Conditions: Alcohol Dependence Alcohol Use Disorders Alcohol Abuse Alcoholism
Keywords: Alcohol-Related Disorders Substance-Related Disorders Mental Disorders Mifepristone Glucocorticoid Antagonists Alcohol Treatment Alcohol
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
This is an 8-week, randomized, double-blind, placebo-controlled, 2 arm, parallel groups, study of 1-week of treatment with mifepristone (0, 1200 mg/d) given in conjunction with 8 weeks of manual-guided counseling, and a follow-up visit at Week 12.

Detailed description:

Arms:
arm 1: 1200 mg mifepristone daily for 1-week given in conjunction with 8 weeks of standardized behavioral therapy arm 2: Placebo pills daily for 1-week given in conjunction with 8 weeks of standardized behavioral therapy

Interventions: intervention 1: Mifepristone 1200 mg daily intervention 2: Standardized behavioral therapy intervention 3: Placebo
Intervention descriptions: intervention 1: Mifepristone, 300 mg tablets, Four tablets daily/am for 1-week duration. intervention 2: Standardized behavioral therapy 1 time per week for 8 week duration. intervention 3: Placebo tablets, Four tablets daily/am for 1-week duration.

Protocol document:
ICF_002.pdf: 



















Prot_SAP_ICF_000.pdf: 
IND # 114497 
Date submitted: July 2, 2014 
Title: Glucocorticoid Antagonist Treatment of Alcohol Use Disorder 
Responsible Investigator: Barbara J Mason, Ph.D. 
 
 
 
INTRODUCTORY STATEMENT  
 
 
Available medications for alcohol use disorders are of limited efficacy and grossly underutilized. 
Risk for relapse is highest in the first 90 days1 and the development of safe and effective 
medications to increase rates of initial recovery in Alcohol Use Disorder (AUD) that can be 
implemented by a wide range of treatment providers is a high public health priority. With chronic 
heavy alcohol use and in alcohol dependence the neuroendocrine stress system becomes 
dysregulated, i.e., the CORT response of the HPA axis becomes blunted and CRF systems in 
the amygdala become sensitized, conditions associated with greater craving and risk for relapse 
in protracted abstinence.  
 
Mifepristone is a GR antagonist that, with 1-week of treatment, restores normal HPA feedback 
for prolonged periods across a range of disorders and ameliorates cognitive deficits associated 
with HPA axis dysregulation. Mifepristone produced dramatic effects in blocking compulsive 
alcohol seeking in animal models of alcohol dependence and protracted abstinence. Similarly, 
1-week of treatment with mifepristone reduced cue- and stress-induced craving in a human 
laboratory POC study of risk factors for relapse in protracted abstinence, with significant effects 
on decreased drinking and craving persisting for 1-month post treatment in 50 non treatment 
seeking subjects with alcohol dependence relative to placebo. Improvement on tests of learning, 
memory and executive function were also found with mifepristone relative to placebo in our AUD 
sample. Mifepristone is FDA-approved for two indications and was well tolerated in our POC 
study in AUD and in studies involving 1-week of treatment aimed at "re-setting" the HPA/CRF 
axis at doses up to 1200 mg/d without titration. We propose to study a treatment seeking 
sample, with 1-week of mifepristone to increase rates of initial response by re-setting the HPA 
axis, followed by 8 weeks of counseling to consolidate and sustain medication effects. Based on 
the association between drinking outcome and mifepristone plasma concentration found in our 
POC study, we propose to conduct a 3-arm dose-ranging study with randomization to double-
blind treatment with 600 or 1200 mg/d of mifepristone or matched placebo to identify optimal 
dosing for AUD.  
 
Furthermore, a collaboration with Dr. David Goldman, Director, Neurogenetics Lab, NIAAA, will 
permit an exploratory evaluation of genetic predictors of response; the high affinity of 
mifepristone for the glucocorticoid receptor makes mifepristone a good candidate for 
pharmacogenetic analysis that may guide future studies and clinical applications. 
 
GENERAL INVESTIGATIONAL PLAN 
 
SUBJECTS 
Sample Size 
Power and sample size estimates are based on the change in the number of drinks per week 
found in our POC study that involved 1-week of mifepristone 600 mg/d vs placebo in 50 subjects 
with AUD and in our 12-week clinical trial of gabapentin 900mg, 1800mg and placebo in 150 
subjects with AUD.2 Repeated measures ANCOVA performed on the change in number of 


drinks per week from baseline through Week 5 in the POC study found significant (F=3.82, df=2, 
p=0.03) slope effects between mifepristone (-9.19, SEM 7.5) and placebo (+3.62, SEM 7.5), 
yielding a Cohen’s d=0.485 (medium effect size). Continuous outcomes will be assessed for 
trend dose effects. Based on estimates of change of 0, -2.2 and -6.7 (SE 1.6) drinks per week 
for placebo, 900mg and 1800mg, respectively, in our gabapentin study, the test for linear trend 
contrast resulted in highly significant (p<0.001) linear trends with post hoc power at least 99% at 
the target alpha. Power calculation of cumulative mean drinks per week vs. dose with a planned 
linear contrast indicates that with 50 subjects per arm (placebo, low dose, high dose), and 
means which decrease by at least 32% as dose increases, we achieve 91% power to detect a 
non-zero contrast of the means versus the alternative that contrast is zero using an F test. 
These calculations assume an alpha=0.05, a common SD+/-12, and hypothesized means of 
approximately 16, 11 and 8 drinks per week based on the gabapentin data. Estimating early 
termination by approximately 40% subjects based on clinical trials of similar design,2,3 the same 
power analysis for a conservative total of 30 subjects per arm indicates 82% power to test the 
interactive term (week*treatment) at the alpha of 0.05.  
 
Subject Characteristics 
A total of 150 subjects will be randomly assigned to 1 week of double-blind treatment with 
mifepristone 600 mg/d (n=50), 1200 mg/d (n=50) or placebo (n=50); all subjects will receive 8 
weeks of counseling, 4 scheduled phone calls and a Week 12 follow up visit. Subjects will be 
medically healthy male or female volunteers, 18-65 years of age. Subjects must meet DSM-V 
criteria for current alcohol use disorder of moderate or greater severity, defined in DSM-V as ≥ 4 
symptoms, because this is the level of severity likely to merit pharmacotherapy and to involve 
neuroadaptations in the stress systems that mifepristone is hypothesized to treat. Subjects must 
be abstinent ≥ 3 days (but ≤ 30 days) prior to randomization, as verified by the TLFB and BAC 
and have a CIWA ≤ 9, to eliminate acute alcohol or withdrawal effects on study measures. 
Abstinence at randomization will be verified retrospectively by ethyl glucuronide/ethyl sulfate 
(EtG/Ets) testing, which can reliably detect alcohol metabolites in the urine 80 hours after 
alcohol consumption. EtG/EtS testing showed only 1 of 50 participants in our mifepristone lab 
study violated the 3-day abstinence requirement at baseline. Additionally, breathalyzer and 
Timeline Followback data are collected at every study visit; GGT data are collected monthly. 
 
Inclusion Criteria:  
• 
Male or female volunteers, 18-65 years of age  
• 
Meets DSM-V criteria for current alcohol use disorder of moderate or greater severity, 
defined by DSM-V as ≥ 4 symptoms 
• 
In the month prior to screening, reports drinking > 21 standard drinks per week if male, > 
14 if female, with at least one heavy drinking day (males: ≥ 5 drinks, females: ≥ 4 drinks) 
per week  
• 
Seeking research-based outpatient treatment for AUD and willing to comply with the 
protocol, take daily oral medication for 1-week and complete 11 study visits 
• 
Abstinent a minimum of 3 days (but not more than 30 days) prior to randomization 
• 
Negative BAC and a CIWA  score of ≤ 9 at randomization  
• 
In acceptable health in the judgment of the study physician, on the basis of interview, 
medical history, physical exam, ECG, urine test and lab tests 
• 
Females with childbearing potential must have a negative serum pregnancy test on the 
screening visit and a negative urine pregnancy test at randomization and agree to use 
non-hormonal effective birth control for the study duration and one month thereafter 
• 
Subjects must be able to complete and understand questionnaires and study procedures 
in English and sign an informed consent 


• 
Willingness to comply with the provisions of the protocol and take daily oral medication 
  
 
Exclusion Criteria  
• 
A medical condition that contraindicates the administration of mifepristone, such as:  
o history of adrenal failure, Addison's disease, or adrenal insufficiency 
o concurrent systemic corticosteroid therapy 
o hemorrhagic disorders 
o concurrent anticoagulant therapy 
o cardiovascular, hypertensive, hepatic, respiratory or renal disease 
o insulin dependent diabetes mellitus 
o severe anemia (< 12 hemoglobin) 
o inherited porphyria 
o females with history of unexplained vaginal bleeding, endometrial hyperplasia 
with atypia or endometrial carcinoma 
• 
Significant medical disorders or clinically significant findings on ECG (e.g., prolongation 
of the QTc interval), urine or blood tests that increase potential risk or interfere with study 
participation as determined by the Study Physician. Note: serum potassium below the 
normal range must be replaced to normal prior to randomization; individuals with serum 
potassium outside the range of normal will not be randomized 
• 
Liver function tests more than 3 times the upper limit of normal or elevated bilirubin  
• 
Female subjects with childbearing potential who are pregnant, nursing, or refuse to use 
effective non hormonal birth control for the 1-week of medication administration and one 
month thereafter   
• 
Active suicidal ideation   
• 
Meets DSM-V criteria for a major Axis I disorder including mood or anxiety disorders or 
substance use disorders other than alcohol or nicotine use disorders  
• 
Positive urine drug screen at screening  
• 
Treatment within the month prior to screening with an investigational drug or vaccine, or 
drugs that may influence study outcomes, e.g., disulfiram, naltrexone, acamprosate 
• 
Chronic use or need for psychotropic drugs. Note: some drugs with psychotropic 
properties (e.g., anti-hypertensive drugs) are allowed if their use is judged by both the 
investigator and study physician not to pose a safety risk or impact the results of the 
study  
• 
Current use of drugs that are CYP3A substrates and inhibitors (such as calcium channel 
blockers, azole antifungals, macrolide antibiotics, crythromycin, protease inhibitors) due 
to risk of interactions with mifepristone; CYP3A inducers (such as rifampin, rifabutin, 
rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort), which may 
decrease mifepristone exposure and possibly compromise efficacy or consuming 
grapefruit juice or chronic use of drugs that are CYP2C8/2C9 substrates (such as 
NSAIDs, warfarin, and repaglinide), or as determined by the Study Physician 
• 
No fixed domicile and/or no availability by home or mobile telephone   
• 
Treatment mandated by a legal authority 
 
 
Subject Recruitment and Retention 
This is the first test of the clinical efficacy of mifepristone for AUD, and as such, requires 
recruiting individuals with AUD who are both treatment-seekers and free from clinically 
significant medical and psychiatric disorders or use of concomitant medications that could 
influence study outcomes. Our experience conducting two N=150, 12-week clinical trials in AUD 


with similar admission criteria at Scripps reliably shows we must recruit about 5 subjects for 
each subject who is successfully randomized, resulting in a rate of randomization of 
approximately 33 subjects per year. This rate of randomization is consistent with the average 
rate of 30-36 subjects randomized annually by single sites in recent AUD trials with similarly 
restrictive admission criteria. 
 
Per procedures established by NIAAA’s Clinical Investigations Group,4 progressive incentive 
payments will be provided for attendance and completion of study assessments to enhance 
compliance with study procedures and retention. Subjects will earn a base rate starting at $25 
that will increase by $5 for each subsequent consecutive visit. The 4 weekly phone calls will be 
compensated at a flat rate of $10 each. Perfect attendance and participation in 4 phone calls will 
result in a subject earning $590 over the 12 weeks of study and follow up. 
 
 
PROCEDURES 
This is a Phase II, single-site, randomized, double-blind, placebo-controlled, 3-arm, parallel 
groups, dose-ranging study of 1-week of treatment with mifepristone (0, 600, 1200 mg/d) given 
in conjunction with 8 weeks of manual-guided counseling, and a follow up visit at Week 12. 
Subjects will be 150 outpatient men and women seeking treatment for current AUD of moderate 
severity or greater, who are abstinent ≥ 3 and ≤ 30 days and not in acute withdrawal (CIWA ≤ 9) 
at time of randomization. 
 
Initial Phone Screening: Clinically trained study personnel provide information about the study. 
Interested individuals who appear eligible are scheduled for a face-to-face intake evaluation. 
 
Week -1, Screening: After providing written informed consent, subjects complete a Screening 
Visit for evaluation of eligibility (see Table 2). The Structured Clinical Interview for DSM-V 
(SCID-V) will be administered to determine the inclusion criteria of current AUD with ≥ 4 
symptoms and to rule our AXIS I disorders that would warrant study exclusion. The subject’s 
demographic information, medical and alcohol use history, and use of concomitant treatments 
will be recorded using standardized forms. Vital signs and breath alcohol concentration (BAC) 
will be assessed, and specimens for urinalysis, serum pregnancy test (if female), urine drug 
screen, blood chemistry that includes liver function tests (LFT’s) and gamma glutamyl 
transferase (GGT), and complete blood count with differential (CBC w/diff) will be collected by 
the medical assistant and prepared for same day pick up by LabCorp for analyses. An 
electrocardiogram (ECG) will be performed. Subjects at risk of clinically significant symptoms of 
alcohol withdrawal (CIWA≥9) are ineligible and will be referred for detoxification treatment. 
However, our community dwelling subjects typically do not require medical detoxification, and 
are advised to reduce their alcohol intake incrementally such that 3 consecutive days of 
abstinence are achieved prior to their baseline (Week 0) visit. The CIWA is then repeated at 
Week 0 to further rule out risk of significant withdrawal symptoms during double-blind treatment. 
 
Week 0, Randomization: Subjects complete evaluation for eligibility. Study physicians review 
all laboratory results, EKG’s, vital signs, medical and alcohol histories, use of illicit substances 
and concomitant treatments, and perform a physical exam to medically clear an individual for 
admission to study. Medically cleared subjects complete baseline assessments and are 
randomized to receive a 1-week supply of double-blind drug. 
 
Weeks 1-8: Subjects complete weekly study assessments and counseling described below and 
in Table 2. Subjects will be seen by the same study personnel and have their visits scheduled at 


the same time of day (typically midday) across the study to avoid effects of uncontrolled sources 
of variance on study measures. 
 
Weeks 9-11: Weekly phone calls are scheduled to maintain contact with the participant and 
obtain TLFB data. 
 
Week 12: Subjects complete a follow up visit to assess persistence of treatment effects on 
outcome and safety assessments. Procedures to maximize the likelihood of participation in the 
follow-up visit include: scheduled weekly phone calls to maintain contact with subjects, paying 
for the follow up visit, obtaining multiple back-up addresses and phone numbers, to assist in 
locating subjects. Patients who are found to have relapsed, or who display other clinically 
significant symptoms, will be offered referral for appropriate treatment. 
 
 Table 2. Schedule of Procedures for Study Visits 
Scheduled Procedures Week 
-1 
0 1 2 3 4 5 6 7 8 12 
Informed consent, demographics, medical and alcohol history, SCID-V 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Dependence Scale; Fagerstrom Test for Nicotine Dependence;  Illicit 
Drug Use Index; Childhood Trauma Questionnaire; Treatment Goals Checklist 
X 
 
 
 
 
 
 
 
 
 
 
BAC, Vital signs Adverse events, Concomitant Medications  
X 
X X X X X X X X X X 
Pregnancy test1  
X 
X  
X X  
 
 
 
 
 
Clinical Institute Withdrawal Assessment-Revised (CIWA) 
X 
X  
 
 
 
 
 
 
 
 
CBC w/diff, blood chemistry2, UA, UDS 
X 
 
X  
 
X  
 
 
X X 
ECG 
 
X  
 
 
 
 
 
 
 
 
Plasma cortisol, ACTH 
 
X X X  
X  
 
 
X X 
Mifepristone plasma concentration 
 
 
X  
 
 
 
 
 
 
 
Alcohol Craving Questionnaire (ACQ); Timeline Follow Back Interview (TLFB); 
Pittsburg Sleep Quality Index (PSQI); Beck Depression Inventory-II (BDI-II), 
State-Trait Anxiety Inventory (STAI) 
X 
X X X X X X X X X X 
Neurocognitive Assessment, EtG/EtS 
 
X  
 
 
 
 
 
 
X 
 
Physical exam, saliva and WBC for pharmacogenetics, dispense study drug 
 
X  
 
 
 
 
 
 
 
 
Manual-guided counseling 
X 
X X X X X X X X X 
 
1  Females of child-bearing potential only, with serum pregnancy at Week -1 and urine at Week 0, 2 and 3. 
2  Chemistry panel to include: Glucose, GGT, ALT, AST, alkaline phosphates, bilirubin, uric acid, serum creatinine, 
BUN, electrolytes, calcium, inorganic phosphorus, total protein and albumin. Only GGT and UDS will be obtained at 
Weeks 4, 8 and 12. 
 
OUTCOME MEASURES AND ASSESSMENTS 
 
Study Measures to Characterize the Sample:  
Alcohol Dependence Scale (ADS)5 provides a reliable and valid quantitative measure of severity 
of alcohol dependence (Week -1, self-report, 5 minutes). Ethyl glucuronide/Ethyl sulfate 
(EtG/EtS): EtG/EtS’s presence in urine can reliably detect alcohol metabolites in the urine 80 
hours after alcohol consumption and will be used to retrospectively validate abstinence at 
randomization (Week 0). Childhood Trauma Questionnaire (CTQ) 6 provides a reliable and valid 
retrospective measure of childhood abuse and neglect (Week -1, self-report, 5 minutes). Clinical 
Institute Withdrawal Assessment for Alcohol-Revised (CIWA-AR)7 is a reliable and valid scale to 
assess severity of alcohol withdrawal symptoms; scores ≥ 9 indicate pharmacological treatment 
may be warranted (Weeks -1 and 0, Study Physician or Research Nurse, 5 minutes). 
Fagerstrom Test for Nicotine Dependence (FTND)8 is a 6-item rating scale of nicotine 
dependence (Week -1, self-report, 2 minutes). Illicit Drug Use Index9 is a composite index of 
frequency and duration of illicit drug use (Week -1, Study Clinician, 7 minutes). Standardized 
History form will record demography, medical and alcohol history, including age of onset of 
alcoholism, prior detoxifications, treatments and durations of abstinence, and family history of 


alcoholism (Week -1, Study Clinician, 10 minutes). Structured Clinical Interview for the DSM V 
(SCID V; expected to be released in the winter of 2014 – http://www.scid4.org) will be used to 
establish the DSM-V categorical diagnosis of current alcohol use disorder of ≥ moderate 
severity (≥4 symptoms) and to rule out exclusionary Axis I disorders10 (Week -1, Study Clinician, 
30 minutes). Treatment Goals Checklist11 is a 6-choice checklist subjects use to indicate their 
treatment goal, e.g., to quit drinking entirely, to quit but realizes a slip is possible, controlled use, 
etc. (Week -1, self-report, 2 minutes). 
 
Primary Outcome Measure:  
Timeline Followback Interview (TLFB)12 provides quantity and frequency estimates of alcohol 
consumption for the 90-day period prior to and throughout study. A standard drink is defined as 
14g of absolute ethanol content which is equivalent to 12 oz beer, 1.5 oz hard liquor or 5 oz 
wine.10 A heavy drinking day is defined as ≥ 4 drinks per day for women and ≥ 5 for men.10 TLFB 
drinking data will be supported with weekly drinking diaries as a memory guide, and validated by 
weekly breathalyzer determination, and monthly GGT values. If unresolved inconsistencies 
between sources occur, then the most negative outcome will be assumed accurate. 
(Assessment Coordinator, 10 minutes at Week -1, 5 minutes thereafter).  
 
Secondary Outcome Measures:  
Alcohol Craving Questionnaire-Short Form (ACQ-SF)13 provides an assessment of current 
drinking urges, difficulty resisting urge and anticipation of positive outcome or relief from 
negative affective state by drinking (every study visit, 2 minutes). Neurocognitive Functioning 
The California Verbal Learning Test-II (CVLT-II)14 and the Verbal Fluency, Trail Making, Color-
Word Interference, Design Fluency and Towers tests from the Delis-Kaplan Executive Function 
System (D-KEFS)15 and Letter Number Sequences from the Wechsler Adult Intelligence Scale-
IV (WAIS-IV)16 will be used to measure aspects of executive functioning, learning and memory, 
which are thought to be impacted by the hypothalamic-pituitary-adrenal (HPA) axis and alcohol 
use and to expand on the mifepristone POC study findings (Weeks 0 and 8, Neuropsychologist, 
45 minutes). 
 
Exploratory Measures:  
Genetic Indicators of Mifepristone Effects Saliva samples will be collected using Oragene DNA 
(OG-500) 2 ml saliva kits (DNA Genotek, Inc) and genotyped on the Illumina Human Omni 
Express Exome beadchip, with analysis limited to selected candidate genes. Differences in 
response to mifepristone may also be reflected in cellular differences in response to the drug 
and to cortisol. To study this, blood samples will be collected and sent by same day transport to 
Dr. Bruce Barshop’s Biochemical Genetics Laboratory at UCSD, which is located less than 1 
mile from our lab and where peripheral white blood cells (PWBC’s) will be extracted and 
cryopreserved. PWBCs will be isolated by density centrifugation through Nycoprep from whole 
blood (2 x 8ml) stabilized with acid citrate dextrose and stored at -140°C in tissue culture 
medium supplemented with 10% DMSO to maintain viability. Dr. Goldman’s lab at NIAAA will 
generate lymphoblastoid cell lines and iPSC lines from cryopreserved PWBCs. Cell lines 
established from high and low responders to mifepristone will be analyzed for gene expression 
and methylation differences by RNA-seq and whole genome methylation analysis (Week 0, 
samples collected by Medical Technician). Cortisol and ACTH Blood is collected, spun, 
prepared, frozen and stored in Dr. Mason’s lab for periodic batch analysis in the Parsons’ lab 
using Enzyme Linked ImmunoSorbent Assay (ELISA) kits to provide quantitative determination 
of ACTH and cortisol in plasma (Weeks 0, 1, 2, 4, 8 and 12). 
 
Safety Measures:  


Breath Alcohol Concentrations (BAC) Subjects are informed prior to the screening visit that if 
they present with positive BAC’s, they will not be paid and will be rescheduled, and have to wait 
until BAC is normal or will be accompanied home by a friend or taxi driver (beginning of every 
study visit, Research Nurse, 2 minutes). Adverse Event– Case Report form records each 
adverse event and onset, duration, severity, relation to study medication and clinical action 
(every study visit, Research Nurse, 5 minutes). Urine screen for illicit drug use (Weeks -1, 1, 4, 
8 and 12). 
 
 
PHARMACOTHERAPY CONDITIONS AND MEDICATIONS DISPENSED  
 
Pharmacotherapy Conditions 
Simple randomization procedures will be followed to randomly assign subjects to double-blind 
treatment with 600 mg/d or 1200 mg/d mifepristone or matched placebo in a 1:1:1 ratio, using a 
computer-generated randomization code provided by our laboratory biostatistician. Dose 
titration is not indicated. 
 
Rationale for Dose Selected 
The daily doses selected (600 and 1200 mg) are consistent with those used in a recent large 
scale (N=433) efficacy and safety study of mifepristone for the treatment of psychotic 
depression17 which found no significant  differences between mifepristone 600mg, 1200 mg and 
placebo for the percentages of patients with > 1 adverse event or with serious adverse events. 
The most commonly reported side effects were: headache, dizziness and dyspepsia for 
mifepristone, and nausea and somnolence for placebo. 
 
Rational for Study Duration 
Dosing duration (1-week) provides a duration of drug exposure that is compatible with optimal 
drug effects for resetting the HPA axis and for maintaining subject safety. 
 
Medication Supply 
Mifepristone 300 mg tablets and matched placebo tablets will be provided by Corcept 
Therapeutics.  
 
Medication Compliance 
Subjects will receive a 1-week supply of double-blind study medication in a blister card package. 
Blistercards are consecutively numbered for each participant and prepared according to the 
randomization code. Neither subject nor study personnel involved in subject care or assessment 
will know the identity of the randomly assigned study drug. Medication will be identical in 
appearance and all subjects will be given the same number of double-dummy tablets to 
preserve the blind. Subjects will be instructed to take the study drug each morning, preferably 
with food, and to return the blistercard and any unused drug at the next visit (Week 1). A brief 
scripted phone call will be scheduled on Day 3 of medication to assess medication compliance, 
any AE’s and subject concerns that could prompt study discontinuation. Compliance will be 
verified with returned medication package and pill count. Mifepristone plasma determinations 
will be obtained at Week 1 and will be analyzed retrospectively to verify correct medication 
assignment per the randomization code and ingestion of active medication and will be examined 
for an association with outcome. 
 
Drug Accountability 
All study medication is kept in a locked metal cabinet in the medication preparation room. The 
research technician labels and prepares the blinded medication in blistercards which are 


identified by randomization code, and keeps a record of all medication dispensed and returned 
throughout the study. 
 
 
 
Concomitant Pharmacological Treatments 
Subjects will be instructed to not use any herbal, over-the-counter or prescribed medication 
without consulting the study physician, who will consult with the P.I. to determine the continued 
eligibility of the subject for participation in the study. All approved medications, e.g., NSAIDS or 
antihypertensives, will be recorded in the case report form with any changes recorded 
throughout the study. 
 
Data and Safety Monitoring Plan 
Potential risks and benefits for participants 
Stringent procedures will be followed to minimize the risk of adverse reactions for participants, 
including the following:  
• 
The P.I. is experienced and qualified to distinguish a serious adverse event (SAE) from a 
non-serious adverse event (AE). The P.I. will be responsible for monitoring the conduct of 
this single-site clinical trial to ensure the safety of participants and the integrity of the data. 
The P.I. will monitor subject side effect complaints, clinically significant lab abnormalities and 
findings on physical exam in consultation with study physicians and Dr. Michael Skinner, 
MD, Pharm D, our independent Medical Safety Monitor, who has over a decade of 
experience as a Research Physician in the pharmaceutical industry involved in Phase I, II 
and III clinical trials. Dr. Mason will meet with members of her staff and the Medical Safety 
Monitor, Dr. Skinner, on a weekly basis to discuss progress of the study, subject enrollment 
and retention, the clinical status of active subjects and any safety issues as they arise. 
• 
If a SAE occurs, the P.I., in consultation with the chief Study Physician, Farhad Shadan, 
M.D., and the Independent Medical Safety Monitor, Michael Skinner, M.D., PharmD., will 
report it to the Scripps-IRB, our NIAAA Project Officer and the US FDA within 48 hours of 
becoming aware of the event. The written report will capture all safety information including 
the date of SAE onset, a description of the event, action taken, and whether a relationship 
between the SAE and drug exists. A summary of all AE’s and SAE’s that occurred during 
the previous year will be included in an annual progress report to the FDA, our NIAAA 
Project Officer and the Scripps-IRB.  
• 
The study physician will be responsible for managing the SAE and/or making referrals for 
appropriate care, as needed, until the problem has resolved or stabilized with no further 
change expected, or is clearly unrelated to study medication, or results in death. 
• 
Female subjects who are pregnant and nursing, or not using effective non-hormonal 
methods of birth control will be excluded from study. 
• 
Participants who are found to require additional treatment at their follow up visit due to 
significantly increased alcohol consumption or serious psychiatric/medical symptoms will be 
offered referral for appropriate treatment. Treatment resources include the adjacent Scripps 
Green Hospital and Clinic where our study physicians have staff privileges and the nearby 
Scripps MacDonald’s Center for Chemical Dependency that provides inpatient and 
outpatient services. We also provide referral to no-fee and sliding fee facilities. 
• 
SAE’s during follow up will be reported to the Scripps-IRB, our NIAAA Project Officer and 
the FDA within 48 hours of our becoming aware of the event, using the procedures for 
SAE’s described above. All AE’s and SAE’s during follow up will be compiled in our annual 
reports to the Scripps-IRB, our NIAAA Project Officer and the FDA. 


• 
Data forms and behavioral ratings for each subject will be formatted into a standardized 
case report form (CRF) upon which participants will only be identified by an assigned study 
number. Each CRF will be checked for accuracy and completeness. Data will be entered 
into a computerized database immediately after each subject completes the study. All data 
are routinely checked after entry, and distributional statistics are calculated and examined to 
identify outlying and/or potentially inaccurate data values and missing data. Data entry 
errors are promptly corrected and missing data verified with the CRF. All data are backed up 
on a nightly basis. Data will be stored and analyzed using computer facilities at the 
Laboratory of Clinical Psychopharmacology. 
• 
Confidentiality will be preserved by the following measures: keeping CRF’s in locked metal 
cabinets; CRF’s and computerized data will be identified only by numerical code so that 
neither the subject’s name nor initials will be used; the electronic database is password 
protected and accessible only to designated research personnel; no information will be 
released to non-study personnel regarding the identity or progress of subjects without 
written request by the individual subject to the Principal Investigator. A Certificate of 
Confidentiality will be applied for to protect against involuntary disclosure of the identities of 
research participants. 
 
 
Stringent procedures will be followed to minimize the risk of adverse reactions for participants, 
including the following:  
• 
Study medication will be administered according to a protocol reviewed for safety by the 
FDA and conducted under an approved amendment to IND #114497 that we hold for our 
POC study in AUD. The medication studied is considered safe when used in accordance 
with the procedures to be employed in the study.  
• 
Subjects are required to be abstinent ≥ 3 days prior to randomization and some subjects 
may be at risk for withdrawal. Withdrawal risk is evaluated at the screening visit with the 
Clinical Institute Withdrawal Assessment-Alcohol Revised (CIWA-AR). Subjects with CIWA 
scores ≥ 9 are ineligible for randomization and referred for medical detoxification. However, 
our community dwelling subjects typically do not require medical detoxification, and are 
advised to reduce their alcohol intake incrementally such that 3 consecutive days of 
abstinence are achieved prior to their randomization (Week 0) visit. The CIWA-AR is then 
repeated at Week 0 to further rule out risk of significant withdrawal symptoms during double-
blind treatment. 
• 
Subjects will be excluded who are at increased risk through an extensive medical history, 
complete physical exam, including ECG, complete blood chemistry (CBC), liver function 
tests (LFT's), urinalysis, and urine toxicology screen for drug of abuse.  
• 
Subjects with any conditions that would expose them to unusual risk (e.g., use of 
contraindicated medications, suicidal ideation, significant medical disorders including 
prolongation of the QTc interval, or pregnancy) will be excluded.  
• 
A menstrual history, 2 negative pregnancy tests, and birth control will be documented in 
women of childbearing potential, to avoid giving study drug to women with unrecognized 
pregnancies.  
• 
Female subjects of childbearing potential will be informed that mifepristone may interfere 
with the effectiveness of hormonal contraceptives and will be required to use effective non-
hormonal birth control for the 1-week duration of medication and for one month thereafter. 
• 
Subjects will be advised neither to drive a car nor operate complex machinery until they 
have gained sufficient experience on drug to gauge whether or not it affects their mental 
and/or motor performance adversely. 


• 
Subjects will be provided with their Study Clinician’s business card and a copy of the 
informed consent that includes 24/7 phone numbers for study physicians. 
• 
Participants will be asked about adverse events and concomitant medications at the 
scheduled phone call on Day 3 of medication and at each study visit.  
• 
Participants will be instructed about signs and symptoms of adrenal insufficiency and how to 
contact the study physician in case they occur. The following language will be used in the 
informed consent:  
Tell your doctor right away if you have any of these symptoms: 
 *   Unusual tiredness or weakness 
 *   Nausea and/or vomiting 
 *   Dizziness when standing 
 *   Aches and pains 
 *   Loss of appetite 
 *   Being depressed 
• 
Female participants will be instructed to report unexplained vaginal bleeding. 
• 
Participants reporting symptoms of adrenal insufficiency or unexplained vaginal bleeding 
during the 1-week of study medication will be discontinued from study drug and seen 
promptly for medical evaluation. 
• 
Laboratory evaluations and electrocardiogram will be repeated at the conclusion of 
medication to identify any abnormalities potentially related to drug exposure. Any clinically 
significant abnormalities persisting at the end of medication will be followed by the 
investigator until resolution or until a clinically stable endpoint is reached. 
• 
Participants will be evaluated at the end of study medication for:  
o Evidence of QT prolongation (ECG)  and if present will be monitored until 
resolution 
o Signs and symptoms of adrenal insufficiency.  If adrenal insufficiency is 
suspected, it will be followed-up closely. We note that no case of adrenal 
insufficiency or QT prolongation has been reported in studies of similar duration 
and dosing (also see Darpo et al., 2013). 
• 
Following 1-week of study drug, subjects will be evaluated weekly through Week 8 and 
provided with manual-guided counseling, and will complete a follow up visit at Week 12. 
Project MATCH found that 4 sessions of Motivational Enhancement Therapy (MET) in 12 
weeks was as efficacious as 12 weekly sessions of Cognitive Behavioral Therapy or Twelve 
Step Facilitation for reducing drinking, leading to the conclusion that multiple types of 
behavioral interventions of varying intensity are equally helpful in early recovery.18 The 
manual-guided counseling we provide is most similar to MET. We chose 8 weeks of 
counseling and assessment based on the 8-weeks of aftercare and assessment in the 1-
week mifepristone psychotic depression studies.17, 19, 20 Duration of mifepristone effects 
beyond 8-weeks has not been evaluated in controlled trials, but we will collect outcome data 
for Weeks 9, 10, and 11 by scheduled phone calls, and conduct an in person assessment at 
Week 12, in conjunction with referral for additional treatment if warranted. 
• 
Highly trained and experienced personnel will provide a degree of supervision that might not 
be available under usual treatment conditions. 
• 
Subject clinical status will be carefully monitored by the P.I. and Michael Skinner, M.D., 
PharmD, Safety Monitor, during weekly laboratory meetings with all personnel involved in 
the study and by quarterly review of blinded tables of safety data, including rates per group 
of adverse events, serious adverse events and discontinuation due to adverse events, 
provided by our statistician. Dr. Skinner will advise the PI and study physicians if trends 
emerge that warrant changes to the study protocol to protect the safety of research 


participants.  Dr. Mason will present any safety findings and proposed remedial actions to 
the Scripps-IRB and our NIAAA Program Officer. 
• 
The clinical ratings and blood tests will be performed by experienced personnel to minimize 
complications and unnecessary fatigue and distress. 
• 
The study physician will evaluate any subject experiencing clinical deterioration and make a 
clinically-based decision regarding study discontinuation and referral for appropriate care in 
consultation with the P.I. Criteria for study termination include: development of intolerable 
side effects; development or worsening of a physical or psychiatric disorder that requires 
treatment that would be in violation of the protocol. If a subject is discontinued, every 
attempt will be made to perform the evaluations specified for the final visit at the time of 
discontinuation. Reason(s) for premature termination will be documented in the case report 
form. 
• 
At the follow-up visit, subjects who report significantly increased alcohol consumption or 
serious psychiatric/medical symptoms will be offered a referral to treatment specific to their 
needs. 
• 
Importantly, the research group has a well-established record of subject safety in the 
conduct of analogous clinical trials and subjects will receive careful monitoring of their health 
status while in the study.  
 
 
Risks to patient confidentiality will be mitigated by the following measures:  
• 
Keeping the subject case report forms in locked metal file cabinets. 
• 
Case report forms and computerized data will be identified only by numerical code so 
that neither the subject's name nor initials will be used. 
• 
Access to computerized data will be password protected and available only to authorized 
study personnel 
• 
No information will be released to non-study personnel regarding the identity or progress 
of subjects without written request by the individual subject to the P.I. In addition to the 
aforementioned protection of privacy, a Certificate of Confidentiality will be applied for to 
protect against involuntary disclosure of the identities of research participants.  
• 
Published results will not reveal the identity of individual participants. 
• 
Confidentiality of genetic data will be protected including by coding and anonymization of 
samples and maintaining data under lock and key and limiting access to electronic data 
to authorized personnel. No genetic results will be communicated to study 
participants. The following language will be used in the informed consent to advise 
participants of available protections against discrimination based on genetic information 
obtained in this study, should confidentiality not be preserved: 
“A new federal law, called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information. This law 
generally will protect you in the following ways: 
o Health insurance companies and group health plans may not request your 
genetic information that we get from this research 
o Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premium 
o This new Federal Law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance or long-term care 
insurance” 
 


 
 
Collection and Reporting of AEs and SAEs 
 
The P.I. will be responsible for monitoring the conduct of this single-site human laboratory study 
to ensure the safety of participants. The P.I. will monitor subject side effect complaints, clinically 
significant lab abnormalities and findings on physical exam in consultation with study physicians 
and Dr. Michael Skinner, MD, Pharm D, our independent Medical Safety Monitor, who has over 
a decade of experience as a Research Physician in the pharmaceutical industry involved in 
Phase I, II and III clinical trials. If a SAE occurs, the P.I., in consultation with the Study 
Physician, Farhad Shadan, M.D., and the Independent Clinical Safety Monitor, Michael Skinner, 
M.D., PharmD., will report it to the IRB, our NIAAA Project Officer and the US FDA within 48 
hours of becoming aware of the event. The written report will capture all safety information 
including the date of SAE onset, a description of the event, action taken, and whether a 
relationship between the SAE and drug exists. In addition, a summary of all SAEs that occurred 
during the previous year, and their outcomes, will be included in the annual progress report to 
the FDA, NIAAA and our IRB. AEs will be documented at each study visit on the Adverse Event 
case report form by recording of each adverse event and onset, duration, severity, relation to 
study medication and any clinical action. These will be compiled and reported to the FDA, 
NIAAA and our IRB in the annual progress report. 
 
Management of SAEs or Other Study Risks  
 
The study physician will be responsible for managing a drug-related SAE and/or making 
referrals for appropriate care, as needed, until the problem has resolved or stabilized with no 
further change expected, or results in death.  
 
DSM Plan Administration 
 
Responsibility for data and safety monitoring 
The P.I. is responsible for monitoring this single-site human laboratory trial. Dr. Mason will meet 
with members of her staff and the Study Safety Monitor, Dr. Skinner, on a weekly basis to 
discuss progress of the study, subject enrollment and retention, the clinical status of active 
subjects and any safety issues as they arise. 
 
Frequency of DSM 
All case report form data will be entered into an electronic file on a daily basis as they are 
completed. Data safety monitoring will be conducted by the P.I. and Safety Monitor who will 
review adverse events on a weekly basis. The Safety Monitor will advise the P.I. and the study 
physicians if any changes in the study plan may be needed to improve subject safety.   
 
Data safety and monitoring reports will be provided annually to the IRB, NIAAA and the FDA. 
We will use pre-established criteria and procedures for reporting AEs, SAEs, issues potentially 
arising from conflicts of interest significant protocol changes, and/or cause for trial termination to 
the IRB, NIAAA and the FDA. 
 
DSM board plan  
Per NIAAA guidelines, no DSM board is required for this single-site, early Phase II trial. 
 
 


 
 
References 
 
1. 
 Miller WR. What is relapse? Fifty ways to leave the wagon. Addiction. 1996; 
91(Suppl:S15-27). 
2. 
Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment 
for alcohol dependence: a randomized clinical trial. The Journal of the American 
Medical Association Internal Medicine. 2014;174(1):70-77. NIHMSID#533947 
3. 
Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of 
naltrexone and acamprosate for treating alcohol use disorders: when are these 
medications most helpful? Addiction. 2013;108(2):275-293. 
4. 
Fertig J. NIAAA Clinical Investigations Group. Paper presented at Alcohol and Stress: 
A Framework for Future Treatment Strategies. May 2011; Volterra, Italy. 
5. 
Skinner H, Horn J. Alcohol Dependence Scale: Users Guide. Addiction Research 
Foundation: Toronto;1984. 
6. 
Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto 
E, Ruggiero J. Initial reliability and validity of a new retrospective measure of child 
abuse and neglect. The American Journal of Psychiatry. 1994;151(8):1132-1136. 
7. 
Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of 
alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol 
scale (CIWA-Ar). British Journal of Addiction. 1989;84(11):1353-1357. 
8. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerstrom Test for 
Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. British 
Journal of Addiction. 1991;86(9):1119-1127. 
9. 
Clayton  RR, HL Voss. Young men and drugs in Manhattan: a causal analysis. NIDA 
Research Monograph. 1981;39:1-187. 
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders-Fifth Edition. Washington, DC: American Psychiatric Press; 2013. 
11. Hall SM, Havassy BE, Wasserman DA. Commitment to abstinence and acute stress in 
relapse to alcohol, opiates, and nicotine. Journal of Consulting and Clinical 
Psychology. 1990;58(2):175–81. 
12. Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported 
alcohol consumption. In: Litten RZ, Allen JP eds. Measuring Alcohol Consumption: 
Psychosocial and Biochemical Methods. New Jersey: Humana Press, 1992:41-72.  
13. Singleton EG, Henningfield JE, Tiffany ST. Alcohol Craving Questionnaire: ACQ-Now: 
Background and Administration Manual. Baltimore, MD: NIDA Addiction Research 
Center;1994. 
14. Delis, D., Kramer, J.,  Kaplan, E., Ober, B., California Verbal Learning Test-Second 
Edition 2000, San Antonio, TX: The Psychological Corporation. 
15. 
Delis, D., Kramer, J.,  Kaplan, E., Manual for the Delis-Kaplan Executive Function 
System (D-KEFS) 2001, San Antonio, TX: Psychological Corporation. 
16. Wechsler, D. Wechsler Adult Intelligence Scale – Fourth Edition 2008, San Antonio, 
TX: Pearson. 
17. Blasey CM, Block TS, Belanoff JK, Roe RL. Efficacy and safety of mifepristone for the 
treatment of psychotic depression. Journal of Clinical Psychopharmacology.  
2011;31(4):436-440. 
18. Project MATCH Research Group. Matching alcoholism treatments to client 
heterogeneity: treatment main effects and matching effects on drinking during 
treatment. Journal of Studies on Alcohol. 1998;59(6):631-639. 


19. Simpson GM, Sheshai AE, Loza N, Kingsbury SJ, Fayek M, Rady A, Fawzy W. An 8-
week open-label trial of a 6-day course of mifepristone for the treatment of psychotic 
depression. Journal of Clinical Psychiatry. 2005;66(5):598-602. 
20. Blasey CM, Debattista C, Roe R, Block T, Belanoff JK. A multisite trial of mifepristone 
for the treatment of psychotic depression: a site-by-treatment interaction. 
Contemporary Clinical Trials. 2009;30(4):284-288. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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As of January 2009, the Scripps IRB has a new policy concerning Conflict of Interest disclosure. Disclosure forms must be submitted for 
You 
ALL personnel on all New and Continuing Review studies that are sponsored, funded or have any involvement of an outside institution. 
can access the new policy document and the new Conflict of Interest disclosure form by clicking on the 'Help' link in the upper right of 
your screen (has a question mark next to it).
  
  To download the disclosure form, click on the 'Scripps IRB Conflict of Interest Form' link. This will open the form in another window. 
Press the F12 key on your keyboard. This will open a 'Save As' dialog box for you to save the form to your computer. 
  This form can be completed electronically in Word on your computer. But you will have to print it out in order to get a 
signature. Fax completed and signed forms to (858) 652-5554. Or you can upload and attach a scanned copy of the completed and signed 
forms by clicking on the green button below.
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As of January 27, 2009, all Scripps IRBs were combined into a single, system-wide IRB known as “Scripps IRB”, 
which is registered with 
OHRP as IRB00004335
Office for the Protection of Research Subjects
Approval Notice (Modification)
Investigator:
Barbara J Mason, Ph.D.
Department: 
The Scripps Research Institute – Dept. of Neuroscience 
Approved
Research Sites:
The Scripps Research Institute  
Project Title:
Glucocortoid Antagonist Treatment of Alcohol Use Disorder
Protocol No:
IRB-14-6372
Risk Category:
Greater than Minimal 
Type of Review:
Expedited
The modification to the protocol above was reviewed and approved by an IRB Officer.  This modification 
does not extend the expiration date of the protocol’s last IRB review.
Current, approved study documents can be downloaded from iMedRIS at https://research.scripps.org 
(Revised Informed Consent dated 1-09-18: Removes the 600mg/day dosing arm of the study. Jenny Miller, 
BS, is added as a medical assistant and Melissa St. John is removed)
Signature applied by Jennifer Holmes  on 01/18/2018 06:47:42 PM PST
IRB Officer
Scripps IRB
4275 Campus Point Court, CPB 200
San Diego, CA 92121

SAP_001.pdf: 
Statistical Plan  
Glucocorticoid Antagonist Treatment of Alcohol Use Disorder  
From NIH Grant Application #AA023152  
P.I. Barbara J Mason, Ph.D. 
Submitted 2/7/2014 
 
All analyses will be conducted in the intention-to-treat sample with p<0.05 for two-tailed 
tests of significance. Demographics and baseline measures will be examined for 
differences between treatment groups and tested individually for correlation with each 
outcome. Any baseline variable significantly associated with outcome or differing 
between treatment groups will be included in subsequent analyses as a covariate. 
Trend dose effects will be determined using single or multi parameter tests of Mixed 
Effect Model (MEM) effects, as required.  All MEMs are repeated measures centered on 
the relevant time period. Time, treatment, and time x treatment will be evaluated as 
fixed effects in each model.  
Mifepristone plasma concentration and baseline drinking levels were significant 
predictors of response in our Proof of Concept (POC) study and will be evaluated as 
predictors in the proposed study. Sex, age, age of onset and family history of alcoholism 
will be examined as covariates of response because of a potential association with 
cortisol in the case of the latter 3 variables and to assess differential treatment response 
for males and females, given mifepristone’s antiprogesterone effects, and the trend for 
females to have better drinking outcome in our POC study. Motivation, e.g., to have 
abstinence as a treatment goal, will be examined as a non-specific predictor of 
treatment outcome. Potential pharmacogenetic predictors of response will be evaluated 
on an exploratory basis.