Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking
Phase: PHASE1
Conditions: Alcohol Use Disorder
Sponsor: Johns Hopkins University

INIA Stress and Chronic Alcohol Interactions:  Glucocorticoid 
Antagonists in Heavy Drinkers
NCT02989662
3/17/2021

 
 
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Date: March 17, 2021 
Principal Investigator: Mary E. McCaul 
Application Number: IRB00138426 
 
JHM IRB - eForm A – Protocol 
 
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1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the 
research hypothesis, and the importance of the research. 
 
Alcohol use disorders affect millions of Americans, increasing morbidity and mortality 
with substantial negative health, social and economic impact.  Despite decades of research, 
there are still only 3 FDA approved medications for alcohol use disorder (AUD), all of which 
have very modest effects with a high prevalence of relapse post-treatment. Clearly there is 
urgent need for identification of treatment medications that target novel mechanisms of alcohol 
action. 
In preclinical and clinical models, stress plays a central role in initiation, maintenance 
and relapse to alcohol use.  The HPA axis is one of the main stress response pathways.  Like 
stress, alcohol activates the HPA axis to release glucocorticoids in humans and laboratory 
animals.  Glucocorticoids impact drug use behaviors through at least three mechanisms: 
amplifying the mesolimbic dopamine reward signal, increasing the stress peptide CRF causing 
anxiety and dysphoria, and increasing habit formation circuits. 
  
Mifepristone (MIFE), a competitive antagonist at the glucocorticoid receptor (GR), is FDA 
approved or under investigation for treatment of several endocrine and psychiatric disorders. 
Preclinical studies have shown that MIFE attenuates alcohol-induced mesolimbic DA 
neurotransmission in mice and reduces voluntary alcohol intake in rats.  In alcohol dependent 
rodents, MIFE blocks the escalation of alcohol intake and compulsive drug-seeking responses 
during abstinence; it also reduces alcohol-withdrawal induced hyper-excitability and memory 
deficits.  There is a single human study of MIFE for AUD treatment, showing MIFE reduces 
alcohol cue-induced craving in alcohol dependent subjects.  Over time, MIFE should permit 
“healing” of dopaminergic neurotransmission and other drug-seeking circuitry dysregulated from 
excessive exposure to cortisol. 
We are proposing a Phase I study of MIFE that examines safety, drug-drug interactions, 
and preliminary evidence of efficacy in reduction of alcohol effects.   We will compare the effects 
of active and placebo MIFE on: 1) fMRI measures of functional connectivity (FC) and alcohol 
cue-induced brain activation (CA) focused on brain reward and stress pathways, 2) alcohol 
craving and withdrawal symptoms during alcohol abstinence on the CRU; 3) stress-induced 
alcohol motivated responding, and 4) alcohol sensitivity/reward.  Also, using a within-subject 
design, we will assess changes in fMRI before and after MIFE administration.  Subjects will 
receive up to 1200 mg MIFE or matching placebo daily over a 6 day period.  Age-matched 
healthy control subjects will also undergo MIFE dosing over a 4 day period and fMRI procedures 
on an outpatient basis. We predict that MIFE treatment will decrease alcohol withdrawal 

 
 
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symptoms, alcohol motivated responding following stress and subjective experiences of high 
and positive alcohol effects compared to placebo. 
 
2. 
Objectives (include all primary and secondary objectives) 
 
Primary aim: The primary study objective is to determine MIFE effects in AUD and HC persons 
on a variety of alcohol-related measures.  We will examine if there are significant interactions 
between MIFE treatment concurrent with alcohol administration by measuring subjective 
responses, adverse events and cardiovascular responses (heart rate (HR), blood pressure 
(BP)), compared to placebo.  We also will examine MIFE effects on fMRI, alcohol withdrawal 
symptoms and craving, and alcohol motivated responding. 
 
Specific aims are to compare GR antagonism versus placebo for: 
1. Changes in resting state FC and CA across key brain regions, focused on nucleus 
accumbens, amygdala and prefrontal cortex.  Hypothesis 1a. GR antagonism will 
normalize the AUD resting state FC and CA to more closely resemble HC scans. 
Hypothesis 1b. Magnitude of FC and CA normalization induced by GR antagonism will 
predict the magnitude of reductions in self-reported CRU alcohol craving and withdrawal 
in AUD subjects. Hypothesis 1c: The extent of FC and CA dysregulation on day 1 is 
related to alcohol exposure history.   
2. Reduction of alcohol withdrawal symptoms and craving and improvement in low mood 
during early alcohol abstinence. Hypothesis 2a: GR antagonism will decrease alcohol 
withdrawal symptoms and craving compared to placebo. Hypothesis 2b: GR antagonism 
will improve negative mood relative to placebo.  
3. Reduction of stress-induced alcohol motivated responding. Hypothesis 3a: Compared to 
placebo, GR antagonism will decrease alcohol craving and the number of earned drinks 
following social stress. Hypothesis 3b. The magnitude of FC and CA changes induced 
by GR antagonism will predict number of drinks earned following stress.  
4. Reduction of alcohol sensitivity and reward.  Hypothesis 4a: Compared to placebo, GR 
antagonism will reduce the positive subjective responses and attenuate alcohol-induced 
increases in heart rate and skin temperature following alcohol administration. Hypothesis 
4b: Magnitude of FC and CA changes induced by GR antagonism will predict intensity of 
self-reported alcohol subjective and physiological effects.  
5. Side-effects will be closely monitored in both AUD and HC participants. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
Mechanisms through which cortisol may influence drug related behaviors.  
DA Reward circuitry.  Glucocorticoid receptors (GRs) are abundantly expressed in 
mesolimbic dopaminergic neurons of the reward system (Harfstrand et al., 1986; Morimoto et 
al., 1996). Plasma glucocorticoids levels are positively associated with the magnitude of 
dopamine release (DAR) (Oswald et al., 2005; Wand et al., 2007; Niwa et al., 2013) and 
modulate postsynaptic DA receptors as well as increase synaptic strength in midbrain DA 
neurons. Rodent studies have shown that cortisol, through the epigenetic mechanism of 
cytosine methylation, increases tyrosine hydroxylase expression in the mesolimbic system 
resulting in robust dopamine release (Niwa et al., 2013). Rodent studies have also 
demonstrated that administration of CORT increases the reinforcing effects of many abused 
drugs by acting on the mesolimbic DA system (Deroche et al., 1995; Piazza and Le Moal, 1996; 

 
 
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Cho and Little, 1999; Barrot et al., 2000). Thus, medications that would either reduce cortisol 
levels or block cortisol actions should attenuate DAR, reduce the positive subjective effects of 
acute alcohol ingestion, and alleviate negative mood and craving during early alcohol 
abstinence. 
Extrahypothalamic stress systems.  Second, CORT increases the expression of extra-
hypothalamic sources of CRF and thereby promotes stress-induced relapse (Schulkin et al., 
1998; Shepard et al., 2000). This circuitry is hypothesized to play an important role in mediating 
the relationship between stress and reward dysfunction, and to produce negative emotional 
states that motivate habitual drug-seeking (Gray and Bingaman, 1996; Makino et al., 2002; 
Koob, 2009; Haass-Koffler and Bartlett, 2012). Up regulation of CRF by CORT contributes to 
anxiety-like behaviors and enhanced or exaggerated emotional and fearful reactivity to 
perceived stress; in turn, anxiety and negative emotional states facilitate the initiation, 
maintenance and relapse back to alcohol use (Sinha, 2013).  Increasing levels of anxiety and 
arousal are reported with increasing levels of drug craving as blood drug levels decrease in the 
addicted person (Foltin and Haney, 2000).  MIFE administration has anxiolytic effects in various 
animal stress models (Korte et al., 1995; Sufka et al., 2009; Jakovcevski et al., 2011).  Anxiolytic 
actions of MIFE may be especially helpful during cessation of alcohol use, when there is 
heightened nervousness and restlessness and greater sensitivity to stress as a relapse trigger.  
Habitual learning. Secretion of CORT in response to acute stress affects learning and 
memory. CORT has been shown to induce a bias for promoting habit forms of learning and 
memory in lieu of goal-directed performance (van Stegeren et al., 2010; Smeets, 2011; Everitt 
and Robbins, 2013). These effects of cortisol on habit-based learning may be a primary basis 
for the relationship between cortisol, vulnerability to development of alcohol dependence as well 
as relapse after abstinence. We posit that cortisol blockade will reduce habitual learning related 
to chronic alcohol use and help extinguish drug seeking behaviors. 
Potential Efficacy of MIFE for Alcohol Treatment. 
Alcohol Preclinical Research. Support for the potential of MIFE for treating AUD comes 
from preclinical studies in rodents. In a rodent model, mifepristone has been shown to normalize 
DA levels as well as block excessive release of DA after methamphetamine challenge (Niwa et 
al., 2013), thereby having the potential to attenuate the reinforcing effects of alcohol and other 
drugs of abuse. Relatedly, MIFE has been shown to reduce voluntary alcohol ingestion (Koenig 
and Olive, 2004), and block the development of ethanol-induced conditioned place preference, 
a measure of alcohol reward, as well as associated adaptations in DA D2 receptors in the 
frontal cortex (Rotter et al., 2012). MIFE also attenuates stress-induced and alcohol-induced 
motor sensitization (Roberts et al., 1995). Rats exposed to chronic intermittent alcohol vapor 
develop physical dependence, escalate voluntary alcohol intake, and show persistent alcohol 
seeking responses during protracted abstinence; these effects are blocked by MIFE 
(Richardson et al., 2008; Vendruscolo et al., 2012; Silva and Madeira, 2012). Likewise, MIFE 
reduces the severity of alcohol withdrawal (Vendruscolo et al., 2012; Sharrett‐Field et al., 2013) 
and prevents alcohol-withdrawal induced hyper-excitability and memory deficits (Jacquot et al., 
2008).  MIFE administration into the central amygdala suppresses yohimbine-induced 
reinstatement of alcohol-seeking (Simms et al., 2012). MIFE also has anxiolytic effects in 
various animals models of stress-induced anxiety (Korte et al., 1995; Sufka et al., 2009; 
Jakovcevski et al., 2011). Thus, MIFE treatment during early abstinence may reduce anxiety, 
craving and alcohol-seeking behaviors that are associated with altered HPA axis activity and 
relapse to heavy drinking. 
Alcohol Clinical Research. In humans, MIFE is used medically as an emergency 
contraceptive, for the treatment of endometriosis and progesterone sensitive tumors. More 

 
 
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recently MIFE (300-1200 mg) was approved for treatment of Cushing’s syndrome, a serious 
endocrine disorder caused by endogenous hypercortisolism (DeBattista and Belanoff, 2006). 
MIFE doses of 300-1200 mg/day have also been effective in clinical trials of other disorders 
associated with cortisol dysregulation including psychotic depression and bipolar depression 
(Blasey et al., 2011; Watson et al., 2012). We are aware of only one randomized placebo-
controlled clinical trial of 7-day 600 mg/day MIFE treatment in non-treatment seeking alcohol 
dependent subjects (ClinicalTrials.gov identifier: NCT01548417).  A meeting abstract of this 
ongoing study reported that MIFE reduced alcohol cue-induced craving (Mason, 2012).   
In addition to examining the behavioral and psychopharmacologic effects of GR 
antagonism, we will measure functional connectivity (FC) and alcohol cue-induced brain 
activation (CA) in the presence and absence of GR blockade in both AUD and HC participants.  
Resting-state FC research has identified a number of networks including those associated with 
the sensory/motor system, executive functioning as well as visual and auditory processing 
(Khanna et al., 2015). Although agnostic regarding direction of connections, FC can identify 
neural systems that are coupled and share functional properties as measured by a positive or 
negative correlation in the resting state (rs) BOLD signal over time between the regions.  
Measurements at rest and during alcohol cues have already advanced our 
understanding of the neural correlates of alcohol craving and relapse risk. Han and co-workers 
(2015) showed that AUD subjects have positive FC between the dorsolateral prefrontal cortex 
(DLPFC), cingulate, and cerebellum, and negative FC between the DLPFC and the orbitofrontal 
cortex. In this study, AUD participants also showed positive FC between the DLPFC, temporal 
lobe and striatal areas. Beck and co-workers (2012) showed that alcohol-related cues elicited 
increased activation in brain areas associated with attentional bias toward these cues (the 
ventral tegmental area extending into the subthalamic nucleus and ventral striatum) and that, in 
patients who remained abstinent, increased activation and connectivity were observed in brain 
areas associated with processing of salient or aversive stimuli. In a particularly rigorous study, 
Sinha and co-workers (2013) identified that disrupted vmPFC/ACC function plays a role in 
relapse.  Most recently, the GR gene has been identified as a primary regulator of a network of 
brain areas involved in alcohol reward, including the mPFC, NAcc, central nucleus of the AM, 
and ventral tegmental area (Repunte-Canonigo et al., 2015).  As we would hypothesize, stress 
in the absence of alcohol also modulates AM- mPFC conductivity (Quaedflieg et al., 2015).  We 
will extend these finding by measuring resting and CA patterns before and during GR blockade, 
with a particular focus on NAcc, AM and PFC, (see Fig 3), allowing comparisons between 
human findings from the proposed study and animal findings from other grants funded as part of 
the NIAAA INIA consortium. We also will perform exploratory analyses of whole brain functional 
connectivity. This combination of analyses will provide unprecedented information of how 
glucocorticoids alter synchronously interacting neural circuitry in persons with AUD and provide 
exciting new therapeutic targets for AUD medication development. 
Thus, there is clear evidence for the role of glucocorticoids in the development and 
maintenance of alcohol use disorders.  To date, there has been very limited research targeting 
the HPA axis for treatment of this disorder.  MIFE is a novel and promising pharmacotherapy. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Study Overview:  This is a randomized, double-blind inpatient or outpatient human laboratory 
study.  Procedures will be completed as a 7-day inpatient protocol in AUD subjects (N=75) and 
a 4-day outpatient protocol in an age and gender-matched comparison group of healthy control 

 
 
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(HC) subjects (N=75).  On day 1, AUD subjects will be administered an alcohol beverage to 
control time from last drink before undergoing the first fMRI session. Two hours after alcohol 
administration, resting-state and alcohol-cued activity will be measured. Following the fMRI 
session on day 1, all subjects will be randomized to once-daily MIFE or placebo administration. 
They will also complete cognitive assessment tasks such as the Wisconsin Card Sorting Task 
(WCST) and two parts of the Wechsler Adult Intelligence Scale-III (WAIS-III), the digit span and 
the digit symbol substitution tests.  They will receive their first medication dose on day 1.  Over 
the next 3 days, AUD participants are monitored as they go through supervised alcohol 
withdrawal. On day 4, all subjects will complete a second fMRI session to quantify FC changes 
as a function of alcohol withdrawal and medication administration across key brain regions 
recently shown to be under GR regulatory control. They will also repeat cognitive assessment 
tasks.  On day 5, AUD subjects complete the Trier Social Stress Test (TSST) followed by the 
Alcohol Motivated Response (AMR) procedure, during which subjects work for either their 
preferred alcohol beverage or money. On day 6, AUD subjects will participate in a cumulative 
alcohol administration procedure during which subjective and physiological responses to alcohol 
are repeatedly assessed. AUD subjects are discharged on day 7 after completion of the 
cognitive assessment tasks and a brief intervention.  AUD participants are followed for two 
weeks post discharge.  HC participants are followed for one week post second fMRI. 
 
Table 1.   Study Day AUD Procedures 
HC Procedures 
Pre-admission 
Assessment, Medical History, Vital Signs, blood work 
Assessment, Medical History, Vital Signs, blood work 
Day 1 
Updated assessment, blood work, urine pregnancy 
test; alcohol administration and fMRI session 1 
MIFE/placebo randomization and dosing; Cognitive 
Assessment 
Updated assessment, blood work, urine pregnancy 
test; fMRI session 1 
MIFE/placebo randomization and dosing; Cognitive 
Assessment 
CRU stay 
Days 2-6: Alcohol withdrawal monitoring 
 
MIFE/placebo dosing 
Days 2-6 
Days 2-4 
Day 4  
fMRI session 2; Cognitive Assessment 
fMRI session 2; Cognitive Assessment 
Day 5 
TSST and AMR 
 
Day 6 
Alcohol sensitivity session 
 
Day 7 
Cognitive Assessment; Discharge 
 
Day 11 
 
OP safety follow-up visit 
Day 14 
OP safety follow-up visit 
 
Day 21 
OP safety follow-up visit 
 
 
All visits will be completed remotely where possible (ex. Assessment and follow-up 
visits), although many procedures require in person assessment, including an inpatient stay for 
AUD participants.  For all in-person visits, staff  will use appropriate PPE (face mask/shield, 
gowns, gloves) and will practice physical distancing.  Participants will be required to wear 
facemasks and if they do not have one, a facemask will be provided by our staff. Office spaces 
will be cleaned by sanitizing surfaces between office visits.  
 
 
Assessment. 
 
All potential subjects will be screened by telephone using a standardized initial 
questionnaire, which includes demography, drug and alcohol use patterns and associated 
problems, and a brief personal medical and mental health status. This telephone screen 
addresses the major inclusion/exclusion criteria for the study and quickly rules out respondents 

 
 
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who disqualify.  We typically telephone screen 5 persons for each participant scheduled for in-
person assessment.   
 
Subjects who appear eligible based on phone screen will be invited to provide written 
informed consent.  Teleconsent will be used as opposed to in person consenting where possible 
to reduce unnecessary in person encounters specifically for a consent procedure.  
 
We will be using DocuSign, the Institution’s approved and 21 CFR Part 11-compliant 
software, to obtain a secure electronic signature.  We will send the consent to the participant via 
DocuSign, providing a participant-specific code in advance of sending the document via 
DocuSign, that will be required when the participant accesses and signs the consent. The 
consent discussion may take place via phone or video conference (e.g. Zoom).  Participants will 
be given adequate time to consider the research study and ask questions prior to signing the 
consent form.  When ready to sign, the participant will enter their code, verifying that the person 
signing the consent is the person that we spoke with previously, and sign the consent within the 
DocuSign system.  (Note: For studies requiring multiple signatures, e.g. two parental signatures 
or if a witness is required, all individuals will receive codes in order to sign).  Once the 
participant has electronically signed, the study team member obtaining informed consent will be 
notified that the electronic form is ready for his or her signature.  Once signing is completed by 
all parties, both the study team and the participant can download the signed consent as a PDF.  
The study team will also have access to the audit log and the Certificate of Completion.  The 
study team will load the signed consent into Epic. 
 
In instances where Docusign cannot be executed or the potential participant declines to 
use it, Teleconsent will still be used as opposed to in person consenting where possible to 
reduce unnecessary in person encounters specifically for a consent procedure. Participants will 
be provided with a copy of the Informed Consent prior to the teleconsent meeting either via 
email, fax, mail or previously provided during an in person visit.    
 
The consent designee must verify the participant physically signed the consent 
document either by viewing via video conference, obtaining a photo of the signed consent 
document; or obtaining verbal confirmation from the participant that he/she signed the consent 
form or agreed to participate electronically.  The participant will sign and date/time the informed 
consent document.  The document is then mailed, emailed or faxed to the consent designee. 
The participant will be asked to return the original signed document on their first in person 
visit.  If the Informed Consent form is mailed to the consent designee by the participant the IRB-
approved consent designee will sign the copy, which they possess after the participant has 
acknowledged signature on their copy.  Once the original is received by the consent designee 
the copies will be attached to make a single document.  In all other instances, once received, 
the IRB-approved consent designee signs, dates/times the informed consent document.   
 
After the Informed Consent process is completed, the IRB approved study team member 
files the consent document in EPIC, including a note confirming the consent process. The entire 
consent document is also then filed in the research record. 
 
To the extent possible, assessment instruments will be completed remotely, either by 
interview with the study coordinator or on paper to be returned with the signed consent form. 
 
Assessment instruments include the following.  The MINI International Neuropsychiatric 
Interview 7.0 (Sheehan et al., 1998) will be used to assess the presence/absence of alcohol or 
other substance use disorders, as well as mood, anxiety and psychotic disorders to establish 

 
 
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study eligibility. The pattern, amount and route of administration of alcohol use are 
characterized using the 90-day Time Line Follow Back (TLFB) (Sobell and Sobell, 2003; 
Robinson et al., 2014).  Subjects complete the Alcohol Use Disorders Identification Test 
(AUDIT) (Bohn et al., 1995) to characterize alcohol-related problems.  The Fagerström Test for 
Nicotine Dependence (FNDT) (Heatherton et al., 1991) characterizes smoking 
quantity/frequency and severity of nicotine dependence.  The Shipley-2 Vocabulary evaluation 
and or the Rapid Estimate of Adult Literacy in Medicine (REALM Health Literacy Test) will be 
used to determine reading grade level. 
 
Initial assessment findings will be reviewed and those participants who still appear to be 
eligible for study participation will be invited to come to the research office for blood work, urine 
toxicology and a medical history and vital signs. A urine toxicology screen is obtained to check 
for recent drug use.  Women will complete urine pregnancy testing.  Subjects will undergo a 
medical history , and standard laboratory tests (complete blood count, comprehensive metabolic 
panel) and a 12-lead ECG. In rare cases, MIFE can cause low blood potassium and cardiac 
changes.  We will exclude individuals with potassium levels below the normal range or who 
have any clinically significant abnormality on the ECG.  The ECG and medical records will be 
reviewed by the study physician (Dr. Wand). Psychiatric and behavioral assessments will be 
reviewed by Dr. McCaul, Co-PI and a licensed psychologist. We are eliminating all sections of 
the brief physical examination (PE) from the protocol except vital signs to enhance safety for 
staff nurse and physician. We have determined that the PE findings have never contributed to 
ruling out participation by participant.  The detailed medical history will be obtained.  We expect 
to assess 3 people for each eligible participant; thus the total assessed sample will be 450 
subjects.  Because of the risk of confounding by smoking rates and severity among AUD 
subjects, we will recruit an equal number of HC smokers, matched on Fagerstrom scores. 
 
General CRU procedures: 
For AUD subjects, this study will be completed as a 7 day (6 night) inpatient protocol on 
the Bayview Clinical Research Units (CRU).  We will conform with all COVID-related safety 
procedures implemented by the CRU. 
 
On Day 1 prior to completion of any study procedures, subjects will undergo a urine 
toxicology for recent alcohol and drug use; a drug positive other than marijuana will result in 
rescheduling study procedures. Female subjects will complete a urine pregnancy test; positive 
subjects will be excluded from further study procedures.  Vital signs (BP and HR) and laboratory 
tests (CBC and CMP) will be obtained.  Updated assessment measures will include an interim 
timeline follow-back of alcohol use.  
During the Bayview CRU stay, participants will be allowed to smoke; subjects will be 
smoking abstinent for 2 hours prior to study procedures.  They will have the option to receive a 
transdermal patch (21 mg) while off the CRU to complete study procedures. 
 
Daily at 8:00 pm, participants will complete self-reports of alcohol craving, including 
Visual Analog Scale for alcohol and tobacco craving (VAS); Penn Alcohol Craving 
Questionnaire (PACS) (Flannery et al., 1999), Beck Depression Inventory-II (BDI-II), Beck 
Anxiety Inventory (BAI), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Urge 
Questionnaire (AUQ).  Nursing staff will complete clinician-administered instruments for alcohol 
withdrawal assessment (see below). Participants will have PRN access to over the counter 
medications to treat headache, gastrointestinal upset and body aches. 
   
Each day of the CRU stay, the CRU nurse will administer the Systematic Assessment for 
Treatment of Emergent Events (SAFTEE) (Johnson et al., 2005). This standardized, structured 

 
 
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instrument is specifically adapted for use in substance use disorder clinical trials, to collect 
information on incidence and severity of medication side effects and adverse events.   
 
To determine if the degree of elevation of CORT in response to GR blockade by MIFE 
correlates with any of our outcome measures, each morning upon wakening and at bedtime on 
the CRU, a salivary cortisol sample is obtained. Baseline samples will be collected on day 1, 
prior to beginning study medications. Measurement of CORT in saliva is not invasive and 
multiple samples per day are easily obtained.  Unlike serum CORT, salivary CORT is unbound 
to protein and reflects the physiologically relevant fraction. For each sample, subjects chew a 
pad for 90 sec, which they then place into a capped salivette.  Saliva is harvested by 
centrifugation and stored in a cryotube at -70 until assayed in duplicate (Diagnostic Systems 
Laboratories; Webster, Texas). The intra- and inter-assay coefficients of variation are below 5%. 
As we expect variability in CORT within and across MIFE doses, these data will be included in 
our analyses. 
 
Because MIFE is occasionally associated with hypokalemia, serum potassium level is 
obtained before study procedures on day 1 and again on day 7 and at the 1 week follow-up visit. 
Potassium replacement will be addressed as needed. 
 
Outpatient procedures for HC:  Healthy control subjects will complete the study as a 4-
day outpatient protocol.  
 
On day 1, the study procedures will be similar to those for inpatient participants.  
However, the outpatient participants will not receive alcohol prior to the fMRI and will be given 
take-home mifepristone doses and instructed on at-home medication observation and saliva 
collection procedures at the end of the day.   
 
On days 2 and 3, participants will be asked to complete a video teleconference with 
nursing staff or a research coordinator.  Video teleconference will be on a HIPAA compliant 
telemedicine app or website (participant preference) and does not require the participant to 
enter any potentially identifying information.  The participant is free to enter their study ID or a 
pseudonym to enter the virtual waiting room to connect with the provider. This service uses end-
to-end encryption and no identifying information is recorded.  On this video teleconference, 
nursing staff will administer the Systematic Assessment for Treatment of Emergent Events 
(SAFTEE) (Johnson et al., 2005).  This standardized, structured instrument is specifically 
adapted for use in substance use disorder clinical trials, to collect information on incidence and 
severity of medication side effects and adverse events.  Nursing staff will also administer the 
adrenal insufficiency questionnaire.  Participants will then be observed taking their dose of 
MIFE.   
 
To determine if the degree of elevation of CORT in response to GR blockade by MIFE 
correlates with any of our outcome measures, each morning upon wakening and at bedtime 
participants will be asked to collect a salivary cortisol sample.  Baseline samples will be 
collected on day 1, prior to beginning study medications. Measurement of CORT in saliva is not 
invasive and multiple samples per day are easily obtained.  Unlike serum CORT, salivary CORT 
is unbound to protein and reflects the physiologically relevant fraction. For each sample, 
subjects chew a pad for 90 sec, which is then placed into a capped salivette.  Saliva is 
harvested by centrifugation and stored in a cryotube at -70 until assayed in duplicate 
(Diagnostic Systems Laboratories; Webster, Texas). The intra- and inter-assay coefficients of 
variation are below 5%. As we expect variability in CORT within and across MIFE doses, these 
data will be included in our analyses. 

 
 
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Because MIFE is occasionally associated with hypokalemia, serum potassium level is 
obtained before study procedure at 7:00 am on day 1 and at the 1 week follow-up. Potassium 
replacement will be addressed as needed.  MIFE levels will also be tested at day 4. 
 
On day 4, outpatient HC participants will return to the office in the morning and complete 
the study procedures. 
 
Alcohol Withdrawal Management:  
 
AUD subjects will complete medically supervised alcohol detoxification as in our 
earlier studies (McCaul, Wand, Eissenberg et al., 2000; McCaul et al., 2001; Bencherif et al., 
2004; Weerts et al., 2008; Weerts et al., 2011; Wand et al., 2013; Weerts et al., 2013). 
Participants will be required to wear a mask before nurse, staff or housekeeping enter the room. 
All AUD subjects will receive intravenous D5W NS over the first 12 hours following admission. 
The Clinical Institute Withdrawal Assessment - Alcohol Revised (CIWA-Ar) (Sullivan et al., 
1989), which includes 10-items (nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, 
tactile disturbances, auditory disturbances and visual disturbances), will be completed by CRU 
nurses every 4 hours while the participant is awake. This well-validated clinical tool will assess 
alcohol withdrawal symptom severity, and is the gold standard to guide benzodiazepine (BZ) 
administration during symptom-driven withdrawal management (Saitz et al., 1994). We have 
successfully studied alcohol withdrawal in our prior research.  Scores on the CIWA-Ar are 
sufficiently elevated that we are able to see reductions in withdrawal severity as a result of 
research pharmacological intervention.  If the CIWA score is ≥12 the subject is given 
intravenous diazepam (5mg) or lorazepam (1mg). The CIWA score is repeated 1 hour after the 
first diazepam dose. If the score remains ≥10 then a second intravenous diazepam dose (5mg) 
or lorazepam dose (1mg) is given. This procedure is repeated one more time and if the CIWA-
Ar score remains ≥10 then the participant is transferred to the Bayview ED and terminated from 
the protocol. Based on our previous study, we anticipate that few subjects will require BZ 
treatment since we exclude subjects who report a history of withdrawal complications.  If systolic 
blood pressure increases above 180 and/or diastolic blood pressure increases above 105, we 
may administer atenolol 25 mg po and then titrate as needed.  Subjects will be removed from 
the protocol for seizures, hallucinations, or disorientation or following three doses of diazepam 
or lorazepam.  At that point in time, the physician on call will be contacted.  The subject will be 
transported to the Johns Hopkins Bayview Emergency Department for care.  The subject is now 
terminated from the study. 
 
MIFE Administration: 
MIFE has a rapid onset of action and achieves peak plasma levels within 1 - 2 hrs of oral 
dosing. Peak plasma levels and bioavailability increase as a function of dose but are not directly 
proportional to dose.  However, plasma concentrations of MIFE metabolites do increase in 
direct proportion to dose; metabolites have antiglucocorticoid activity and contribute to long-
acting drug effects (Pomara et al., 2002). MIFE is effective with once-a-day dosing.  The half-life 
is 40 hrs following a single dose and 84.6 hrs following multiple doses.  Following 
discontinuation of MIFE, plasma levels are detectable for up to 2 weeks (Heikinheimo et al., 
2003).  For this study, we selected to use the high MIFE dose of 1200mg, based on recent 
clinical trials for other neuropsychiatric disorders associated with HPA-axis dysfunction, and that 
1200 mg MIFE has been safely administered over extended periods (MIFE Investigator 
Brochure, Corcept Therapeutics).  This study only exposes subjects to MIFE for up to 6 days.  
We are not planning to reduce MIFE dose during such a brief treatment period.  If a subject 
experiences significant medication side-effects or any serious adverse event or if the participant 
declines to continue medication, then we will discontinue that participant from the study.  It 

 
 
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should be noted that inpatient subjects are under continuous nursing observation throughout the 
CRU stay and thus adverse events can be identified and addressed rapidly.  HC subjects will be 
instructed to call the study doctor if they have any adverse events.  Subjects will be randomized 
to active MIFE and placebo on a 2:1 ratio. 
 
In the proposed study, MIFE will be administered under an IND (Wand 124365). MIFE 
(300 mg) and matching placebo will be provided by Corcept Therapeutics, Menlo Park, CA. We 
will overencapsulate the medication and placebo as necessary. The Johns Hopkins Bayview 
Investigational Drug Services (IDS) will maintain the inventory and dispense the medication. 
MIFE absorption and elimination are not affected by age, body weight, BMI, race or sex 
(Mifepristone Investigator Brochure, Corcept Therapeutics). 
 
Since MIFE has potent antiprogestational effects, women participants will undergo a 
urine pregnancy test at the time of the initial alcohol sensitivity and prior to the first MIFE dose. 
On day 1, participants will be dosed after the fMRI session under nursing observation.  On all 
subsequent days, inpatient participants will be dosed once daily at 9 am under nursing 
observation and HC outpatient participants will be given take home medication and asked to 
take the medication under nursing observation via video teleconference.  Blood draws for MIFE 
trough and peak plasma level determinations will be drawn at 15 minutes before dosing and 90 
minutes after dosing, respectively. MIFE blood draws will be completed for outpatient HC 
participants on day 4 only. Subjects can discontinue taking study medication at any time, ending 
study participation. Discontinued subjects will be asked to complete post-discharge follow up. 
 
fMRI scans for functional connectivity and alcohol cue activation on Days 1 and 4:  Both 
AUD and HC participants undergo fMRI sessions.  On day 1, all subjects report to the IPSAR 
office at 9 am, complete interim assessment procedures, urine drug and pregnancy screens and 
receive a calorie-controlled breakfast. AUD and HC smokers with tobacco use disorder (TUD) 
will receive a nicotine patch (21mg).  At 10 am on day 1 only, AUD subjects will receive an 
alcohol drink in a standardized calorie-free mixer targeting a blood alcohol level of 80mg% 
based on gender and BMI.  We have included this drink for several reasons. Most importantly, 
we want to standardize time from last drink to start of scanning across AUD subjects, since 
subjects will come for admission with varying abstinence durations. Secondly, we want to 
minimize the impact of both alcohol intoxication and withdrawal on this initial scan, and so have 
attempted to time the scan to begin when BAL is at or near 0mg%.  Finally, we anticipate that 
this pre-scan drink will act as a primer for the alcohol cuing procedure employed in the study.  At 
1 pm, all subjects undergo rs-FC and CA fMRI procedures. 
 
fMRI Scanning procedures:  All studies will be conducted at 3T in the F.M.Kirby 
Research Center for Functional Brain Imaging. We will follow all COVID-related safety 
procedures implemented by the Kirby Research Center.  We will counter-balance for 
handedness and always use the right hand for responses. 
fMRI scanning. fMRI data will be acquired at 3.0 Tesla using gradient-echo EPI BOLD. 
Typical parameters are: 47 axial slices with TR = 3000 ms; TE = 30 ms; flip angle =85 degrees; 
field of view = 214 (LR) x 214 (AP) mm2; nominal acquisition voxel size 3 x 3 mm2; matrix size 
= 72x 72, slice thickness = 3 mm, no slice gap, yielding coverage in the inferior-superior 
direction of 141 mm. These parameters replicate those used in the MGH-USC Human 
Connectome Project (www.humanconnectomeproject.org). 
In-plane structural scans.  Anatomical scans are acquired to overlay functional activation 
onto anatomical structures.  A 3D magnetization-prepared rapid acquisition with a gradient echo 
(MP-RAGE) sequence is used for this (TR = 8.0 ms, TE = 3.7 ms, Flip = 8 deg, Inter-shot time = 
3000 ms, FOV =256 mm, 200 z-phase encoding steps, with a linear profile acquisition order, 1 

 
 
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mm slice thickness, TI = 854 ms, matrix = 256 x 182, rFOV = 78%, 1 average, for a total scan 
duration of 6 min 25 sec with SENSE reduction factor of 2.)  
rs- fMRI Brain Connectivity methods, including pre-processing, artifact detection, 
physiological noise removal using CompCor methods, and generation of seed-based 
connectivity maps will be similar to those in our Preliminary Studies, using scan parameters 
described above.   
     rs- fMRI analysis. Motion statistics and artifact frequency will be compared to insure 
that there are no group differences. If necessary, outlier subjects will be removed to achieve 
equality, or, if this is not possible, motion covariates will be used in analyses. We will determine 
connectivity using a priori specified seed voxels derived from two sources. The first is from 
coordinates from previously published studies (Muller-Oehring et al., 2015), or anatomical 
regions derived from published probability atlases (Hammers et al., 2003; Amunts et al., 2005). 
Primary regions of interest (ROIs) include ventral striatum/NAcc, mPFC, and central nucleus of 
the AM (Repunte-Canonigo et al., 2015). Additional seed regions of interest may be identified 
from group differences observed in the alcohol cue task described below. Connectivity will be 
measured using the peak cross-correlation between the seed region and other brain regions. 
These cross correlation results obtained for each subject can then be used in a second-stage 
analysis for making population inferences and group comparisons. For example, the correlation 
between the resting-state time series from NAcc and the time series from all other brain regions 
can be used to create a NAcc correlation volume for each subject. The differences in these 
correlation volumes before and after drug treatment can be compared for the placebo and drug 
groups in order to characterize group-dependent differences in altered NAcc connectivity 
resulting from GR antagonist treatment. We hypothesize that medication groups will exhibit 
significant differences relative to the AUD placebo group and that fewer differences in 
connectivity will be observed between HCs and medication groups than between HCs and the 
AUD placebo group, ie. drug treatments will tend to normalize connectivity toward patterns seen 
in HCs. In addition to seed-based analyses, we will perform exploratory analyses of whole brain 
functional connectivity using independent component analyses.  Group comparisons will be 
performed using methods developed and published by our collaborator, Dr. Pekar (Calhoun et 
al., 2001; Calhoun et al., 2004).  Most recently, Dr. Pekar and collaborators (Nebel et al., 2015) 
have used these methods to identify functional connectivity ‘signatures' associated with 
individual differences in symptom severity in children with autism. 
fMRI during Alcohol-related Cues.  Several investigations, including studies conducted 
by our consultant Dr. Myrick, have found that AUD adults exhibit increased brain activation in 
response to alcohol-related cues in reward circuitry regions, including ventral striatum, anterior 
cingulate, and medial prefrontal region, as well as in parietal and temporal regions (Schacht et 
al., 2013).  These changes in brain activation have been shown to be sensitive to medication 
effects, including aripiprazole and naltrexone (Myrick et al., 2008; Myrick et al., 2010).  To 
promote robust and rigorous conduct of the study, Dr. Myrick has agreed to serve as a 
consultant for this project and to provide the visual stimuli that were used in his studies to elicit 
ventral striatal activations. 
      Alcohol-Cue Methods: As described in reports by Myrick et al. (2004, 2008) six 120-
second epochs of stimuli will be presented to subjects during fMRI scanning, using scan 
parameters described above. Each epoch will contain four 24-second blocks of alcoholic 
beverage pictures (beer, wine, or liquor), nonalcoholic neutral beverages, visual control pictures, 
and rest. Each epoch will have a different order of these stimuli and epoch order will be 
counterbalanced across subjects. Each block will have 5 pictures presented for 4.8 s each. After 
each block there will be a 6 second period where the subject will indicate the magnitude of 
alcohol craving rating (ranging from not at all to greatest ever) by pressing one of 4 MRI 
compatible response buttons. Subjects will be given a sip of their preferred spirits in non-
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Beverage pictures will be obtained from the Normative Appetitive Picture System supplemented 
by additional pictures from advertisements to prevent picture repetition. Visual control pictures 
will be scrambled versions of the alcohol pictures. Rest blocks will consist of a crosshair fixation. 
Visual stimuli will be back-projected to subjects using a MRI-compatible projector.  A PC in 
conjunction with Eprime software will be used to generate visual stimuli and control 
experimental parameters.  
    Alcohol-cue fMRI Data Analysis:  Standard pre-processing, including timing 
correction, motion correction, anatomical/functional coregistration, spatial normalization into MNI 
space (via segmentation), and spatial smoothing, as well as whole brain statistical analyses of 
fMRI data will be performed using the SPM12 software package.  Following pre-processing, 
parameter estimation involves deriving least square estimates of the fit between regressor(s) 
and the fMRI timeseries at each voxel. Regressors consist of events of interest (e.g., alcoholic 
and nonalcoholic picture presentation) convolved with the hemodynamic response function. 
Population inferences will be performed on contrasts of parameter estimates for each subject 
(e.g., alcoholic pictures minus nonalcoholic pictures) using a random effects model that is 
appropriate for population inference. Corrections for multiple voxel comparisons will be 
accomplished using False Discovery Rate (Genovese et al., 2002) methods. Artifact detection 
software (Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC)) from head 
motion will be used to exclude artifactual timepoints and output from this software can be used 
to test whether there are motion or task-correlated-motion differences between groups. If such 
differences exist, outlier subjects will be removed to eliminate differences, or motion parameters 
will be entered as covariates in statistical tests. In addition to whole-brain methods, ROI 
analyses will be performed to test specific hypotheses of this proposal. Specific ROIs will 
include the ROIs examined under rs-FC as well as ROIs defined from prior fMRI studies of cue-
induced activation (Neto et al., 2008; Myrick et al., 2008; Schacht et al., 2013; Muller-Oehring et 
al., 2015). 
 
Cognitive Assessment:  To study cognitive effects of mifepristone, all subjects will 
complete the cognitive battery of assessments on days 1 and 4.  AUD participants will 
additionally repeat the cognitive battery on day 7 prior to discharge.  The battery will include the 
Wisconsin Card Sorting Task (WCST) and two parts of the Wechsler Adult Intelligence Scale-III 
(WAIS-III), the digit span and the digit symbol substitution test (DSST).  The WCST asks people 
to sort cards based on different criteria with the only feedback being whether the classification is 
correct or not.  The classification rule changes over time and this task measures how well 
people can adapt to the changing rules (Puente, 1985).  The WAIS-III digit span task requires 
subjects to repeat verbatim a string of digits that sequentially increases in length until the 
consecutive failure of two trials of the same digit span length (Wechsler et al., 1997).  The 
WAIS-III digit symbol substitution test requires the rapid copying of symbols paired with 
numbers in 90 seconds (Wechsler et al., 1997).  All three tests are available for computer 
administration. Computer tablets will be sanitized immediately after use. 
 
Trier Social Stress Test (TSST) and Alcohol Motivated Responding (AMR) session on 
Day 5: To examine GR antagonist effects on stress-induced motivation to drink, AUD subjects 
undergo the TSST followed by an AMR session on day 5. The TSST consists of a public 
speaking component and a mental arithmetic component (Kirschbaum et al., 1993) and is one 
of the most validated human stress procedures (Kirschbaum et al., 1993).  Confederates who 
are unknown to the study participants are used to implement the stress components.  We 
engage JHU SOM employees to carry out these procedures since they are available on-site and 
the task is brief, requiring 10 minutes of their time.  We have typically identified confederates 
through flyers posted in the SOM. No data are collected on the confederates; all data are 
generated by the study participants. Confederates are not provided with any information on the 

 
 
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identity of the study participants and do not have access to study files or data. Confederates 
and participants will be required to wear a facemask before, during and after the procedure.  
The conference room in which the procedure takes place allows for physical distancing. 
 
Immediately following the TSST, subjects begin the AMR session.  We have 
successfully developed an alcohol motivated responding (AMR) model using progressive ratio 
operant conditioning procedures widely used in preclinical laboratories and adapted for human 
research. At the start of the session, participants receive a primer drink consisting of one-half of 
a standard drink of their preferred alcohol. Response requirements (i.e., number of mouse 
clicks) increase with each earned reinforcer over a total of 10 reinforcement opportunities. 
During each response set, subjects elect to work for their preferred type of alcohol (0.5 standard 
drink) or money ($1.00). At baseline and at 10-min intervals during the AMR session, subjects 
provide a saliva sample for CORT measurement and complete the two-item Tiffany Brief 
Craving Scale (Tiffany et al., 2000) (How badly would you like an alcoholic drink right now?; 
Rate your current desire to drink alcohol) on a visual analog scale (VAS) from 0 (not at all) to 10 
(extremely). At the end of the 60 min AMR period, participants receive earned drinks and/or 
vouchers for earned money. AMR sessions last for 60 min or until no response is made for 10 
min, whichever comes first. If the session is terminated, subjects do not gain access to alcohol 
until the end of the 60-min session. The maximum amount of alcohol that can be earned is 5 
standard drinks (SD), earned in 10 response sets (0.5 SD each set). Subjects drink their 
preferred type of alcohol; alcohol volume is standardized to ensure equivalency across subjects 
for the amount of absolute alcohol that can be earned.  Drinking is paced to ensure that subjects 
cannot exceed 0.5 SD every 5 minutes or the total consumption of all 5 SDs in a 50-minute 
period. Subjects also are provided their preferred mixer and snacks. 
 
Alcohol Sensitivity Session: 
On day 6, AUD subjects will participate in an alcohol sensitivity session to assess 
subjective and cardiovascular responses to oral alcohol administration after stabilization on 
MIFE/placebo.  On the morning of the procedure, subjects receive a calorie-controlled breakfast 
and lunch to control for dietary effects on alcohol absorption.  We will obtain a blood sample for 
MIFE plasma level determination prior to the alcohol session.  
In this cumulative alcohol dosing procedure, placebo and three active alcohol drinks are 
administered at timed intervals to increase BAL progressively (0, 0.03, 0.067, 0.10%) during a 
single session.  Alcohol doses for each subject are determined using a Computerized Blood 
Alcohol Calculator (CBAC©) which adjusts for age, height and gender differences in body water 
and duration of drink consumption. This allows us to target similar BALs in males and females. 
Investigational Drug Services prepares each 120 mL drink by mixing the appropriate mL of 95% 
ethanol and a non-caloric sweetened beverage using a w/v metric. The placebo drink is blinded 
by floating 1 mL of ethanol on top of the beverage and by placing an ethanol-soaked wristband 
around the glass to deliver a strong alcohol odor. Active alcohol drinks are prepared in the same 
manner.  Subjects are monitored continuously by staff, who also ensure consumption of each 
drink is paced over 10 min. Staff will physically distance from the participant during alcohol 
consumption when participants will have to remove their masks. 
 
 
Subjects complete a computerized battery of subjective assessments at baseline before 
alcohol consumption (-45 minutes) and every 45-min thereafter.  The battery requires 10 
minutes for completion and includes the (1) Drug Effect Visual Analog Scale (VAS) (Uhart et al., 
2013) , (2) Brief Craving Scale (Cox et al., 2001), (3) Biphasic Alcohol Effects Scale (BAES) 
(Martin et al., 1993), (4) Subjective High Assessment Scale (SHAS) (Schuckit, 1980), (5) POMS 
(D. M. McNair et al., 1992; D. McNair and Heuchert, 2003) Tension Anxiety subscale.  At time 0, 
the placebo drink is administered. Active alcohol drinks are administered at 45 min intervals 

 
 
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(+45, +90 and +135). Breath alcohol levels are determined at baseline (-15) and 15 min after 
consumption of each drink. Heart rate, skin conductance and skin temperature are recorded 
continuously using a noninvasive monitor; blood pressure is recorded every 5 min.  Participants 
also complete a brief battery of psychomotor/reaction time tasks to measure level of 
intoxication.   
Periodically throughout the session, we will perform measurements of blood alcohol 
levels using a handheld breathalyzer device. The technique has the potential to aerosolize 
water vapor during the participant’s exhalation. The staff member running these sessions will be 
wearing full PPE attire. The staff member will leave the research room each time the participant 
exhales into the breathalyzer.  Participant then removes disposable mouth piece and places it in 
a basket containing a red bag designed to hold toxic materials. A fresh mouth piece is attached 
by staff after re-entering procedure room. 
 
After the session, subjects return to the Clinical Research Unit for monitoring and data 
collection.  A staff member must accompany the participant on the car ride from the JHH 
campus to the Bayview CRU.  Staff and participants will use face masks and physically distance 
to the extent possible during the ride.  The subjective assessment battery and an Alcohol 
Hangover Scale (McCaul, Turkkan et al., 1991a) are completed hourly for 4 hours post session 
and once the next morning.  
 
We have safely administered alcohol in a range of doses to social drinkers and heavy 
drinkers (Turkkan et al., 1988; McCaul et al., 1991a; McCaul, Turkkan et al., 1991b).  We have 
demonstrated reliable alcohol dose-related increases in heart rate and subjective effects of 
alcohol, and these effects are sensitive to medications used for the treatment of alcohol use 
disorder (e.g., naltrexone, acamprosate) (McCaul et al., 2000; McCaul, Wand, Rohde et al., 
2000; McCaul et al., 2001; Brasser et al., 2004).  We have used single dose and cumulative 
alcohol dose procedures in our research. Since it requires multiple sessions to generate full 
alcohol dose-effect functions when each dose is administered within a single session, we 
selected the cumulative alcohol dosing procedure for this study as it minimizes subject research 
burden and reduces dropout rates. In addition, since an alcohol dose effect function is 
generated in a single session, downward, leftward and rightward dose shifts in response to 
MIFE treatment can be detected. 
 
 
As shown in Figure 1, cumulative alcohol dosing procedures generate highly 
reproducible BALs and subjective effects, with little between-subject variability.  Subjective 
effects track BAL across the ascending and descending limb of the curve.  Using this procedure, 
we have shown that the GABRA2 gene influenced alcohol subjective and physiological effects 
(Uhart et al., 2013). To date, we have completed this procedure over 150 subjects. 
 
  
Figure 1. Time course of BAL and self-rated effects on the VAS and SHAS.   Arrows indicate times of placebo 

 
 
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(P) and each alcohol drink (A1, A2, A3) consumed. 
 
 
Discharge and Follow-up: 
 
 
 
 
AUD subjects are discharged on day 7 following cognitive assessment and 
participation in a brief motivational intervention for alcohol use; information on treatment 
availability will be provided prior to discharge from the CRU.  Under the supervision of Dr. 
McCaul, the intervention is delivered by Master’s-level staff following procedures outlined in 
NIAAA Clinician Guide to Brief Intervention.   
 
All female participants are advised to use nonhormonal birth control (e.g., condoms) 
for the duration of a one month period following discharge.  All male participants will also be 
advised to use condoms for the duration of the follow-up visits and for at least 5 half-lives of 
the drug plus 90-days after the last dose of mifepristone.  All subjects will be given a supply 
of condoms. 
 
 
AUD subjects return weekly for 2 follow-up visits.  HC subjects return one week post-
second fMRI for a follow-up visit.  As described above, MIFE is a long acting compound; 
plasma levels will likely remain elevated throughout the first two weeks post-discharge at the 
time of the follow-up visits.  At each follow-up visit, participants provide self-reported alcohol 
use using TLFB procedures for the period since they were last seen, complete self-report 
measures of alcohol craving (as listed under the inpatient stay), medication side effects 
(SAFTEE) and adverse events.  In addition, we will obtain a blood spot for PEth 
determination as a biomarker of recent drinking intensity.  We also will get a blood sample 
for MIFE level and, at week 1 follow-up, a sample will be obtained to test for potassium level.  
Subjects will be reminded of the importance of use of nonhormonal birth control and/or 
condoms and will be provided with condoms.   
 
b. Study duration and number of study visits required of research participants. 
 
Each subject will participate in an initial assessment, and a possible second assessment 
visit for completion of medical history, vital signs and laboratory tests.  AUD participants will 
be admitted to the CRU for 6 nights.  HC participants, who participate in the study on an 
outpatient basis, will continue MIFE dosing and salivary sample collection at home.  For 
AUD participants, there are two follow-up visits at 1 and 2 weeks following CRU discharge.  
For HC participants, there is one follow-up visit at 1 week following the second fMRI.  It is 
anticipated that subjects will complete all study procedures within a 6 month period. 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Staff and subjects will be blind to the alcohol and MIFE doses administered during this study 
to reduce expectancy effects.   
 
d. Justification of why participants will not receive routine care or will have current 
therapy stopped. 
 
Subjects are not seeking treatment for their AUD; they will not currently be engaged in 
therapy. 
 

 
 
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e. Justification for inclusion of a placebo or non-treatment group. 
 
A placebo MIFE dose is included for comparison with the active drug effects and to control 
for expectancy effects. 
 
f. Definition of treatment failure or participant removal criteria. 
 
A participant will be removed from the study if s/he experiences a moderate or severe 
adverse event, is noncompliant with study or CRU rules, or if it is determined by the study 
physician to be unsafe to continue. 
 
g. Description of what happens to participants receiving therapy when study ends or 
if a participant’s participation in the study ends prematurely. 
 
MIFE dosing is discontinued at the time of discharge from the study.   
 
5. 
Inclusion/Exclusion Criteria 
 
Healthy, non-treatment seeking, 21-60 years old, male and female subjects will be 
recruited through the media.  Recruitment uses a mix of newspaper, radio, and on-line 
advertisements. Based on the 2011 census, the Baltimore metropolitan area is mostly 
Caucasian (61%) or African-American (30%); the remaining 9% is Asian (4%) and persons 
reporting two or more races (5%); 8.8% of the population report Hispanic ethnicity. 
 
This study will include two groups of participants – persons with AUD and healthy 
controls.  AUD subjects will have a current DSM 5 alcohol use disorder and will be actively 
drinking at least 50% above NIAAA recommended guidelines (women >10 drinks/week and 
men >20 drinks/week) and at least 5 binge drinking episodes in the past 30 days.  Recent 
heavy drinking will be confirmed by PEth blood spot analysis => 50 ng/mL.  HC subjects will 
not meet DSM 5 criteria for AUD and will not be drinking above NIAAA recommended 
guidelines as confirmed by PEth blood spot analysis < 50 ng/mL. We expect to consent 450 
subjects in order to accrue 150 subjects into the study procedures (N=75 for AUD and N=75 
healthy controls).   Historically, our retention in the CRU has been outstanding, with over 
90% of subjects completing the protocol. 
Additional Inclusion Criteria for all subjects: 
• 
Nontreatment seeking volunteers; 
• 
21 – 60 years old; 
• 
English speaking; 
• 
5th grade literacy to ensure ability to read study assessment instruments; 
• 
no current serious psychiatric or health problems that would contraindicate study 
participation; 
• 
BMI > 19 and < 40; medication dosing is not weight-adjusted. We have restricted 
the weight range of participants to reduce weight-associated variability; 
• 
For women, negative urine pregnancy test prior to initiating MIFE treatment and 
agreement to use nonhormonal birth control for 2 weeks following last MIFE 
dose.  A medical record of surgical sterilization or elevated FSH level confirming 
post-menopausal status is required to document non-childbearing potential; 
• 
No adult seizure history; 
• 
No serious alcohol withdrawal complications in prior alcohol withdrawal episodes; 

 
 
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• 
Some non-drinking days on 90-day TimeLine Followback Drinking Calendar; 
• 
Study Physician and PI recommendation. 
 
Exclusion criteria for all subjects: 
• 
Women on hormonal birth control, or who are pregnant, nursing or planning 
pregnancy; women with unexplained vaginal bleeding; 
• 
Current DSM 5 mood, anxiety or psychosis diagnosis or currently treated with 
psychiatric medication; 
• 
Current substance use disorder except alcohol, marijuana (mild) or tobacco; 
current illicit drug use other than marijuana; 
• 
History of serious alcohol withdrawal symptoms (e.g., seizures, hallucinations) or 
history of inpatient, medicated alcohol withdrawal management, and CIWA-Ar 
score at time of assessment ≥ 12; 
• 
Elevation of aspartate aminotransferase or alanine aminotransferase exceeding 
5 X the upper limit of normal; 
• 
History of clinically significant ECG abnormality or cardiovascular illness; 
• 
Potassium levels below normal range at screening or CRU admission; 
• 
Use of CYP3a inhibitors in the 3 months prior to study participation, including 
simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, 
such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, and tacrolimus; itraconazole, nefazodone, ritonavir, 
nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, 
clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, 
telithromycin, or voriconazole; midazolam, triazolam, sildenafil; 
• 
Any illness, condition, or medication use known to interact with MIFE metabolism 
(as outlined in the FDA package insert) that, in the opinion of the study 
investigators and the admitting physician, would preclude safe and/or successful 
study completion; 
• 
History of metal implantation that would preclude MRI scanning, including 
implants, pumps, pacemakers. 
 
6. 
Drugs/ Substances/ Devices 
 
a. The rationale for choosing the drug and dose or for choosing the device to be 
used. 
 
Mifepristone.  MIFE has been developed by Corcept Therapeutics and is currently 
FDA-approved or under investigation for hormone sensitive tumors and various 
neuropsychiatric disorders.  MIFE acts as an antagonist at GR and progesterone receptors 
(PR) (DeBattista and Belanoff, 2006).  We are examining effects of MIFE 1200 mg and 
matching placebo.  This MIFE dose has been safely used over extended administration in 
humans.  In our pilot data, we observed an effect of this dose on subjective responses to 
alcohol administration.  MIFE has demonstrated a strong safety profile in severely medically 
compromised patients with Cushing Syndrome, suggesting that it will be well tolerated in 
clinical populations with less morbidity. Indeed, very few adverse experiences have occurred 
in clinical trials with diverse psychiatric populations, including AUD, bipolar, schizophrenia 
and dementia patients (Yararbas and Pogun, 2011; Watson et al., 2012; Howland, 2013; 
Morgan and Laufgraben, 2013; Mason, 2014). At present, the most clinically significant 
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While this is clearly important clinically, there are several factors that mitigate the concern: 
1) at present, there are very few effective AUD medications, so the potential benefit of 
alcohol cessation for women of child bearing age may outweigh this limitation; 2) the 
elevated HIV risk of persons with substance use disorders makes condom use a priority in 
this population, thus nonhormonal birth control methods are advocated; and 3) at present, 
Corcept is investigating medications without progestational blockade effects; however, these 
compounds are still under review at the FDA.  Importantly, safety findings from the proposed 
research will be highly applicable to these new compounds and so a proof-of-concept study 
of MIFE is fully warranted at this time.   
 
Alcohol.  One of the aims of the project is to examine MIFE effects on alcohol 
sensitivity, including subjective intoxication and heart rate.  We are using a cumulative 
dosing procedure for alcohol administration that is based on targeted breath alcohol levels 
(BrAL).  The maximum target BrAL is 0.10 mg/dL; this is achieved by administration of 
approximately 4 standard drinks over a 90 minute period.  This alcohol dose is below the 
typical amount self-administered by participants but sufficient to produce subjective euphoric 
and sedating effects. 
Alcohol is available at the conclusion of the AMR session.  A maximum dose of 5 
standard drinks of the participant’s preferred type/brand of alcohol is paced at 0.5 standard 
drinks every 5 minutes to slow intoxication. 
 
Nicotine patch.   Active nicotine patch (21mg) is the standard of care for 
management of nicotine withdrawal.   
 
b. Justification and safety information if FDA approved drugs will be administered 
for non-FDA approved indications or if doses or routes of administration or 
participant populations are changed. 
 
Mifepristone is FDA-approved to terminate intrauterine pregnancies of up to 49 days 
gestation.  It also has been FDA-approved for treatment of refractory Cushing Syndrome 
patients. More recently, it has been under investigation for treatment of various 
neuropsychiatric disorders, including AUD, bipolar, schizophrenia and dementia patients 
(Yararbas and Pogun, 2011; Watson et al., 2012; Howland, 2013; Morgan and Laufgraben, 
2013; Mason, 2014). A small-scale pilot study of MIFE in AUD has been conducted. 
Additional research on MIFE/alcohol interactions are warranted at this time. 
 
c. Justification and safety information if non-FDA approved drugs without an IND 
will be administered.  
 
During the alcohol sensitivity session, subjects will drink 3 doses of alcohol intended to bring 
their terminal BrAL to 0.10 mg/dL. Also, at the conclusion of the AMR session, participants 
can consume up to 5 standard drinks of their preferred alcohol type/brand, based on the 
number of alcohol reinforcers earned during the session.  Beverages containing more than 
7% alcohol are not regulated by the FDA; they are regulated by the Bureau of Alcohol, 
Tobacco, Firearms and Explosives.  These beverages are legally sold to adults. 
 
7. 
Study Statistics 
 
a. Primary outcome variables: 
 
• 
adverse events and side-effects; 

 
 
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• 
fMRI changes in re-FC and CA across brain regions under GR regulatory 
control; 
• 
Reduction in TSST-induced alcohol motivation and drinking; 
• 
cardiovascular responses (HR, BP, ECG) during alcohol sensitivity 
sessions; 
• 
alcohol euphoric and sedating effects during sensitivity sessions using 
VAS and Adjective Scales. 
 
b. Secondary outcome variables will examine the effects of MIFE on a variety of 
psychological measures during alcohol abstinence, alcohol sensitivity sessions 
and outpatient visits. Secondary outcome measures include: 
• 
Craving for alcohol during the inpatient stay, assessed using VAS, PACS, 
OCDS, and AUQ; 
• 
Alcohol withdrawal symptom severity, assessed using the CIWA-Ar; 
• 
Mood and personality assessments during the inpatient stay (BPRS, BDI, 
and BAI); 
• 
Alcohol use during the outpatient follow-up, assessed using timeline 
followback self-report and PEth levels. 
 
c. Statistical plan including sample size justification and interim data analysis. 
 
 
 
Primary and secondary outcome variables will undergo data cleansing and 
Corrective/Preventive Measures based confirmation of accuracy and missing data. We 
will perform exploratory data analyses initially (stem-leaf displays, box plots, histograms, 
and Q-Q plots) and, if necessary, appropriate data transformations will be performed.  
 
Power analyses: All power estimates are based on type I error =0.05, Power > 0.8. Specific 
aims are to compare GR antagonism versus placebo for: 
Aim 1.   Changes in rs-FC and CA across key brain regions under GR gene regulatory 
control.  From the data obtained in preliminary fMRI studies (4.1c), we extracted each subject’s 
connectivity measure (r value converted to Fisher Z score) between left NAcc and 6 mm ROI in 
the right inferior parietal cortex. Mean and SD connectivity measurement of 0.134, .082 were 
obtained from alcohol subjects and -.058, .062 were obtained for controls. We made the 
following assumptions: (a) t1 connectivity will be that of Alc mean (.134) for drug and placebo 
groups; (b) t2 connectivity will not change for placebo group; (c) t2 connectivity for the drug 
group will normalize by at least one-third toward HC values, ie: t2(expt group) = Alc mean – (Alc 
mean – HC mean)/3 = 0.07; (d) SD for each cell is the pooled SD (.076); (e) the correlation 
between repeated measurements (t1 and t2) is 0.5. Using these assumptions a partial eta 
squared of 0.1563 was calculated for the group x time interaction for a repeated measure 
ANOVA. Using this estimate with GPower3 (Faul et al., 2007) software we calculated that 25 
subjects per group will result in 83% power for detecting a significant interaction at p < .05. 
Cue-induced Activation: Myrick et al (2008) showed that AUD compared with HC subjects 
showed increased ventral striatal activation to alcoholic beverage pictures relative to neutral 
beverage pictures, and that treatment with a combination of naltrexone and ondansetron 
significantly decreased CA activation. Their paper provided mean and SD information for 
placebo and drug group ventral striatal activation that was used to estimate effect size for the 
present proposal for the interaction for a repeated measures anova with between group factor of 
drug treatment (placebo vs drug) and within group measure of time (baseline and after 

 
 
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treatment). Because this study was performed on a 1.5T scanner, the contrast to noise ratio 
was multiplied by a factor of 1.3, as described by Hoenig et al.,(2005) to accurately reflect 
scanning at 3T in the present study. These calculations revealed a partial eta squared value of 
0.185, assuming that the drugs in the present study produce at least a comparable effect to the 
naltrexone/ondansetron treatment. Using this estimate with GPower3 (Faul et al., 2007) 
software we calculated that 25 subjects per group will result in 90% power for detecting a 
significant interaction at p < .05. 
Aim 2. Reduction of alcohol withdrawal symptoms and craving, and improvement in low 
mood during early alcohol abstinence. Power for this aim was based on Vendruscolo et al 
(2015) (Fig 2A) in which MIFE effects were examined on VAS craving scores. Our hypotheses 
test if placebo (size = n) is different from MIFE. Comparing placebo effects (mean=11.5 
(SD=2.1) to active drug effects (mean=9.3 (SD=2.2), total sample size required for the proposed 
aim is 39 (i.e.,20 in each group). 
Aim 3. Reduction of stress-induced alcohol motivation and drinking. Power for this aim was 
based on Vendruscolo et al (2015) (Fig 2B) in which MIFE effects were examined on drinking 
during an outpatient treatment phase of the study.  This calculation is based on between-subject 
calculation which overestimates the sample size requirement.  Comparing placebo effects 
(mean (SEM) = 38.0 (10.2)) to active drug effects (mean (SD) = 27.5 (10.2)), total sample size 
required is 32. Using data from our AMR session in which mean number of drinks is 4.33 (sd = 
3.17), we are powered to observe a 50% or greater reduction in drinks earned within the 
session. 
Aim 4. Reduction of alcohol reward and sensitivity.  Based on our preliminary data (4A1, Aim 
3) and a sample of 50 GR antagonist vs 25 placebo subjects, we are powered to detect a 
difference of 3.0 degrees (3.3%) in peak skin temperature.  Further, using data from our current 
alcohol sensitivity procedure (mean peak VAS total=168 (SD=118); mean peak liking=47.9 
(SD=36.9)), we are powered to observe a 45 - 50% or greater reduction in alcohol subjective 
effects. 
Aim 5. Side-effects. Power calculation is based on the assumption that the number of side-
effect reports and adverse events follows a Poisson distribution. In preliminary data (Corcept 
Investigator Brochure), an average of 12 events was reported in MIFE treated subjects. We 
estimate that 22 subjects in each group will give power > 0.8 for this statistical test. 
 
Statistical Analyses:  For aims 1 – 4, AUD and HC subjects will be separately grouped.   
Aim 1: CA will be measured from contrasts of parameter estimates derived from event-
related analysis. FC will be measured using the peak cross-correlation between seed regions 
and other ROIs. In both cases, results obtained for each subject can then be used in a second-
stage analysis for making population inferences and group comparisons (as was done in Fig 6). 
For example, the correlation between the resting-state time series from NAcc and the time 
series from all other brain regions can be used to create a NAcc correlation volume for each 
subject. Using repeated-measure ANCOVA with between-subject factors of drug group 
(Placebo, GR antagonist) and alcohol history (AUD, HC) and within-subject factors of time (scan 
1, scan 2), differences in these correlation volumes before and after drug treatment can be 
compared for the medication and AUD vs. HC groups in order to characterize group-dependent 
differences in altered NAcc connectivity resulting from the medication intervention. Potential 
confounding factors will be examined and added to the model as covariates if necessary. Multi-
linear regression will be used to test the correlation between post-treatment FC and CA with the 
self-reported alcohol craving and withdrawal measures (VAS, OCDS) in AUD subjects. Finally, 
we test the correlation between FC and CA dysregulation and alcohol exposure history collected 
from 90-day Time line follow-back (TLFB). Daily alcohol use data collected from TLFB will be 
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per drinking day for all subjects. Then linear regressions models will be constructed to test the 
correlation between these drinking measures and FC and CA measures from scan 1. 
Aim 2: The main outcomes are CIWA-Ar scores for alcohol withdrawal, VAS and OCDS 
scores for alcohol craving, and Profile of Mood States 2-Short Version subscale scores. The 
normality of the measures will be examined first and two sample t-test, or equivalent non-
parametric methods will be used to compare outcomes between GR antagonist-treated and 
placebo-treated groups. We will also use ANCOVA model to adjust for potential confounding 
factors as covariates. 
Aim 3. AMR variables include: total number of alcohol drinks earned; total number of 
responses during the 60-minute session; distribution of responses for alcohol versus money; 
progressive ratio breakpoint for alcohol (maximum completed ratio value); response rate 
(responses/min) and response latency to compete the ratio for alcohol and money.  We also 
measure alcohol craving using the Tiffany Craving Scale; these data will be summarized using 
peak score and area under the curve. The normality of the outcome measures will be examined 
first and two sample t-test, or equivalent non-parametric methods will be used to compare the 
outcomes between GR antagonist-treated group and placebo-treated group.  
Aim 4: Subjective and physiological data will be collected repeatedly during the alcohol 
sensitivity session. We will test outcome measures between the two groups using mixed-effect 
linear regression with random intercept. Baseline measures will be examined as potential 
confounding factors and added to the model if needed. We will summarize the baseline adjusted 
area under the curve and peak values of the outcome measures and compare between the two 
groups using repeated measure ANCOVA model.  
Aim 5: We use the SAFTEE to collect comprehensive side-effect information. We will 
construct negative binomial generalized linear regression model with the number of events as 
the dependent variable and grouping and other covariates as independent variables. The model 
will give the difference in the logs of expected numbers of side effect events between the two 
treatment groups. We will then also make comparisons taking into consideration the duration 
and severity of the side effects, which are both collected in SAFTEE for each reported side 
effect event. A summary side-effect score will be calculated as the sum of the duration 
multiplying the severity of each side effect event.  
Secondary analyses: Another objective of this study is to generate power estimation for a 
full-size future clinical trial. 
 
d. Early stopping rules. 
 
Individual subjects will be discontinued from the protocol if they experience a moderate-
to-severe adverse reaction to MIFE.  They also will be discontinued for repeated rule 
violations on the CRU.  The study will be discontinued if there is a pattern of MIFE-
related AEs or SAEs. 
 
8. 
Risks 
 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
 
Subjects will be carefully screened and fully informed of study procedures and risks prior 
to participation in any study procedures. This study involves several procedures, each of 
which entails some risk of discomfort or side-effects.  It also employs several drugs, 
each of which entails some risk. These risks are discussed by procedure and 
medication. Participants will receive a thorough description of all potential risks in the 
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Assessment procedures: The major disadvantage is the time taken to complete study 
instruments and questionnaires. Our experience with these evaluations indicates they 
are acceptable to participants. This study involves questions about dangerous or illegal 
behavior, psychiatric history, a medical history, and laboratory tests. There is a small risk 
that participants will become upset during the assessment interview. There also is a risk 
of breach of confidentiality if the responses were to be disclosed.  
 
Blood draws and urine collection: We will collect blood for health assessment and 
medication levels.  Blood chemistries and urinalysis are performed at baseline, at the 
time of admission to the CRU (or day 1 for HC participants completing the study on an 
outpatient basis), and on protocol days 4 – 6. Urinalysis for drug toxicology assessment 
is performed to identify illicit drug use. A blood spot for PEth testing is obtained for 
detection of recent heavy drinking; PEth blood spot is collected at assessment and each 
follow-up visit. Urine pregnancy tests are completed in female subjects at screening and 
on day 1.  A urine pregnancy test is obtained prior to the initial MIFE dose. Blood draw 
procedures involve minimal risks such a slight risk of discomfort at the intravenous site. 
A small amount of bleeding under the skin will produce a bruise in about 5% of cases. 
The risk of temporary clotting of the vein is about 1%. The risk of infection or significant 
blood loss is less than 1 in 1000. In rare cases, fainting could occur.   
 
Alcohol Withdrawal: Applicants with a history of prior inpatient medicated withdrawal, 
alcohol withdrawal-related seizures, or other serious alcohol withdrawal symptoms will 
be excluded from participation. Eligible participants will undergo monitored alcohol 
abstinence and medically supervised alcohol withdrawal on the CRU.   
 
Mifepristone (MIFE) Administration: Since MIFE blocks the progesterone receptor, 
treatment of a pregnant woman would result in the termination of pregnancy.  All females 
must have a negative urine pregnancy test prior to MIFE initiation; women on hormonal 
birth control, who are pregnant, nursing or planning pregnancy, and women with 
unexplained vaginal bleeding are excluded from study participation. In addition, women 
must agree to use a non-hormonal form of birth control for at least 1 month after 
stopping MIFE treatment. We will provide female participants with condoms at each 
outpatient follow-up visit. Women may experience endometrial thickening or unexpected 
vaginal bleeding; there is a low likelihood of these events.   
 
Due to the anti-progestin effects of mifepristone and given the lack of adequate data on 
the potential levels of mifepristone in semen, male subjects will be required to employ 
barrier protection with their female partners. Males should use barrier protection during 
intercourse for at least 5 half-lives of the drug (half life = 18 hours) plus 90-days (the 
duration of one spermatogenic cycle in men and residence time for unejaculated sperm) 
after last dose of mifepristone to avoid risk of anti-progestin effects transmitted to female 
sexual partners. We will provide male participants with condoms for at least 94-days 
after the last dose of mifepristone. 
 
Based on prescribing information for MIFE treatment of Cushing Disease, MIFE may 
produce prolongation of the QT interval of the electrocardiogram (ECG) and use of MIFE 
with QT interval-prolonging drugs is contraindicated. A recent evaluation of the cardiac 
safety of three doses of 1200 mg MIFE given every 12 hrs to subjects found no clinically 
meaningful QT prolongation in healthy subjects (Corcept Therapeutics Investigator 
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Based on data in individuals with Cushing Disease, MIFE may cause adrenal 
insufficiency.  Symptoms of adrenal insufficiency may include abdominal pain, vomiting, 
muscle weakness and fatigue, depression, extremely low blood pressure (hypotension), 
weight loss, changes in mood, and shock (adrenal crisis).  There has been no evidence 
of the development of adrenal insufficiency during short-term administration of MIFE 
doses up to 1200 mg in clinical trials for other psychiatric disorders. 
  
MIFE has been shown to infrequently cause low blood potassium (hypokalemia) in 
patients with Cushing Syndrome. Symptoms of low potassium may include muscle 
weakness, aches, or cramps, abnormal or irregular heartbeats (palpitations).  Although 
hypokalemia has not been observed in other patient populations, we will exclude 
subjects with potassium levels below the normal range at screening or day 1.  
 
MIFE administration also has been associated with the possibility of developing a rash 
and/or a dry mouth.  Both side effects are mild-to-moderate in severity and both have 
been found to discontinue when drug administration is terminated. 
 
 
Use of MIFE with strong CYP3A inhibitors is counter indicated, as concomitant use can 
 
increase mifepristone plasma levels. Subjects using CYP3A inhibitors in last 3 months 
 
are ruled out prior to study enrollment. 
 
Alcohol administration:  Alcohol may produce mood and behavioral effects that are 
dysphoric and that can result in impairment in performance and judgment and, in cases 
of overdose, ethanol can produce medically serious toxic effects.  Prior to the fMRI on 
day 1, subjects receive an alcohol drink in a standardized calorie-free mixer targeting a 
blood alcohol level of 80mg% based on gender and BMI. Following the Alcohol 
Motivated Responding Session, during the alcohol self-administration period, the 
maximum dose of alcohol that subjects can self-administer is five standard drinks over 
50 minutes; this dose will produce a blood alcohol level of approximately 120mg/dL.  In 
the alcohol sensitivity session, the proposed alcohol dose is one that produces a blood 
ethanol level of approximately 100 mg/dL. Study subjects are those who regularly drink 
doses of alcohol greater than the amount used in this study, reducing the likelihood of 
serious adverse events. These are medically safe but behaviorally intoxicating levels, 
associated with impairment of psychomotor and cognitive performance and with 
emotional and behavioral effects that may range from sedation and drowsiness to 
agitation, irritability, depression, and emotional lability.  These effects dissipate as blood 
ethanol levels decline. 
 
Nicotine Patch:  Participants have the option to receive a nicotine patch on session days. 
The nicotine patch dose selected for study in this protocol is FDA-approved and has 
been shown to have a low incidence rate of serious side-effects or adverse events in 
clinical trials with nicotine-dependent patients. Less than 5% of smokers have to stop 
using a nicotine replacement product because of side effects. Side effects of nicotine 
patches may include: skin rash at the location of the patch; sleep problems when using a 
24-hour patch, such as having trouble sleeping or having especially vivid dreams. On 
rare occasions, there have been reports of severe allergic reactions (rash; hives; itching; 
difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); 
fast or irregular heartbeat; mouth, teeth, or jaw problems; pounding in the chest; severe 
diarrhea, dizziness, nausea, vomiting, or weakness.  
 

 
 
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Functional MRI:  Subjects may experience discomfort while lying in the MRI machine for 
the scans. Subjects may experience claustrophobia before entering the MRI machine 
and during the performance of the MRI while lying in the MRI machine. Subjects may 
experience fear and discomfort during the MRI due to the noise of the machine. 
 
Radiation Exposure:  If a subject has had metal removed from the eyes or head in the 
past; or if the subject has worked as a machinist, welder, or metal worker and did not 
routinely wear eye protection, or had an incident in which metal fragments got in the eye, 
we will require an x-ray of the orbits/head to verify that there is no remaining metal in the 
eyes or head before conducting any MRI scanning. This will involve 3 exposures of an 
X-ray procedure that will result in a total exposure of 0.03 rem. We anticipate that this 
procedure will rarely need to be done, but if it is necessary, the total exposure is less 
than the 0.3 rem that the average person in the United States receives each year from 
natural sources. The risk from the radiation exposure in this study is therefore very 
small. 
 
Trier Social Stress Test:  Subjects will participate in the Trier Social Stress Test as part 
of the experimental protocol.  This test combines the stressors of public speaking and 
mental arithmetic and has been shown to elevate a variety of physiological measures, 
including neuroendocrine and autonomic variables.  Participants are monitored carefully 
throughout the procedure.  It is possible but extremely unlikely that a subject will 
evidence clinically significant symptoms of anxiety or grossly elevated autonomic 
reactivity.   
 
Rating Scales and Questionnaires: The major disadvantage is the time taken to 
complete study instruments and questionnaires and a possible breach of confidentiality. 
Our past experience with these evaluations indicates they are acceptable to patients. 
 
b. Steps taken to minimize the risks. 
 
Subjects with any eligibility contraindications are excluded from participation. Subjects 
are permitted to discontinue their participation at any time. Subjects are carefully and 
continually monitored throughout their participation. In case of a medical adverse event, 
the study physicians Dr. Wand or Dr. Andrews are available by cell phone for 
assistance. In the event of psychological distress, Dr. McCaul, a licensed psychologist, 
or Dr. Andrews, a licensed psychiatrist, is available to meet with the participant. 
 
Insuring protocol comprehension: We exclude potential subjects below the 5th grade 
reading level because of concerns about their ability to adequately comprehend the 
informed consent document and participate in study procedures. Many of our 
behavioral/subjective measures are paper and pencil, self-report instruments and require 
basic literacy and language skills (e.g., English is not primary language). If subjects are 
not at a 5th grade reading level, they have difficulty responding accurately to the study 
questionnaires.  
 
Psychosocial assessments: The risk of distress or personal discomfort elicited during 
assessment is minimized by the use of standardized assessment procedures widely and 
successfully used in many research settings. Also, all study staff are trained in 
nonjudgmental interview techniques. Employees are carefully trained to monitor subjects 
for any adverse effect and to contact an Investigator immediately if such an event 

 
 
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occurs. If serious psychological concerns (e.g., suicide risk) arise, staff has been trained 
to immediately refer these to Dr. McCaul, a licensed psychologist, or a study physician. 
 
Medically supervised and alcohol withdrawal and monitored abstinence: Subjects will be 
closely monitored by nursing and physician staff for alcohol withdrawal signs and 
symptoms.  All AUD subjects will receive iv administration of 1 liter of normal saline with 
vitamins over the first 12 hours following admission. On days 1 – 4, the Clinical Institute 
Withdrawal Assessment - Alcohol Revised (CIWA-Ar), which includes 10-items 
(nausea/vomiting, tremor, paroxysmal sweats, anxiety, agitation, tactile disturbances, 
auditory disturbances and visual disturbances), will be completed by CRU nurses every 
4 hours while the participant is awake. This well-validated clinical tool will assess alcohol 
withdrawal symptom severity and is the gold standard to guide benzodiazepine (BZ) 
administration during symptom-driven withdrawal management (Saitz et al., 1994). If the 
CIWA score is ≥12 the subject is given diazepam (5mg). The CIWA score is repeated 1 
hour after each dose. If the score remains ≥10 then another diazepam dose (5mg) is 
given up to a maximum of three doses. Based on our previous study, we anticipate that 
few subjects will require BZ treatment since we exclude subjects who report a history of 
withdrawal complications.  If systolic blood pressure increases above 180 and or 
diastolic blood pressure increases above 105, we may administer atenolol. The most 
common symptoms of atenolol include dizziness, lightheadedness, tiredness, 
drowsiness, depression, nausea and diarrhea.  Less common but more serious side-
effects include: shortness of breath, and swelling of the hands, feet, ankles or lower legs. 
Subjects who experience seizure activity or delirium tremens will be discontinued from 
the study; also subjects will be discontinued on recommendation by the study physician.  
To date we have successfully withdrawn over 98% of our alcohol-dependent subjects 
without medications requiring protocol termination. Exclusion of subjects with a history of 
alcohol withdrawal complications, and/or high CIWA scores at assessment is a 
successful strategy to help ensure subject safety.  In the event of a severe reaction or 
medical emergency, the participant will be transported to near-by emergency services. 
 
Mifepristone administration: The use of MIFE in this study will be under FDA IND 
124365; Dr. Wand, Co-Principal Investigator, holds the IND.  We are taking multiple 
precautions to ensure that MIFE is not administered to women who are pregnant or 
planning pregnancy.  Alcohol is highly toxic and pose significant risk to fetal 
development.  We believe it is imperative to study therapeutic agents in women of 
childbearing age to further the development of potential treatments for this population.   
• 
Only persons with no medical exclusions will be enrolled for study participation.  
• 
Subjects are under continuous observation while on the Clinical Research Unit.  
Subjects not on the CRU are checked on daily while receiving MIFE. 
• 
Medication side effects and adverse effects are formally monitored daily on the CRU 
for inpatient subjects, on the phone for outpatient subjects, and during outpatient 
visits via the SAFTEE. In case of an emerging or adverse event, the study physician 
is available by cell phone for assistance.  
• 
Women who use hormonal birth control, are pregnant, planning to become pregnant 
or are nursing are excluded from study participation. All females must have a 
negative urine pregnancy test prior to MIFE initiation. Females must use a non-
hormonal medically acceptable method of contraception (e.g., condoms, IUD, 
diaphragm) for a one month period following discharge, unless the subject has had a 
surgical sterilization. We will provide female participants with condoms for the month 
following study participation.  Women who provide a report of surgical sterilization or 

 
 
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who provide a lab report with FSH level greater than 25 confirming post-menopausal 
status may be exempt from pregnancy testing.   
• 
Due to the anti-progestin effects of mifepristone and given the lack of adequate data 
on the potential levels of mifepristone in semen, male subjects will be required to 
employ barrier protection with their female partners.  Males will be instructed to use 
barrier protection during intercourse for at least 5 half-lives of the drug plus 90-days 
(the spermatogenic cycle in men and residence time for unejaculated sperm) after 
last dose of mifepristone to avoid risk of anti-progestin effects transmitted to female 
sexual partners. 
• 
Women who develop unexplained vaginal bleeding during the study will be excluded 
for further study procedures.  Female study subjects will be educated to report and 
be evaluated for unexplained vaginal bleeding. 
• 
Subjects with potassium levels below the normal range at screening will be excluded. 
We will also monitor potassium on days 1 and 7 (AUD participants only), and at the 1 
week follow-up. Potassium will be administered if clinically needed. 
• 
Based on data from studies and clinical trials, which encompass over 1500 subjects 
and patients treated for one to two weeks with MIFE doses ranging from 300 mg/day 
to 1800 mg/day, the risk for development of adrenal insufficiency in persons without 
Cushing Syndrome is low. Specifically, in studies of psychotic depression and in 
volunteers with antipsychotic drug induced weight gain as well as healthy volunteers 
and subjects with hepatic and renal impairment who participated in PK, PD, and DDI 
studies, there were no AEs of adrenal insufficiency reported (Personal 
Communication, Corcept Therapeutics). Still, in the current study, subjects will be 
monitored for the development of the signs and symptoms of adrenal insufficiency 
(weakness, nausea, increased fatigue, hypotension) during the CRU stay and during 
outpatient visits. Once on the CRU and following MIFE administration, we monitor for 
hypoadrenalism by measuring blood pressure and heart rate along with all vital signs 
q6 hours.  For inpatient participants, we also will be asking questions q6 hours 
regarding emergence of symptoms of hypoadrenalism, including the development of 
fatigue, nausea, vomiting, abdominal pain, loss of appetite, light headedness, 
arthralgias, and myalgias.  Outpatient participants will be asked these questions 
once daily either in person or by phone.  If an AUD subject on the CRU is thought to 
be developing hypoadrenalism, we will discontinue the MIFE, support blood pressure 
with intravenous fluids and infuse 8mg of dexamethasone intravenously.  Outpatient 
healthy control participants will be provided with oral dexamethasone 8 mg to take 
home.  They will be given an instruction sheet (see supplemental study documents) 
that advises them of the symptoms of adrenal insufficiency and advises them to call 
Dr. Wand if these symptoms start to develop. This dose is more than adequate to 
reverse the glucocorticoid receptor blockade. The proposed single dose of 
dexamethasone is routinely used in the determining the etiology of Cushing 
Syndrome.  In patients with impaired glucose tolerance or frank diabetes mellitus, 
this dose of dexamethasone can transiently increase blood sugar; however, in our 
study, participants with impaired glucose tolerance are excluded.  Dexamethasone 
will only be used in the unlikely event of adrenal crisis in which we do not anticipate 
any negative side-effects from the treatment. 
• 
Dr. Wand, a board certified neuroendocrinologist, has extensive clinical experience 
in treating patients with adrenal insufficiency and will manage care if needed. 
• 
Subjects will be educated about the signs/symptoms of adrenal insufficiency 
including unusual tiredness or weakness, nausea and/or vomiting, dizziness when 
standing, aches and pains, loss of appetite, and being depressed.  Subjects will be 

 
 
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instructed to report these symptoms and to follow up with the physician if they 
experience any of them. 
 
 
Nicotine Patch:  Some subjects may develop a skin rash at the location of the nicotine 
patch. This may be a reaction either to the sticky backing on the patch or to the nicotine. 
Moving the patch to a different part of your body or using a nonprescription antihistamine 
cream, ointment, or gel (such as Benadryl) may relieve some of the discomfort. People 
who experience significant allergic reaction to the patch will be discontinued and will be 
provided with medical care to reverse symptoms.  
 
 
Alcohol Administration Sessions:  Our laboratory has substantial experience 
administering alcohol to human subjects under a variety of experimental and dosing 
conditions.  In conducting alcohol administration procedures in heavy or dependent 
drinkers, we are taking several important steps to ensure the safety and well-being of 
subjects participating in this protocol.  First, we will follow the guidelines of the National 
Institute on Alcohol Abuse and Alcoholism for alcohol administration to persons with an 
alcohol use disorder. Second, we recruit only persons who are not seeking treatment 
and who are volunteering for remuneration.  Third, we house subjects on the CRU under 
nursing observation to reduce potential harm during alcohol withdrawal and alcohol 
intoxication.  Fourth, the dose of alcohol that will be available during the alcohol 
sensitivity session is well below doses routinely self-administered by the participants and 
drinking will be paced to prevent rapid ingestion of the available alcohol.  
 
All alcohol doses are administered under doctor's orders and utilize pharmacy-grade 
ethanol or commercially available alcohol.  Participants are monitored carefully 
throughout the laboratory session; should a subject evidence a medical or behavioral 
adverse effect, a medical staff member will be called immediately and the subject will 
receive appropriate evaluation and treatment. Thus, the careful choice of doses, the 
medical observation and monitoring, and the use of human volunteers who regularly 
drink doses of ethanol comparable to and higher than the ones selected for this study 
reduce the likelihood of serious adverse ethanol-induced effects.   
 
Blood draws: Experienced medical personnel using sterile equipment will perform the 
blood draws, minimizing risks associated with venipuncture. The total volume of blood 
drawn in the protocol is very low and is not expected to lead to discomfort or health 
concerns.  
 
Trier Social Stress Test:  Following completion of the AMR and drinking session, 
subjects are debriefed about the TSST stress procedures. 
 
fMRI risks: Participants will be escorted to KKI scan room by one of our staff members 
while maintaining physical distancing.  Throughout the time at the KKI facility, we will 
follow all COVID-related safety policies of the center, including physical distancing, use 
of PPE and sanitizing. After the KKI technician positions the volunteer in the scanner, 
our staff person will position the hand-held response device and show the participant 
how to make responses during the alcohol-cued fMRI. Staff members will leave scan 
room remaining outside the room monitoring subject’s responses and safety. This space 
is large enough to accommodate one KKI staff member and one of our staff members.  
Subjects will be monitored by video camera throughout the scanning procedure and 

 
 
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questioned as to their state via intercom between each scan. The staff member will 
monitor the participant for adverse events or distress. Subjects will be provided with a 
squeezeball signaling device in the MRI in case adverse conditions develop during a 
scan. Experimenters will immediately stop the scan and attend to the subject if the 
squeezeball signal is activated by the subject. Should a participant feel discomfort we 
will reposition her/him and cushion the subject with padding.  If subjects are markedly 
 
bothered by claustrophobia, then they will be reassured that the procedure is not 
harmful. If subjects experience claustrophobia unresponsive to reassurance, then study 
procedures will be discontinued. To deaden the noise of the MRI, subjects are asked to 
insert ear plugs before entering the MRI. The Kirby Center for Functional Brain Imaging 
at the Kennedy Krieger Institute has a crash cart nearby, and in case of medical 
emergencies the code team at Kennedy Krieger will be called and we will arrange 
emergency transportation to the JHH ED.  
 
Confidentiality: Our staff is well trained in the matters of confidentiality. Subject numbers 
will be used to code all data forms for computer entry and storage. Study findings are 
reported using group data only. No information about subjects will be provided to anyone 
outside of the study including family members, third persons or organizations.  
 
All members of our research group have completed the Health Insurance Portability and 
Accountability Act (HIPAA) compliance training courses relating to human subjects 
research. All data including information obtained during screening that may be linked to 
an individual’s personal identification (names, addresses, outpatient medical record 
numbers) will be in a hard copy format and stored in a locked cabinet in a locked room 
located in a restricted access office. All laboratory data stored electronically will utilize 
the study code and will be in password-locked files on a LAN server operated by Johns 
Hopkins University School of Medicine with the latest security measures employed. 
Access to the subjects’ study identification codes or other information will be restricted to 
the Principal Investigators, the research coordinator and, upon written request, to the 
Institutional Review Board or other regulatory agencies. Subjects will be advised that the 
results may be published in manuscript(s) but their identities will remain anonymous. 
 
All remote contacts will use a HIPAA compliant telemedicine app or website (participant 
preference) and will not require the participant to enter any potentially identifying 
information.  This service uses end-to-end encryption and no identifying information is 
recorded by the service itself.   
 
COVID infection risk: Study activities will be conducted remotely as opposed to in person 
when possible to reduce unnecessary in-person encounters. For all in-person visits, we 
will follow HEIC clinical standards for maintaining staff and participant safety.  Staffwill 
use appropriate PPE (face mask/shield, gowns, gloves) and practice physical distancing.   
Participants will wear face masks. Any equipment that participants are asked to handle 
to complete study procedures (e.g., MRI compatible response buttons) will be cleaned 
prior to use.  Office spaces will be cleaned by sanitizing surfaces between office visits.  
We will limit the number of people within spaces (e.g. KKI MRI suite).  For procedures 
that require contact (e.g. phlebotomy, obtaining vital signs), we will limit the amount of 
time the contact lasts and ensure both staff and patients use appropriate PPE.   
 
A staff member must accompany the participant on the car ride from the JHH campus to 
the Bayview CRU.  Staff and participants will use face masks and physically distance to 
the extent possible during the ride. 

 
 
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Blood alcohol levels measured by breathalyzer are obtained serially during the alcohol 
sensitivity session. The staff member running these sessions will be wearing full PPE 
attire. The staff member will leave the research room each time the participants exhales 
into the breathalyzer.  Participant then removes the disposable mouth piece and places 
it in a basket containing a red bag designed to hold toxic materials. A fresh mouth piece 
is attached by staff after re-entering procedure room. 
 
When utilizing both the CRU and the imaging suites, we will follow policies to limit 
COVID infection exposure risk established by those locations. 
 
 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
Dr. McCaul has responsibility for communication with the JHU SOM IRB and will be 
responsible for reporting of AEs and SAEs. SAEs that are deemed to be severe and 
have a high probable or definite relationship to study procedures will be promptly 
reported to the Johns Hopkins Medical Institute IRB, Corcept Therapeutics, and the 
FDA.  
 
Dr. McCaul also is responsible for notifying Corcept of (a) any serious and/or 
unexpected adverse drug experiences (as those terms are defined in 21 C.F.R. § 
312.32(a), as amended), and (b) all adverse events of special interest (AESI) that occur 
during the course of the Study no later than twenty-four (24) hours after receipt of such 
information. AESI shall mean any of the following events, irrespective of the level of 
severity:   
1. Major adverse cardiovascular events including death related to coronary or 
cerebrovascular disease, acute myocardial infarction, stroke, and revascularization 
(coronary or cerebral) 
2. Retinopathy 
3. Endometrial hyperplasia and/or abnormal vaginal bleeding of any cause 
 
The PI shall notify Corcept of all serious adverse events each time that a report is made 
to the IRB. 
 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
Our staff is well trained in the matters of confidentiality including maintenance of 
genotyping information. At present there is no known health implication for the 
polymorphism under study. Subject numbers will be used to code all data forms for 
computer entry and storage. Study findings are reported using group data only. No 
information about subjects will be provided to family members, third persons or 
organizations.  Our study personnel are trained in the protection of human subject 
confidentiality and are HIPAA trained and certified. 
 
e. Financial risks to the participants. 
 
All costs will be covered by NIAAA grant funds. 
 
9. 
Benefits 

 
 
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a. 
Description of the probable benefits for the participant and for society. 
 
This study is conducted for the advancement of science.  It will provide critical safety 
information and examine pharmacokinetic interactions between MIFE and alcohol. It will 
also determine whether MIFE can be safely used for outpatient treatment of patients 
who may continue to use alcohol. Finally, it will provide preliminary findings of MIFE 
effects on alcohol craving, anxiety and intoxication. 
This Phase 1 study will provide critical safety information and examine drug-drug 
interactions between MIFE and alcohol.  Outpatient clinical trials that will meet 
requirements for FDA new drug approval cannot be pursued without this safety 
information. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, 
proposed bonus, and any proposed reductions or penalties for not completing the 
protocol. 
 
Participants will be paid $75 for the initial in-person assessment procedures.  If all 
eligibility assessment procedures are not completed during the first assessment visit, we 
pay participants an additional $25 to come in a second time to complete procedures.   
 
Subjects who are eligible to continue in the study will be paid for completed procedures 
and their time and effort in the study.  AUD Subjects receive $15/day as basic CRU 
earnings and an additional $10 per day for compliance with CRU and study procedures.   
 
Payments for AUD study completers 
Assessment $75 
CRU stay – 7 days X $25/day ($15/ day + $10/day for following protocol rules) = $175 
   
Alcohol self-administration and sensitivity sessions = $75/session X 2 = $150 
fMRI = $100/scan X 2 = $200 
Follow-up visits X 2 = $100 
Bonus - $200 
Subject payment expense: $900 
 
Payments for outpatient HC study completers 
Assessment $75 
Medication/questionnaire compliance = 4 days X $10/day = $40  
Blood draw on day 4 = $10 
fMRI = $100/scan X 2 = $200 
Follow-up visit = $50 
Bonus - $100 
Subject payment expense: $475 
 
 
Subjects are paid for the eligibility visit in cash after completing the assessment.  If the 
subject is eligible for a bonus payment, it will be dispensed in cash on the day of 
discharge.  Subjects will receive a check for the remaining amount of money that was 
earned during the rest of the study.   
 

 
 
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If the Investigator ends the subject’s participation because s/he broke study or unit rules 
or the subject drops out of the study, s/he will be paid only the amount earned to date for 
completed procedures and the CRU stay.  If the participant leaves during the CRU stay, 
s/he will not be paid any money until the scheduled discharge day, and will forfeit future 
possible earnings and bonus payments. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
 
Costs for all procedures and drugs will be covered by the study. 
 
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