Clinical trial NCT01631630: Role of Proinflammatory Signaling in Alcohol Craving
Official title: Role of Proinflammatory Signaling in Alcohol Craving
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alcohol Dependence
Alcohol Drinking
Stress
Alcohol-Related Disorders
Keywords: Alcohol
Alcohol Dependence
Alcohol Use
Nicotine Dependence
Nicotine
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-06-29
Enrollment: 16
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

- Drinking too much alcohol can injure cells in the body. Inflammation is the body s reaction to injured cells. Studies show that inflammation can cause cravings for alcohol. Researchers want to see if pioglitazone, a drug that decreases inflammation, can reduce alcohol craving. If so, it might help develop new ways to help alcoholics with craving.

Objectives:

- To see if pioglitazone can reduce alcohol craving.

Eligibility:

- Adults between 21 and 65 years of age who are alcoholic and have been drinking within the past month.

Design:

* Participants will be screened with a physical exam and medical history. Blood samples will also be collected.
* All participants will have inpatient treatment at the National Institutes of Health Clinical Center for the 5 weeks of the study. They will have standard treatment for alcoholism during their inpatient stay.
* Half of the people in this study will have pioglitazone. The other half will have a placebo.
* Participants will have different studies during their stay. These studies will include the following:
* Personalized audio recordings of stressful, alcohol-related, and neutral events to monitor mood
* Imaging studies to test alcohol cravings
* Questionnaires about mood and alcohol cravings
* Lumbar puncture to collect spinal fluid
* Inflammation test to see if the study drug can block alcohol cravings
* After the end of the 5-week study, all participants will be offered follow-up outpatient care through the Clinical Center, or referral to outside treatment.

Detailed description: Objective: The objective of the present study is to evaluate the role of proinflammatory signaling in alcohol craving. The peroxisome proliferator-activated receptor y (PPARy) agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery auditory scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration which activates proinflammatory signaling will be used as a novel challenge, and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response.

Study population: Up to 60 subjects will be recruited for a target accrual of 50 completers. Subjects will be aged 21-65 years, with alcohol dependence as their primary complaint, and without other serious medical or psychiatric conditions. They will be admitted to the NIAAA research inpatient unit at the NIH Clinical Research Center (CRC) through one of the screening protocols (05-AA-0121 Assessment and Treatment of People with Alcohol Drinking Problems ) or 14-AA-0181 "Unit and Clinic Evaluations, Screening, Assessment, and Management") which provides basic assessments and standard withdrawal treatment if needed.

Design: Following inclusion, subjects will undergo interviews for construction of guided imagery scripts, and these scripts will subsequently be used as stress-, alcohol- or neutral condition associated stimuli. Subjects will be randomized to pioglitazone (n=25; final dose: 45mg/daily) or identically looking placebo (n=25). Following at least two weeks of treatment, subjects will undergo three sessions of guided imagery, on separate days and in a counter-balanced order, exposing them to the personalized stress-, alcohol- or neutral condition associated auditory scripts, respectively. During the final week, subjects will undergo two challenge sessions, a minimum of five days apart, with lipopolysaccharide (LPS) or placebo, in counterbalanced order.

Outcome measures: Subjective ratings of mood, anxiety and craving will be obtained twice weekly throughout the study. During the challenge sessions that utilize psychological stimuli or LPS, subjective ratings of craving for alcohol, as well as ratings of negative emotions will be obtained. Lumbar puncture will be performed and cerebrospinal fluid (CSF) obtained to determine the effect of pioglitazone on levels of proinflammatory cytokines. Neuroendocrine, psychological and physiological measures will be collected for exploratory purposes. An fMRI scan will be obtained to evaluate the effect of pioglitazone on BOLD signal in response to emotionally salient visual cues.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Diagnostic and Statistical Manual (DSM)-IV diagnosis of alcohol dependence on Structured Clinical Interview for DSM Diagnosis (SCID) alcohol problems as primary complaint among substance use disorders, and alcohol use within the last month.
  2. Age 21 65
  3. Right handed
  4. For women:

     1. post-menopausal or surgically sterile (tubal ligation or hysterectomy); or
     2. if sexually active with a male partner and able to get pregnant, documented agreement to use an effective form of birth control. Acceptable forms of contraception for this study include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); intrauterine device (IUD); diaphragm with spermicide; condom with spermicide.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise participation in research, as determined by medical history, physical examination, laboratory tests (see details under Screening measures below), including, but not limited to:

   1. Diabetes mellitus Type I or Type II
   2. Past or current diagnosis of congestive heart failure
   3. Signs and symptoms suggestive of congestive heart failure
   4. Cardiovascular disease (e.g., history of congenital heart defect, heart disease, symptomatic coronary-artery disease, heart attack, clinically significant arrhythmia, etc.)
   5. Cerebrovascular disease
   6. Infection, autoimmune disease, or fever of unknown origin
   7. Unexplained history of syncope
   8. History of seizures, except for febrile seizures during childhood
   9. History of head injury with loss of consciousness of more than 30 minutes or with postconcussive sequelae lasting more than two days, regardless of loss of consciousness
   10. Chronic renal failure as estimated by glomerular filtration rate (GFR) \<60 milliliters per minute 1.73 per Square
   11. HIV infection
   12. Active bladder cancer, history of bladder cancer, or persistent hematuria
   13. Allergy, hypersensitivity, or intolerance to pioglitazone, other thiazolidinediones, or the metabolites of any of those drugs (determined by medical history)
   14. Pregnancy or breastfeeding (urine pregnancy test; self-report)
   15. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.)
   16. Contraindicated or strongly interacting medications: Gemfibrozil (inhibitor of CYP2C8) and rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine
   17. Any ongoing, or regular use of central nervous system (CNS) active medications within the last week (fluoxetine: last 4 weeks), with the exception of withdrawal medication, obtained according to the NIAAA clinical guidelines if needed
   18. Use of docosahexaenoic acid (DHA) dietary supplements, or consumption of oily fish \>3 times per week (because of effects of DHA on inflammatory parameters)
   19. History of Rhabdomyolysis
2. Psychiatric history:

   1. Cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires, as established by clinical exam, in questionable cases aided by a Mini Mental State Examination (with a score of \<21, indicating more than mild cognitive impairment, being exclusionary)
   2. Current diagnosis of schizophrenia or any other DSM-IV psychotic disorder, bipolar disorder, or major depressive disorder, in each case as established by clinical evaluation and SCID.
3. Substance use disorders:

   1. Current alcohol intoxication on breathalyzer test or positive urine drug screen on enrollment
   2. Current dependence on drugs other than alcohol or nicotine, as established by SCID interview
4. Inability or unwillingness to participate in an fMRI scan, including

   1. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces. Eligibility will be determined by a MRI Safety Screening Questionnaire and verified, if necessary, by a physician.
   2. Subjects that cannot lie comfortably flat on their back for up to 2 hours in the MRI scanner.

Primary outcomes:
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Alcohol Cue Script
timeFrame: 90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 15 minutes prior to the subject receiving an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 1 hour after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 2 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 3 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 4 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 5 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Lipopolysaccharide Challenge
timeFrame: 6 hours after the subject received an intravenous bolus of lipopolysaccharide, which occurred on Day 25 or Day 32 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 15 minutes prior to the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 15 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 5 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 30 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 45 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 60 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 75 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
measure: Alcohol Craving in Response to the Stress Script
timeFrame: 90 minutes after the beginning of script presentation, which occurred on Day 21, 22, or 23 of the treatment period
Secondary outcomes:
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 1 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 3 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 7 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 10 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 14 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 17 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 21 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 24 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 28 of the treatment period
measure: Anxiety Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 31 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 1 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 3 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 7 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 10 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 14 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 17 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 21 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 24 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 28 of the treatment period
measure: Depression Symptom Ratings Measured Bi-weekly During the Treatment Period
timeFrame: Day 31 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 1 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 3 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 7 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 10 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 14 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 17 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 21 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 24 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 28 of the treatment period
measure: Spontaneous Alcohol Craving Measured Bi-weekly During the Treatment Period
timeFrame: Day 31 of the treatment period
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
name: Nancy Diazgranados, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011 May;130(2):226-38. doi: 10.1016/j.pharmthera.2011.01.014. Epub 2011 Feb 17.
citation: Crews FT, Zou J, Qin L. Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun. 2011 Jun;25 Suppl 1(Suppl 1):S4-S12. doi: 10.1016/j.bbi.2011.03.003. Epub 2011 Mar 21.
citation: Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007 Feb;21(2):153-60. doi: 10.1016/j.bbi.2006.09.006. Epub 2006 Nov 7.
citation: Schwandt ML, Diazgranados N, Umhau JC, Kwako LE, George DT, Heilig M. PPARgamma activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study. Psychopharmacology (Berl). 2020 Aug;237(8):2367-2380. doi: 10.1007/s00213-020-05540-w. Epub 2020 May 22.