RAP: Effect of Ramelteon on Smoking Abstinence

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02560324
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH), National Institutes of Health (NIH) (NIH)
• Enrollment: 140
• Location: 1
• Arms: 2
• Actual Duration (Months): 35
• Patients Per Site Per Month: 4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tobacco Use Disorder	Drug: Ramelteon; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Repurposing Melatonin Receptor Agonists as Adjunct Treatments for Smoking Cessation
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Aug 1, 2018
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ramelteon The study will be performed using 8mg of ramelteon, which is currently marketed for the treatment of sleep problems. The proposed study follows the typical dosing regimen for ramelteon (8mg once a day) for 5 days during each quit assessment period. Ramelteon will be purchased and packaged into blister packs by the Investigational Drug Service (IDS) at the University of Pennsylvania. In accordance with FDA recommendations, subjects will be instructed to take study medication within 30 min prior to going to bed and avoid taking study medication with or immediately after a high fat meal.	Drug: Ramelteon
Placebo Comparator: Placebo 5-day placebo-controlled medication period. Placebo ingredients will be purchased, encapsulated, and packaged into blister packs by the IDS at UPenn. Both active medication and placebo will look identical. The study medication assignments for each participant in this project is randomized and counterbalanced. This means that approximately 50% of participants will take ramelteon during the first medication period, followed by the placebo in the second medication period. Alternatively, approximately 50% of participants will take the placebo during the first medication period, followed by ramelteon during the second medication period.	Drug: Placebo; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Subjective Sleep Disturbance [Week 2 and Week 6]

   Sleep onset latency will be assessed via daily sleep diaries during each quit assessment.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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:

2. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam).

3. Anti-psychotic medications (e.g., thorazine, Seroquel).

4. Mood-stabilizers (e.g., Lithium, Lamictal/lamotrigine, valproic acid, Neurontin/gabapentin, Topamax/topiramate, Tegretol/carbamazepine).

5. Prescription stimulants (e.g., Provigil, Ritalin, Adderall).

6. Medications contraindicated with ramelteon (e.g., fluvoxamine, buprenorphine or other medications metabolized by certain cytochrome P450 enzymes)

7. 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):

8. Sleep medications (e.g., zolpidem/Ambien, eszopiclone/Lunesta)

9. Over-the-counter sleep aids (e.g., melatonin, diphenhydramine/Benadryl)

10. 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.

11. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Interdisciplinary Research on Nicotine Addiction, School of Medicine, University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Institute on Drug Abuse (NIDA)
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Rebecca Ashare, Ph.D., University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 16, 2018

More Information

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02560324
• Other Study ID Numbers: 823286; R21DA040902
• First Posted: Sep 25, 2015
• Last Update Posted: Nov 4, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by University of Pennsylvania: Ramelteon; Nicotine; Nicotine dependence; Insomnia; Tobacco Dependence
• Additional relevant MeSH terms: Tobacco Use Disorder

Study Results

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 Detail	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.

Arm/Group Title	Ramelteon Then Placebo	Placebo Then Ramelteon
Arm/Group Description	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.	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.
Period Title: Period 1 (2 Weeks)
STARTED	35	34
COMPLETED	23	25
NOT COMPLETED	12	9
Period Title: Period 1 (2 Weeks)
STARTED	23	25
COMPLETED	23	23
NOT COMPLETED	0	2
Period Title: Period 1 (2 Weeks)
STARTED	23	23
COMPLETED	22	21
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Ramelteon Then Placebo	Placebo Then Ramelteon	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	22	21	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.6 (8.9)	52.1 (7.4)	50 (8.2)
Sex: Female, Male (Count of Participants)
Female	6 27.3%	10 47.6%	16 37.2%
Male	16 72.7%	11 52.4%	27 62.8%
Race/Ethnicity, Customized (Count of Participants)
African American	15 68.2%	16 76.2%	31 72.1%
White	6 27.3%	5 23.8%	11 25.6%
More than one race	1 4.5%	0 0%	1 2.3%
Cigarettes per day (cigarettes smoked per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cigarettes smoked per day]	12.1 (3.3)	16.6 (8.4)	14.3 (6.7)
Education (Count of Participants)
HS/GED or less	9 40.9%	13 61.9%	22 51.2%
Some college or more	13 59.1%	8 38.1%	21 48.8%
Income (Count of Participants)
< $20,000	16 72.7%	13 61.9%	29 67.4%
> $20,000	6 27.3%	8 38.1%	14 32.6%

Outcome Measures

1. Primary Outcome

Title	Total Number of Smoke-free Days (Biochemically Verified) During Each 5-day Quit Assessment.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Participants received 8mg of Ramelteon once per day + transdermal nicotine for 1 week.	Participants received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week.
Measure Participants	43	43
Mean (Standard Deviation) [days of smoking abstinence]	2.7 (1.6)	2.6 (1.6)

2. Secondary Outcome

Title	Subjective Sleep Disturbance
Description	Sleep onset latency will be assessed via daily sleep diaries during each quit assessment.
Time Frame	Week 2 and Week 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Participants received 8mg of Ramelteon once per day + transdermal nicotine for 1 week.	Participants received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week.
Measure Participants	43	43
Mean (Standard Deviation) [minutes]	20.8 (12.7)	23.7 (23.9)

3. Secondary Outcome

Title	Objective Sleep Disturbance
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon	Placebo
Arm/Group Description	Participants received 8mg of Ramelteon once per day + transdermal nicotine for 1 week.	Participants received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week.
Measure Participants	43	43
Mean (Standard Deviation) [% of time in bed spent sleeping]	86.7 (12.5)	86.6 (12.5)

4. Secondary Outcome

Title	Side Effects of Ramelteon
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ramelteon (Baseline)	Placebo (Baseline)	Ramelteon (Quit Week)	Placebo (Quit Week)
Arm/Group Description	Before participants received 8mg of Ramelteon once per day + transdermal nicotine for 1 week.	Before participants received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week.	Participants received 8mg of Ramelteon once per day + transdermal nicotine for 1 week.	Participants received Placebo pills (matching Ramelteon 8mg pills) once per day + transdermal nicotine for 1 week.
Measure Participants	43	43	43	43
Mean (Standard Deviation) [scores on a scale]	0.028 (0.057)	0.034 (0.047)	0.05 (0.078)	0.027 (0.041)

Adverse Events

Time Frame	Through study completion, an average of 7 weeks
Arm/Group Title	Ramelteon		Placebo
Arm/Group Description	Participants received medication (8mg of Ramelteon) once per day + transdermal nicotine for 1 week.		Participants received Placebo once per day + transdermal nicotine for 1 week.
All Cause Mortality
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/57 (0%)
Serious Adverse Events
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/58 (0%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	Ramelteon		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/58 (37.9%)		21/57 (36.8%)
General disorders
Insomnia/Trouble Sleeping	12/58 (20.7%)	34	9/57 (15.8%)	14
Nervous system disorders
Headache	11/58 (19%)	21	12/57 (21.1%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.