEVIATION 8.2 |
| Cigarettes per day | 12.1 cigarettes smoked per day STANDARD_DEVIATION 3.3 | 16.6 cigarettes smoked per day STANDARD_DEVIATION 8.4 | 14.3 cigarettes smoked per day STANDARD_DEVIATION 6.7 |
| Education HS/GED or less | 9 Participants | 13 Participants | 22 Participants |
| Education Some college or more | 13 Participants | 8 Participants | 21 Participants |
| Income < $20,000 | 16 Participants | 13 Participants | 29 Participants |
| Income > $20,000 | 6 Participants | 8 Participants | 14 Participants |
| Race/Ethnicity, Customized African American | 15 Participants | 16 Participants | 31 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 16 Participants | 11 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 57 |
| other Total, other adverse events | 22 / 58 | 21 / 57 |
| serious Total, serious adverse events | 0 / 58 | 0 / 57 |
Outcome results
Primary
Total Number of Smoke-free Days (Biochemically Verified) During Each 5-day Quit Assessment.
The quit assessment will begin the Monday morning of each quit week and will end that Friday. The total number of days of abstinence will be assessed.
Time frame: Week 2 and Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Total Number of Smoke-free Days (Biochemically Verified) During Each 5-day Quit Assessment. | 2.7 days of smoking abstinence | Standard Deviation 1.6 |
| Placebo | Total Number of Smoke-free Days (Biochemically Verified) During Each 5-day Quit Assessment. | 2.6 days of smoking abstinence | Standard Deviation 1.6 |
Secondary
Objective Sleep Disturbance
Sleep efficiency (% of time in bed spent sleeping) will be assessed via the SensewearPro armbands during each quit assessment.
Time frame: Week 2 and Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Objective Sleep Disturbance | 86.7 % of time in bed spent sleeping | Standard Deviation 12.5 |
| Placebo | Objective Sleep Disturbance | 86.6 % of time in bed spent sleeping | Standard Deviation 12.5 |
Secondary
Side Effects of Ramelteon
Side effects will be assessed at each in-person visit using a Side Effects Checklist (SEC) that lists 21 possible side effects of ramelteon. The scale for rating each side effect is None=0, Mild=1, Moderate=2, and Severe=3. The higher the score, the more side effects reported by the participant. The minimum score is 0 and the maximum score is 3 for each possible item on the scale. The Outcome Measure is an average of the 21 listed side effects.
Time frame: Baseline (weeks 1 and 5); Quit assessments (weeks 2 and 6)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Side Effects of Ramelteon | 0.028 scores on a scale | Standard Deviation 0.057 |
| Placebo | Side Effects of Ramelteon | 0.034 scores on a scale | Standard Deviation 0.047 |
| Ramelteon (Quit Week) | Side Effects of Ramelteon | 0.05 scores on a scale | Standard Deviation 0.078 |
| Placebo (Quit Week) | Side Effects of Ramelteon | 0.027 scores on a scale | Standard Deviation 0.041 |
Secondary
Subjective Sleep Disturbance
Sleep onset latency will be assessed via daily sleep diaries during each quit assessment.
Time frame: Week 2 and Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramelteon | Subjective Sleep Disturbance | 20.8 minutes | Standard Deviation 12.7 |
| Placebo | Subjective Sleep Disturbance | 23.7 minutes | Standard Deviation 23.9 |