Glucocorticoid Antagonist Treatment for Tobacco Use Disorder

Study Overview
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Brief Summary
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The purpose of this protocol is to examine whether mifepristone, a medication with glucocorticoid receptor antagonist activity, may be a potential treatment for Tobacco Use Disorder (TUD). Mifepristone has already shown promise as a potential treatment for PTSD (1) and alcohol use disorder (AUD) (2), but no previous studies have examined the therapeutic potential of mifepristone for TUD. This will be a double-blind, placebo-controlled study on the effects of a 7-day treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal severity, and smoking behavior.

Detailed Description
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This will be a double-blind, placebo-controlled study that tests the effects of a 7-day treatment with 600 mg mifepristone, or placebo, on cognitive function, tobacco withdrawal severity and smoking behavior. Once the intake and physical examination is completed and eligibility is determined, subjects will participate in a baseline session to become familiar with the study procedures and to assess baseline measures of withdrawal, smoking urges, pain sensitivity, and cognitive performance. Subjects will be asked to refrain from consuming alcoholic beverages and drugs during their study participation. This will be verified by urine drug screening and breathalyzer before the session and during outpatient visits. If results indicate non-compliance with these study procedures, subjects will be discharged from the study. Participants will be assessed for compliance with medication treatment, withdrawal severity, recent smoking behavior, and cognitive function during treatment visits on Days 1 and 4. On Day 7, following overnight abstinence from smoking, participants will attend a test session that models relapse to smoking. During this session, subjects will have the option to smoke, or to delay smoking in exchange for monetary compensation (45). To examine if mifepristone's proposed therapeutic effects last beyond the treatment duration (as observed in previous studies), there will be 1-week and 1-month follow-up assessments on smoking behavior, urges to smoke, endocrine biomarkers, and cognitive function. Participants in each group will complete the laboratory-based, delayed smoking procedure in a designated, negative pressure room in Bldg. 36 of the West Haven VA just after assessing pain sensitivity with the cPT. This sequence allows the cPT to assess pain sensitivity, a potential biomarker of relapse behavior, and to also be used as a mild stressor prior to participation in the smoking relapse model. Participants will be instructed to abstain from smoking after 10 pm the night before Test Sessions. Abstinence will be confirmed the morning of the session by measuring a breath CO level of < 8 ppm.

Official Title
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Glucocorticoid Antagonist Treatment for Tobacco Use Disorder

Conditions
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Nicotine Dependence

Intervention / Treatment
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* Drug: Mifepristone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male smokers aged 18 to 55 years; History of smoking at least 5 cigarettes daily for the past 12 months; In good health as verified by medical history, screening examination, and -screening laboratory tests Exclusion Criteria: History of mifepristone allergy; Requirement of any form of regular psychotropic medication (antidepressants, antipsychotics, or anxiolytics) and recent psychiatric history (in the past 6 months); Medical illnesses including diabetes, cardiovascular, renal, endocrine, or hepatic disorders; Prolonged QTc interval >450 msec; History of adrenal insufficiency or a morning plasma cortisol level less than 5 mcg/dl at screening; Hypokalemia at screening (defined as potassium level < 3.5 mEq/L); Current use of clinically significant CYP 3A4 substrates including, simvastatin, lovastatin, cyclosporine, ergotamines, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, triazolam, midazolam. use of rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's Wort. Current use of strong 3A4 inhibitors including ketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenivir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole. Treatment with systemic corticosteroids Current use of clinically significant CYP 3A inducers (e.g., rifampin, rifabutin); Abuse of alcohol or any other illicit or prescription drugs; Inability to tolerate cold exposure due to conditions such as peripheral -vascular disease or Raynaud's phenomenon; Inability to fulfill all scheduled visits and examination procedures throughout the study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The primary analyses will use linear mixed models (LMMs). LMMs can handle continuous and dichotomous outcomes, as well as missing data. Analyses will include baseline (pre-treatment) measures of these variables as covariates and other baseline variables where appropriate.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mifepristone<br>Mifepristone 600 mg/day in 2 tablets | Drug: Placebo<br>* Placebo sugar 2 tablets will be compared to mifepristone<br>* Other names: sugar pill;|
| Placebo Comparator: Placebo<br>matching placebo in 2 tablets | Drug: Mifepristone<br>* Mifepristone 600mg 2 tablets will be compared to the placebo<br>* Other names: korlym, mifeprex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minnesota Nicotine Withdrawal Symptom Checklist (M-NWSC) | Smokers will be asked to rate several nicotine withdrawal symptoms on a 100 mm scale, from not at all to extremely. | one week |