Mifepristone for the Prevention of Relapses of Alcohol Drinking

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to determine if, under stress, alcohol drinking is reduced using mifepristone

Official Title
-----------------
A Pilot Study on the Safety and Efficacy of Mifepristone for the Prevention of Relapses of Alcohol Drinking

Conditions
-----------------
Alcohol Use Disorders (AUD)

Intervention / Treatment
-----------------
* Drug: Mifepristone 600-mg/day or placebo for a week


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, 21 to 65 years of age Females must be postmenopausal for at least one year or surgically sterile (proven by medical record) Meet criteria for Alcohol Use Disorders (AUD) DSM-5 diagnosis Meet drinking criteria (≥3 drinks/day for men; ≥2 drinks /day for women) Must be in good health as confirmed by medical history, physical examination, ECG, lab tests Participants must be willing to take oral medication and adhere to the study procedures Breath alcohol (BrAC) = 0.00 at each visit Be able to understand informed consent and questionnaire in English at an 8th grade level Exclusion Criteria: Individuals expressing interest in treatment for alcoholism Premenopausal women Participants who have significant alcohol withdrawal symptoms, defined as a CIWA-Ar score ≥7 A repeated positive urine drug screen at baseline for any illegal substance except marijuana. Individuals diagnosed with a current severe Substance Use Disorder (SUD) diagnosis, other than alcohol or nicotine Meet DSM-5 criteria for a diagnosis of schizophrenia, bipolar disorder, or other psychoses An active illness within the past six months of the screening visit that meets the DSM-5 criteria for a diagnosis of Major Depressive Disorder (MDD) or Anxiety Disorder, or history of attempted suicide Clinically significant medical abnormalities: unstable hypertension, clinically significant abnormal ECG, bilirubin >150% of the upper normal limit, ALT/AST >300% the UNL, creatinine clearance ≤60 dl/min Current use of psychotropic medications that may have an effect on alcohol consumption Current use of any medication involved in the metabolism of alcohol such as aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH) and CYP2E1: Cefamandole, Cefotetan, Sulfamethoxazole, Nitroglycerin, Chlorpropamide, Glyburide. Current use of any medication (CYP3A4 inhibitor and substrate) that may interact with mifepristone: cyclosporine, fentanyl, heparin, escitalopram, lovastatin, simvastatin, warfarin Current use of any medication (CYP2D6 inhibitor and substrate) that may interact with yohimbine: amitriptyline, doxepin, nortriptyline, venlafaxine Medical contraindications for use of mifepristone or yohimbine A history of adverse reaction or hypersensitivity to mifepristone or yohimbine History of suicide History of seizure disorders Hypokalemia (low potassium level)<3.5mEq/L Participated in any behavioral and/or pharmacological study within minimum the past 30 days Neuroendocrine disorders Taking corticosteroids Bleeding disorders Pre-existing QT prolongation on ECG History of porphyria (Mifepristone progesterone receptor antagonist is an inducer of CYP-450 and therefore may have the ability to precipitate or exacerbate attacks of acute porphyria) Not willing to engage in protected sex (condom). This risk includes both women and men. Mifepristone long half-life (t1/2 = 18 hrs) and its three main metabolites retain considerable affinity toward human progesterone and glucocorticoid receptors, with serum level similar to the parent mifepristone and there are no studies on the presence of mifepristone or metabolites in semen

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Mifepristone<br>mifepristone 600-mg/day for a week, in a stress-induced condition triggered by a single dose of 32.4-mg of yohimbine | Drug: Mifepristone 600-mg/day or placebo for a week<br>* 600-mg of mifepristone for a week, compared to placebo for a week, in a stress-induced condition triggered by a single dose of 32.4 mg of yohimbine<br>|
| Placebo Comparator: Sugar pill<br>matching placebo/day for a week, in a stress-induced condition triggered by a single dose of 32.4-mg of yohimbine | Drug: Mifepristone 600-mg/day or placebo for a week<br>* 600-mg of mifepristone for a week, compared to placebo for a week, in a stress-induced condition triggered by a single dose of 32.4 mg of yohimbine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Adverse Events in the Mifepristone Versus Placebo Group as a Measure of Safety and Tolerability | Safety and tolerability was assessed by the number of participants who experienced adverse events (AEs) while taking the medication, in the mifepristone group verses the placebo group during Visit 2 through and until Visit 5. AEs were assessed at each visit and special attention was paid to any AEs experienced after administration of the oral administration of mifepristone or placebo- Visit 2 to Visit 3 (7 days total) and Visit 4 through Visit 5 (7 days total), and when it was administered with alcohol during the laboratory paradigms at visits 3 and 4. | 5 weeks (one week of drug administration, 3 weeks of washout, followed by one week of drug administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol Craving Score on the Alcohol Craving Questionnaire in the Mifepristone Versus Placebo Group | Alcohol craving will be assessed by the Alcohol Craving Questionnaire Short Form - Revised (ACQ-SF-R). The ACQ-SF-R is a 12-item self-report scale that contains items from the 47-item Alcohol Craving Questionnaire (ACQ-Now). ACQ-SF-R also produces scores for compulsivity, expectancy, purposefulness, and emotionality. To assess this outcome, at the alcohol cue reactivity procedures/visits 3 and 5 during alcohol trial 1, the 12-item total ACQ will be summed for each participant and then the total score will be averaged for a mean score. The average ACQ score in the presence of alcohol cues will be compared when participants are taking mifepristone compared to placebo. The ACQ has a total score range between 0-84. A lower score indicates less subjective alcohol craving. | 1 day | 
| Drinking Consumption in the Mifepristone Verses Placebo Group | Number of standard drinks desired to be consumed by participants during mifepristone administration compared to placebo administration during the open bar (free choice procedure) in the alcohol cue reactivity at visits 3 and 5. | 1 day | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stress, alcohol craving, alcohol use disorders