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Brain Inflammation and Function in Alcoholism

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ClinicalTrials.gov Identifier: NCT02233868
Recruitment Status : Recruiting
First Posted : September 9, 2014
Last Update Posted : August 12, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Brief Summary:

Background:

- Brain inflammation due to high alcohol intake may affect thinking, memory, and concentration. Researchers want to measure this using positron emission tomography (PET).

Objective:

- To study how excessive alcohol consumption affects brain function.

Eligibility:

  • Adults 30-75 years old who are moderate or severe alcohol drinkers.
  • Healthy volunteers.

Design:

  • Participants will be screened with medical history, physical exam, interview, and blood and urine tests. Their breath will be tested for alcohol and recent smoking.
  • Phase 1:
  • Participants will stay in the hospital 3 days. They will have blood and heart tests and daily urine tests.
  • A small plastic tube will be inserted by needle in each arm. One will go in a vein, the other in an artery.
  • Participants will have 2 PET scans with 2 different radioactive compounds. Participants will lie on a bed that slides in and out of the scanner with a cap on their head.
  • Participants will have magnetic resonance imaging (MRI) scans. Participants will lie in the scanner either resting with their eyes open or while performing an attention task.
  • Participants will have tests of memory, attention, concentration, and thinking. They may answer questions, take tests, and perform simple actions.
  • Phase 2 of the study will only be done if Phase 1 results show brain inflammation.
  • Phase 2 will repeat Phase 1.
  • For healthy volunteers, Phase 2 will begin 3 weeks after Phase 1.
  • Other volunteers must not have alcohol for at least 3 weeks and stay in a hospital up to 4-6 weeks between Phase 1 and Phase 2. After Phase 2, they will have 5 follow-up calls over 3 months.

Condition or disease Intervention/treatment Phase
Alcohol Use Disorder (AUD) Other: connectivity Other: neuroinflammation Drug: neurofunction Early Phase 1

Detailed Description:

The abuse of high doses of alcohol is associated with cognitive impairment that in extreme cases can result in dementia. However, the mechanisms underlying the neurotoxic effects of alcohol to the human brain are poorly understood. Here we test the hypothesis that alcohol-induced neuroinflammation contributes to its neurotoxic effects in humans

Objectives: The primary objectives in Phase I are to assess if there is inflammation in the brain of alcoholics and if present to determine if it recovers after 3 weeks of abstinence as compared between groups (alcoholic vs. healthy volunteers) in Phase II. Phase II objectives are to assess between group differences in inflammation in the brain of AUD subjects who either abstain from alcohol for at least 3 weeks or relapse (continue to drink alcohol) for at least 3 weeks. Secondary outcomes are to evaluate the functional consequences of inflammation as assessed by: regional brain glucose metabolism, functional brain activation to cognitive tasks, structural brain imaging, resting functional connectivity and neuropsychological tests.

Study population: Participants diagnosed with alcohol use disorder (AD) as per DSM IV or DSM 5 AD and healthy controls. Males and females ages 30-75 will be included

Design: This study has two phases (phase I and II). The two phases can be done as inpatient (AD subjects) or as outpatient (AD and healthy controls) over a 2-3 day period. In phase I participants will undergo two positron emission tomography (PET) scans, one with [11C]PBR28 (marker of neuroinflammation) and one with 18FDG (marker of brain glucose metabolism) and magnetic resonance imaging (MRI) scans to assess brain structure, functional reactivity and functional connectivity. In parallel we will perform neuropsychological tests (NP). Phase II will include the same procedures as Phase I but it will be done at least 3 weeks later over a 2-3 day period only in AUD participants who successfully completed phase I who either abstained from alcohol or relapsed/continued to drink alcohol after Phase I.

Relapsers would be eligible for Phase II if they continued to drink for at least 3 weeks

prior scheduled imaging studies. We will complete Phase II studies on up to 24 additional AUD subjects (n=12 abstainers and n=12 relapsers) to assess whether [11C]PBR28 uptake recovers after abstinence. Since there are not much differences between test/retest studies in healthy volunteers in the literature [1], there is no need to complete Phase II studies in controls.

Outcome parameters: Main outcome measure is to assess if there is neuroinflammation with alcoholism and if it recovers with detoxification. Secondary outcome measures are: to assess if neuroinflammation is associated with markers of brain function, which include (1) regional brain glucose metabolism; (2) MRI based voxel-based morphometry (VBM) to assess cortical atrophy; (3) blood-oxygenation level-dependent (BOLD) activation to a cognitive task, (4) brain functional connectivity, (5) myo-inositol (mI) concentration, and (6) NP testing to assess cognitive performance, and to evaluate if neuroinflammation predicts relapse in AD over a 3 month follow-up period.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Brain Inflammation and Function in Alcoholism
Actual Study Start Date : February 19, 2015
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine



Intervention Details:
  • Other: connectivity
    Magnetic resonance imaging (MRI) scans will be done to assess brain structure, functional reactivity and functional connectivity.
  • Other: neuroinflammation
    The use of [11C] PBR28 will allow us to assess for the first time in vivo if there is neuroinflammation in the brain of alcoholics. It will also allow us to assess if it recovers with alcohol detoxification.
  • Drug: neurofunction
    To assess regional brain glucose metabolism.


Primary Outcome Measures :
  1. To assess inflammation in the brain [ Time Frame: end of study ]
    To assess if there is inflammation detected in the brain of alcoholics subjects as measured with [11C]PBR28 as compared to healthy controls.

  2. To determine if there is neuroinflammation in the brain. [ Time Frame: end of study ]
    To assess if there is neuroinflammation detected in the brain of alcoholics subjects as measured with [11C]PBR28 as compared to healthy controls and if it recovers with at least 3 weeks of abstinence.

  3. To assess between group differences in inflammation in the brain of AUD subjects in Phase II who either abstain from alcohol for at least 3 weeks or relapse (continue to drink alcohol) for at least 3 weeks. [ Time Frame: end of study ]
    We want to see whether [11C] PBR28 uptake in the brain reflects levels similar to controls after at least 3 weeks of alcohol abstinence.


Secondary Outcome Measures :
  1. To assess the impact of neuroinflammation on brain function (assessed with PET and 18FDG and with MRI for fMRI with task activation and for functional connectivity). [ Time Frame: end of study ]
    to assess if neuroinflammation is associated with markers of brain function and to evaluate if neuroinflammation predicts relapse in AUD over a 3 month follow-up period.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

-INCLUSION CRITERIA:

-All Participants

  1. Between 30 and 75 years of age.
  2. Ability to provide written informed consent as determined by physical examination and verbal communication. Capacity to consent will be determined by those giving the informed consent.
  3. Females: Negative urine pregnancy test and not currently breastfeeding. Post-menopausal or surgically sterile (tubal ligation or hysterectomy); or not sexually active with a male partner and able to get pregnant; or documented agreement to use an effective form of birth control. Acceptable forms of contraception include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); IUD; diaphragm with spermicide; condom with spermicide.

    -Specific For AD Participants

  4. DSM-IV diagnosis of alcohol dependence or alcohol abuse or DSM-5 diagnosis of moderate or severe alcohol use disorder (established through history and clinical exam). We include subjects that drink high doses of alcohol since alcohol's detrimental effects are greater with larger doses and particularly with binge drinking.
  5. Participants seeking treatment for their AD as well as those not seeking treatment for their AD will be included.
  6. Minimum 5 year history of heavy drinking (self-report).
  7. Must consume at least 20 alcoholic drinks per week (male) or 15 per week (female) (self-report).
  8. Must have had the last drinking episode (females 3 or more drinks; and males 4 or more drinks) within 1 week of baseline PET scan (self-report).
  9. Alcohol specified as the preferred drug (self-report).

EXCLUSION CRITERIA:

  • All Participants

    1. Unwilling or unable to refrain from use within 24 hours of scheduled study procedures: psychoactive medications or medication that may affect study results (e.g., analgesics [non narcotic], antibiotics (must finish course at least 24 hours prior to a scheduled procedure), antidiarrheal preparations, anti-inflammatory drugs (systemic corticosteroids are exclusionary), antinauseants, cough/cold preparations) (self-report, medical history). The following medications are allowable for entry on this study: analgesics (non-narcotic); antacids; antiasthma agents that are not systemic corticosteroids; antifungal agents for topical use; antihistamines (non-sedating); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of antihyperlipidemics and/or diuretics are permitted as long as they have been taken for at least 1 month before procedure visits and dose has been stabilized. The use of benzodiazepines such as alprazolam (( )Xanax), diazepam (( )Valium) and lorazepam (( )Ativan), will not exclude participants from this study.
    2. Current or past DSM-IV or DSM-5 diagnosis of a psychiatric disorder (other than alcohol in AD participants and nicotine/caffeine use disorders) that required hospitalization (any length), or chronic medication management (more than 4 weeks) and that could impact brain function at the time of the study as determined by history and clinical exam. The following chronically used medications are exclusionary from the study: analgesics containing narcotics; anorexics (sibuteramine); antianginal agents; antiarrhythmics; antiasthma agents that are systemic corticosteroids; antibiotics; anticholinergics; anticoagulants; anticonvulsants; antidepressants; antidiarrheal preparations; antifungal agents (systemic); antihistamines (sedating); antihypertensives; anti-inflammatory drugs (systemic); antineoplastics; antiobesity; antipsychotics; antivirals (except for treatment of HSV with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir, valacyclovir); anxiolytics; cough/cold preparations (dextromethorphan preparations, pseudoephedrine); hormones (exceptions: thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy); insulin; lithium; muscle relaxants; psychotropic drugs not otherwise specified (nos) including herbal products (no drugs with psychomotor effects or with anxiolytics, stimulant, antipsychotic, or sedative properties); sedatives/hypnotics. Note that nicotine and/or caffeine use will not exclude participants.
    3. Major medical problems that can permanently impact brain function (e.g., CNS, cardiovascular, metabolic, autoimmune, endocrine) as determined by history and clinical exam.
    4. Any clinically significant laboratory finding as determined during the screening procedures that could impact brain function or study procedures (evidenced from clinical laboratory results).
    5. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that with the exposure from this study, would exceed NIH annual research limits (self-report, medical history)
    6. Head trauma with loss of consciousness for more than 30 minutes (self-report, medical history);
    7. Positive test for alcohol on the day of the PET, the MRI or the NP tests (clinical laboratory results).
    8. Urine positive for psychoactive drugs (clinical laboratory results) on study days involving imaging (PET and MRI) and neuropsychological testing.
    9. Pregnant or breast feeding (self-report)
    10. History of coagulation disorder (clinical laboratory results, medical history)
    11. Have a history of allergic reaction to lidocaine (self-report, medical history)
    12. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head, fear of enclosed spaces, or other standard contraindication to MRI (self-report checklist).
    13. Cannot lie comfortably flat on your back for up to 2 hours in the PET and MRI scanners (self-report).
    14. Body weight > 250 kg. The MR scanner bed is tested to a weight limit of 250 kg (~550 lbs).
    15. Have a positive HIV test (clinical laboratory results, medical history).
    16. Homozygosity for the rs6971 polymorphism on TSPO that results in LB (Owen et al 2011) (genotyping results).
    17. NIH employees who meet criteria as AD subjects. Although we will include NIH employees as healthy volunteers, study investigators and their superiors, subordinates and immediate family members (adults children, spouses, parents, siblings) will be excluded.

      EXCLUSION CRITERIA SPECIFIC FOR CONTROL PARTICIPANTS:

  • Consumption of moderate to high levels of alcohol. That includes if female, currently (within past 6 months) consuming more than 2 drinks on a given episode and if male, consuming more than 3 drinks on a given episode; and/or consuming if female, more than a total of 7 drinks a week or if male, more than 10 drinks a week (self-report).

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): NCT02233868


Contacts
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Contact: Gene-Jack Wang, M.D. (301) 496-5012 gene-jack.wang@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
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Principal Investigator: Gene-Jack Wang, M.D. National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
ClinicalTrials.gov Identifier: NCT02233868    
Other Study ID Numbers: 140192
14-AA-0192
First Posted: September 9, 2014    Key Record Dates
Last Update Posted: August 12, 2020
Last Verified: September 23, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) ):
Imaging Studies
Alcohol Use Disorder (AUD)
Inflammation
Additional relevant MeSH terms:
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Encephalitis
Inflammation
Alcoholism
Alcohol Drinking
Pathologic Processes
Drinking Behavior
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases