Piogliatazone for Alcohol Craving

Stress Clinical Trial

Official title:

Role of Proinflammatory Signaling in Alcohol Craving

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01631630
• Other study ID #: 120143
• Secondary ID: 12-AA-0143
• Status: Completed
• Phase: Phase 2
• First received: June 27, 2012
• Last updated: August 6, 2016
• Start date: May 2012
• Est. completion date: September 2015

Study information

• Verified date: May 2016
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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 piogliatazone, 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 65 Years

Eligibility

• INCLUSION CRITERIA:

1. DSM-IV diagnosis of alcohol dependence on Structured Clinical Interview for DSM Diagnosis 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); IUD; diaphragm with spermicide; condom with permicide.

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 TZD s, 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 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 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 breathalizer 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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alcohol Dependence
• Alcohol Drinking
• Alcohol-Related Disorders
• Alcoholism
• Stress

Intervention

Drug:
• Pioglitazone
15mg/day for 3 days; 30mg day for 3 days; 45mg/day thereafter, for a minimum total of 13 days
• Placebo

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. Review. — View 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:S4-S12. doi: 10.1016/j.bbi.2011.03.003. Epub 2011 Mar 21. Review. — View Citation

Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007 Feb;21(2):153-60. Epub 2006 Nov 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Craving
Secondary	fMRI Response

External Links

•   NIH Clinical Center Detailed Web Page