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Multimodal Neuroimaging Genetic Biomarkers of Nicotine AddictionSeverity

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ClinicalTrials.gov Identifier: NCT01867411
Recruitment Status : Recruiting
First Posted : June 4, 2013
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Drug Abuse (NIDA) )

Brief Summary:

Background:

- Smoking is a difficult habit to quit, and some people find it more difficult to quit than others do. Nicotine is the substance in cigarettes that makes smoking so addictive. Nicotine changes some patterns of brain activity, and smokers have differences in brain activity when compared to non-smokers. Some genes make it more likely that a person will become addicted to smoking. Researchers want to study how nicotine interacts with genes and brain activity. This may help develop better treatments to help people quit smoking.

Objectives:

- To develop a test of nicotine dependence, using brain activity and genetic analysis, which may be useful in predicting success in smoking cessation and in the development of new smoking cessation treatment targets.

Eligibility:

  • Main group: Current smokers between 18 and 55 years of age who are seeking treatment to quit.
  • Comparison group: Current smokers between 18 and 55 years of age who are not seeking to quit.
  • Comparison group: Healthy former smokers between 18 and 55 years of age.
  • Comparison group: Healthy nonsmoking volunteers between 18 and 55 years of age.

Design:

  • Participants will be screened with a physical exam and medical history. Blood samples will be collected.
  • The three comparison groups will have one magnetic resonance imaging (MRI) scan session. They will have tests of thinking, concentration, and memory both inside the scanner, and while sitting in front of a computer.
  • Current smokers who are trying to quit must be willing to undergo a course of nicotine treatment that includes weekly counseling (for 12 weeks) and e-cigarettes. Participants will attempt smoking abstinence and will have a total of 6 MRI scanning sessions. They will do thinking, concentration, and memory tasks inside and outside of the scanner.
  • For smokers, the first scanning session will take place before they attempt to quit. This will be a baseline scan. The second scanning session will take place 48 hours after having their last real cigarette. After this scan, they will use electronic cigarettes to help quit their habit.
  • After using e-cigarettes for two weeks, smokers will have a third scan session.. They will then gradually taper their use of the electronic cigarettes over the course of three weeks, at which point they will be nicotine abstinent.
  • After about 5 weeks of abstinence, they will have the fourth scan. The fifth scan will be approximately 6 months after start of the study, and the final scan will take place at about 1 year from the study start.
  • Smokers will continue to receive support on quitting smoking until the study ends at about 1 year.

Condition or disease
Nicotine Dependence

Detailed Description:

Objective: To develop a neuroimaging/genetic/epigenetic biomarker of nicotine dependence severity that may be useful in predicting success in smoking cessation and in development of new smoking cessation treatment targets.

Study population: Four groups will be studied: target group of treatment seeking smokers; nontreatment seeking current smokers; never smokers and former smokers. We estimate that we will need n=50/group completers to have sufficient power to develop the brain/genetics biomarkers.

Design: This study consists of a 4 group between/within subject design. The experimental group will proceed in 4 phases: Baseline (scan 1), peak withdrawal (scan 2), stable on e-cigarettes (scan 3), and complete abstinence (scans 4-6). Counseling will start after the first scan session and will generally continue weekly until scan 4 (about 12 weeks). After scan 4, therapeutic support will be provided at least monthly via phone until completion of the protocol. The non-treatment seeking smoker comparison group will be scanned twice; at baseline (scan 1) and at peak withdrawal (scan 2). Each of the non-smoking comparison groups (non- and Ex-smokers) will be scanned only at baseline (scan 1). Genetic and epigenetic markers will be obtained in all groups.

Outcome measures: Network and multivariate pattern analysis, behavior on a decision making task and task based and resting state blood oxygen level-dependent (BOLD) activation in neural circuits relevant to nicotine addiction during fMRI scanning. Secondary outcomes include BOLD response comparisons between e-cigarettes and smoking and genetic markers of nicotine addiction and relapse susceptibility.

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Study Type : Observational
Estimated Enrollment : 360 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Multimodal Neuroimaging Genetic Biomarkers of Nicotine Addiction Severity
Actual Study Start Date : November 6, 2013
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2024

Group/Cohort
ex-smokers
former smokers who have quit
never smokers
never smoked
non-treatment seeking smokers
smokers not interested in quitting smoking
Treatment seeking smokers
smokers interested in quitting smoking



Primary Outcome Measures :
  1. Change in BOLD signal and functional connectivity related to task parameters, between drug conditions (i.e. on and off nicotine) and between groups [ Time Frame: each scan visit ]
    1)Change in BOLD signal and functional connectivity related to task parameters, between drug conditions (i.e. on and off nicotine) and between groups: will provide important insight into the neurobiological mechanisms underlying acute and chronic nicotinewithdrawal, in particular those related to anhedonia, negative affect, cognitive control and impulsive decision making.

  2. Genetic and epigenetic data [ Time Frame: each scan visit ]
    2)Genetic and epigenetic data. These data will be included into the network and pattern classification models discussed above as features in the classifier. They will also be used as regressors, covariates or dichotomous variable in the above BOLD task analysis.

  3. Resting state MRI at followup [ Time Frame: each scan visit (4 weeks, 3, 6 and 12 months) ]
    3)Resting state MRI at follow-up. Resting state MRI will be assessed between- and within- groups as a function of relapse status and time since last treatment visit at each of the follow-up time-points (4weeks, 3, 6 and 12 months). These data will be entered into the network and pattern classification models discussed above. This will allow us to address the following questions:i. What characteristics of rsFC are associated with treatment success (vs. failure)? ii. Are there characteristics of rsFC that vary as a function of time post-treatment in successfully abstinent individuals?

  4. Behavioral performance on each task [ Time Frame: each scan visit ]
    4)Behavioral performance on each of the tasks assessing working memory, attention, processing speed, inhibitory control processes, cognitive control, reward responsiveness, amygdala, striatal, and impulsive decision making (e.g., reaction time, error rate, hit rate, reward bias): will provide task-related parameters necessary for analysis of BOLD and resting state data. Performance data will function as a secondary outcome by providing behavioral validation of acute and chronic nicotine withdrawal effects.

  5. Self-reported craving, withdrawal symptoms & mood/affect [ Time Frame: each scan visit ]
    5)Self-reported craving, withdrawal symptoms and mood/affect: will be employed as regressors in the analysis of task and resting BOLD data. They will also provide the primary means of validating the acute nicotine withdrawal manipulation.

  6. Smoking status at 4wks, 3, 6 and 12 months. [ Time Frame: each scan visit ]
    6)Smoking status at 4 weeks, 3, 6 and 12 months: Smoking status (relapse vs. abstinent) at each of the follow-up time points will be based on 7-day point prevalence defined as no smoking (not even a puff) or use of any tobacco products for the past 7 days. This is astandard method of assessing abstinence and dichotomizing relapse status at follow-up. Whenever abstinence at follow-up is assessed in-person, self-reported abstinence will be corroborated with breath COand urine cotinine levels.


Secondary Outcome Measures :
  1. Structural MRI and DTI data [ Time Frame: each visit ]
    2)Structural MRI and DTI data

  2. Ratings and scores on self-report characterization measures [ Time Frame: each visit ]
    1)Ratings and scores on self report characterization measures



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
No preferences in participant recruitment will be made on the bases of gender, race, or ethnic background. Efforts will be made to avoid participant distribution bias such that if skewing is noted, subjects in the over-represented group may temporarily be excluded from the study until additional participates from under-represented groups can be established. Efforts will be made to include minorities in proportion to their presence in the local population. The major metropolitan Baltimore area (Baltimore City, Baltimore County, Anne Arundel County, Howard County) consists of 64% White, 32% Black or African American, 3% Asian, 0.3% American Indian and Alaska Native, 0.04% Native Hawaiian and Other Pacific Islander and 0.8% some other race (http://www.census.gov/ ). Of this population (any race), 2% are Hispanic or Latino.
Criteria
  • INCLUSION CRITERIA:

All participants must:

  1. Be between the ages of 18-60. Be right-handed.
  2. Be in good health.
  3. Be free of active DSM-IV abuse/dependence, or dependence in partial remission, on alcohol or any drug except nicotine. Past active dependence is acceptable provided it is at least five years in the past. Those with past dependence on substances other than alcohol or marijuana may not have any current use (past 6 months) of the substance on which they were dependent. Individuals with past dependence on either alcohol or marijuana who report current use of the previously dependent substance may be included, provided they do not currently meet any criteria for dependence, with the exception of tolerance.
  4. Be able to abstain from alcohol 24hrs before each of the imaging sessions and able to abstain from caffeine 24hrs before each session.
  5. For the treatment and non-treatment seeking smoker groups, must have a urine cotinine level of greater than or equal to 4 and have been smoking consistently for at least one year. For lighter smokers (less than 10 cpd), this is defined as smoking at their current level or more for at least the past year (excluding any quit attempts in the last year). For heavier smokers (more than 10 cpd), they must have been smoking at least an average of 10 cpd for at least the past year (excluding quit attempts). Based on the correlation between self-reported cpd/FTND and urine cotinine levels [85a, 85b], a single inclusion criterion will be easier to manage and provide adequate characterization of dependent smokers. Urine cotinine level provides a biomarker that does not rely on self-report/memory. Quit attempts will be assessed via clinical interview and judgment.
  6. For the treatment and non-treatment seeking smoker groups, must be willing to attempt an acute abstinence period lasting approximately 48 hours.
  7. For the treatment seeking group, be actively seeking treatment for smoking cessation and willing to engage in 12-weeks of treatment involving weekly counseling sessions, as well as follow-up imaging and behavioral assessments following treatment onset.
  8. For the ex-smoker group, must have smoked approximately 8 or more cigarettes per day for at least 1 year, and have remained abstinent continuously for at least the last 12 months.
  9. For the non-smoking control group, less than 20 cigarettes lifetime, none in past year and no history of daily smoking

EXCLUSION CRITERIA:

  1. are not suitable to undergo an fMRI experiment due to certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia.
  2. have coagulopathies, history of, current superficial, or deep vein thrombosis, musculoskeletal abnormalities restricting an individual s ability to lie flat for extended periods of time.
  3. have HIV or Syphilis.
  4. regularly use any prescription (e.g., antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates), over-the-counter (e.g., cold medicine) or herbal medication (e.g., Kava, Gingko biloba, St. John s wort) that may alter CNS function, cardiovascular function, or neuronal-vascular coupling.
  5. have any current neurological illnesses including, but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
  6. have any current major psychiatric disorders to include, but not limited to, mood, anxiety, psychotic disorders, or substance-induced psychiatric disorders, or any current suicidal ideations or currently under antidepressant or antipsychotic medication treatment. The MAI will reserve the right to exclude on the basis of psychiatric history not explicitly described in this criterion.
  7. Are cognitively impaired or learning disabled.
  8. have significant cardiovascular, cerebrovascular, or respiratory conditions.
  9. have any other major medical condition that in the view of the investigators would compromise the safety of an individual during participation. The following lab values will result in exclusion from the study:

    • Hemoglobin less than 10 g/dl
    • White Blood Cell Count less than 2400/microl
    • Liver Function Tests greater than 3X normal
    • Serum glucose greater than 200 mg/dl
    • Urine protein greater than 2 plus
    • Serum creatinine greater than 2 mg/dl
    • Estimated creatinine clearance less than 60ml/min
  10. pregnant, planning to become pregnant, or breastfeeding. Females are instructed in the consent to use effective forms of birth control during the study period.

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): NCT01867411


Contacts
Layout table for location contacts
Contact: Elliot Stein, Ph.D. (443) 740-2650 estein@mail.nih.gov

Locations
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United States, Maryland
National Institute on Drug Abuse Recruiting
Baltimore, Maryland, United States, 21224
Contact: For more information contact Mathew's Media Group Recruiting    800-535-8254    researchstudies@mail.nih.gov   
Sponsors and Collaborators
National Institute on Drug Abuse (NIDA)
Investigators
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Principal Investigator: Elliot Stein, Ph.D. National Institute on Drug Abuse (NIDA)

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Responsible Party: National Institute on Drug Abuse (NIDA)
ClinicalTrials.gov Identifier: NCT01867411    
Other Study ID Numbers: 999913485
13-DA-N485
First Posted: June 4, 2013    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 14, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Drug Abuse (NIDA) ):
Smoking Cessation
fMRI
e-Cigarettes
Additional relevant MeSH terms:
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Tobacco Use Disorder
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Nicotine
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