Clinical trial NCT02243709
Conditions: Alcohol Use Disorders (AUD)
Keywords: Stress, alcohol craving, alcohol use disorders
Sponsor: Brown University
Start date: 2014-09-01; Completion date: 2021-12-21
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of this study is to determine if, under stress, alcohol drinking is reduced using mifepristone

Detailed description:

Arms: arm 1: mifepristone 600-mg/day for a week, in a stress-induced condition triggered by a single dose of 32.4-mg of yohimbine arm 2: matching placebo/day for a week, in a stress-induced condition triggered by a single dose of 32.4-mg of yohimbine
Interventions: intervention 1: Mifepristone 600-mg/day or placebo for a week
Intervention descriptions: intervention 1: 600-mg of mifepristone for a week, compared to placebo for a week, in a stress-induced condition triggered by a single dose of 32.4 mg of yohimbine

Protocol documents:
Prot_000.pdf: 
  
Center Alcohol and Addiction Studies 
Brown University 
 
 
TITLE: A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of 
alcohol drinking 
PI: Carolina L. Haass-Koffler   
NCT02243709 
IND121984 
DATE: December 15 2014 
 
 


Title: A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of alcohol drinking 
PI: Carolina Haass-Koffler 
 
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CLINICAL PROTOCOL 
 
 
A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of 
alcohol drinking 
 
Principal Investigator: 
Carolina L. Haass-Koffler, PharmD, PhD 
Brown University, Providence, RI 
(415) 519-1385 
(401) 863-6630 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
Objective: The primary objectives of the study include: A) Establish the safety and tolerability of using 600mg of 
mifepristone and 32.4mg yohimbine while consuming alcohol; and B) Demonstrate the feasibility of the study 
design and obtain an effect size to estimate a sample size for an appropriately powered larger R01 application 
using mifepristone and yohimbine together when administering alcohol.    
Rationale:  Glucocorticoids (GC) mediate adaptation to stress and regulate termination of the stress response 
through the hypothalamic–pituitary–adrenal (HPA) axis feedback action. The link between stress and chronic 
relapsing alcohol-use disorders (AUD) and substance-use disorders (SUD) has long been established in the 
addiction research field. Preclinical studies show the GC-receptor antagonist, mifepristone, reduces behavioral 
hyperexcitability during the acute phase of alcohol withdrawal, suggesting that mifepristone is a promising 
pharmacotherapy for alcoholic individuals to reduce the cognitive deficits caused by chronic alcohol use and 
withdrawal symptoms. In our preclinical studies, we showed that in conditions where stress is limited, mifepristone 
has no effect on alcohol intake, corroborating the hypothesis that GC blockade represents a key element in the 
preoccupation/anticipation (craving) stage of the addiction cycle. However, what remains unknown is the role of 
mifepristone in stress-induced craving and relapses of alcohol drinking in humans.  
Overview of Study Design:  The design will be a randomized within, crossover, double-blind, placebo-controlled 
human study with mifepristone in non-treatment-seeking-alcohol-dependent individuals. The study will be 
conducted in in consecutive phases (Figure 1):  
Visit#1: Screening;  
Visit#2: Randomization and drug/placebo dispensed (for seven days);  
Visit#3: First lab-session: single dose of yohimbine;  
Visit#4: Washout period, follow-up (one month) and drug/placebo dispensed (for seven days); 
Visit#5: Second lab-session, single dose of yohimbine; Motivational session (MET); 
Visit#6: Follow-up (one month); END of STUDY. 
 
Study Population: Sixty-five non-treatment-seeking, alcohol-dependent participants will be recruited. Fifty-
eight participants will be enrolled for screening with 50 participants (n = 50) expected to complete the study. 
Participants will primarily be recruited via advertisements placed in local newspapers and posted on buses.  


Title: A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of alcohol drinking 
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Safety Measurement/Parameters: Risks of medication side effects will be minimized through careful and detailed 
screening of participant. Signs of anxiety and stress, adverse events and vital signs will be assessed at each visit 
by psychometric assessments. Safety laboratory tests and will be evaluated at baseline, and at the end of the 
study participants will receive a behavioral motivational session at the end of Visit 5.  
Financial considerations:  There will be no cost(s) to participate in this study. The study medications and all 
procedures that are not part of routine care, but are required for the study, will be provided to the participant.  If eligible 
for the study, participants will receive $25 for the randomization visit (Visit# 2) and for the follow-up visits (Visits #4 
and #6). During the laboratory phase, at each visit (Visits #3 and #5) participants are compensated $100 + another 
possible $3/drink as incentive for not drinking (max $24). Therefore, each participant may be compensated up to 
$323 during the entire study period. Participants will be also compensated for their travel costs. 
Specific Aims: 
Aim 1: to assess the safety and tolerability of mifepristone and yohimbine while consuming alcohol. 
Aim 2: to test the hypothesis that an increase in alcohol craving induced by yohimbine is antagonized by pre-
administration with mifepristone.  
Aim 3: to test the hypothesis that an initial priming drink and alcohol consumption induced by yohimbine is 
antagonized by pre-administration with mifepristone.  


Title: A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of alcohol drinking 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
TABLE OF CONTENTS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
SPECIFIC AIMS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
RATIONALE AND SIGNIFICANCE TO THE ALCOHOL FIELD  
 
 
 
 
 
 
 
 
 
 
 
5 
Stress and alcohol dependence   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Clinical relevance  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Pharmacological stress targets  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Mifepristone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
Stress-induced models 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
Integration: psychoneuroendocrinology and trauma factors  
 
 
 
 
 
 
 
 
 
 
 
6 
Significance for NIAAA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
Innovation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
The Investigator Team 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
The qualified medical personnel during the laboratory sessions 
 
 
 
 
 
 
 
 
 
 
7 
RESEARCH DESIGN AND METHODS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Overview of Proposed Research  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8  
Medications and Doses  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
Study Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
Data Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     10 
Alternative Design Considerations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
PROTECTION OF HUMAN SUBJECTS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
Protection Against Risks  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
Recruting and Inform Consent Form (ICF) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
            12 
Insuring Informed Consent and Comprehension  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
Psychological Assesments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13 
Screening and randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
Inclusion and Exclusion Criteria (Table 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
Source of Materials 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
Description of Potential Risks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
Medications and Drug-drug interactions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
Drug Storage and Accountability  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 
Mifepristone and yohimbine administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 
Alcohol Cue-Reactivity (CR) and Alcohol-Self-Administration (ASA) experiments  
 
 
 
 
 
19 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
Potential Benefits of Proposed Research 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22  
Importance of the Knowledge to be Gained  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
Inclusion of Women, Minorities and Children 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
BIBLIOGRAPHY & REFERENCES CITED  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 
 


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STUDY AIMS 
Although stress has long been linked to alcohol intake and relapse during abstinence, there are no available 
medications that target stress-induced alcohol relapse. Furthermore, the effects of anxiolytics on craving and 
relapse in alcohol-dependent individuals have been inconsistent. The benefits of reducing stress conditions 
using pharmacological interventions that blunt the activation of stress systems in ethanol-dependent preclinical 
models have been well described; however, the integral mechanisms by which stress influences alcohol 
consumption in humans are not well understood.
 The leading goal of this study is to evaluate preventive 
pharmacological interventions that can dampen the influence of stress on alcohol consumption and relapse in 
AUD populations. This protocol will test a preclinical model that investigated whether mifepristone, a 
glucocorticoid receptor antagonist, plays a role on yohimbine-induced reinstatement of ethanol seeking. This 
model builds on the hypothesis and evidence that glucocorticoid receptors play a role in the reinstatement 
behaviors elicited by yohimbine, an α-2 adrenoceptor antagonist, known to induce reinstatement of ethanol-
seeking behaviors.  
Translating preclinical paradigms into effective models for assessing pharmacological approaches for stress-
induced alcohol relapse in humans requires a comprehensive model capable of integrating: alcohol-proximal 
variables that influence drinking (withdrawal symptoms, craving), neuroendocrine variations (cortisol), and 
stress-risk factors (different temporal traumatic events). A comprehensive stress model is needed because 
emotional distress, neuroendocrine activation, stress-related genetic variations, craving, and alcohol 
consumption do not necessarily overlap in alcohol-dependent individuals. Mifepristone may be a valuable 
pharmacotherapeutic strategy for preventing relapse to AUD, and yohimbine is a pharmacological stressor 
capable of increasing craving, creating recall of traumatic memories, and altering neuroendocrine levels in 
alcohol-dependent individuals. As FDA-approved medications, both mifepristone and yohimbine have the 
advantage of being directly applicable to an alcohol clinical setting and being utilized in the translational efforts 
described in this application. 
The overall objective of this study is to conduct a randomized pilot laboratory study consisting of a placebo-
controlled assessment of the effects of 600 mg of mifepristone for a week, in a stress-induced condition 
triggered by a single dose of 32.4 mg of yohimbine in non-treatment-seeking-alcohol-dependent individuals. In 
the following specific aims, I propose: 
Aim 1: to assess the safety and tolerability of mifepristone and yohimbine while consuming alcohol. 
Randomized participants will complete two alcohol laboratory sessions along with a battery of physiological 
and psychological assessments that measure adverse events and pharmacokinetic (PK)/pharmacodynamic 
(PD) interactions. 
Aim 2: to test the hypothesis that an increase in alcohol craving induced by yohimbine is antagonized 
by pre-administration with mifepristone. To test this hypothesis, we will establish the effect of mifepristone 
on alcohol cue-elicited craving during a cue-reactivity (CR) experiment along with a series of physiological and 
psychological tests assessing alcohol craving. 
Aim 3: to test the hypothesis that an initial priming drink and alcohol consumption induced by 
yohimbine is antagonized by pre-administration with mifepristone. To test this hypothesis, we will 
establish the effect of mifepristone in an alcohol self-administration (ASA) experiment. We will also establish if 
mifepristone has an effect on alcohol PK/PD levels. The data obtained from this pilot trial will demonstrate the 
feasibility of the study design and obtain the PK/PD safety data to support a future study and an effective 
sample size for an appropriately-powered larger R01 application. 
 
 
 
 
 
 


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RATIONALE AND SIGNIFICANCE TO THE ALCOHOL FIELD  
Stress and alcohol dependence. Stressful events may lead to a wide range of health and psychiatric 
illnesses including alcohol use disorders (AUD)1-4. Furthermore, exposure to stress at multiple time points 
across an individual life course is associated with risk for AUD4,5. Though stress has been difficult to define6,7, it 
has been widely studied in the AUD field because it has been identified as one of the key factors contributing 
to escalation from social drinking to alcohol dependence8. In addition, AUD prognosis appears to be affected 
by stress and anxiety, both of which appear to promote alcohol craving9,10 and affect relapse11,12.  
Clinical relevance. Stress could influence alcohol intake in different ways. Acute stress has been found to 
contribute to relapse drinking in an alcohol cue reactivity paradigm13. Alcohol consumption, utilized to dampen 
the negative effect of stress14,15, can be used as a coping strategy16. Stress can also influence alcohol 
consumption by altering the rewarding efficacy of alcohol17. Furthermore, the impact of stress does not halt 
when individuals stop drinking. Alcohol abstinence is well known to increase anxiety during the withdrawal 
phase, which is an important factor in relapse18. One of the most difficult aspects in treating AUD is relapse to 
uncontrolled drinking that can be triggered by stressful events after a period of abstinence19.  
Although it is a priority of NIAAA to develop new AUD therapeutic interventions, currently there are only four 
FDA-approved medications to treat AUD. All of these interventions exhibit limited efficacy20, may require life-
long ongoing therapy, and none target the stress component. Furthermore, the effects of anxiolytics used off-
label for alcoholism have been inconsistent21-23. The stress system is thus ideally suited as a target for short-
term therapeutic interventions with a long-enduring effect, as this strategy may both lessen acute distress and 
promote stress resilience during alcohol abstinence. Thus, blunting and resetting the stress system could 
represent an effective and exciting novel pharmaceutical target for treating AUD.   
Pharmacological stress targets. Stress responses involve the (a) neural corticotropin releasing factor (CRF) 
system, and (b) activation of the hypothalamic-pituitary-adrenal (HPA) axis leading to increases in 
glucocorticoids (GCs)24. The use of alcohol dysregulates the stress system both at the neural CRF25-27 and 
HPA levels28-31, as repeated alcohol use leads to stimulation of the HPA axis, and the interruption of chronic 
alcohol use increases activation of CRF32. There are no medications that target stress-induced craving at the 
neural CRF level in order to reduce compulsive alcohol seeking, although CRF-receptor-1 antagonists have 
shown efficacy in preclinical ethanol models33,34 and are currently in clinical trials (NCT01187511 and 
NCT01227980). Preliminary results from those studies, in line with preclinical findings35,26, report that 
medications targeting the CRF system may be more effective in treating alcohol-dependent individuals to 
prevent stress-induced craving and relapse than preventing alcohol relapse that is not related to stressor 
triggers36.  
Alternative pharmacological targets within the stress system are the GCs, which interact with many 
neuroendocrine systems37-39 and mediate adaptation to stress response through the HPA axis feedback 
action40,41. During chronic stress conditions, this feedback becomes dysregulated, leading to a variety of 
maladaptive syndromes including anxiety, depressive disorders42 and alcohol dependence43. An effective 
treatment for AUD would ideally reverse the neurohormonal adaptations caused by excessive GC stress 
hormonal response. Furthermore, identifying targets that can modulate the stress system has the potential to 
benefit other mental disorders, such as posttraumatic stress disorder and psychotic major depression that have 
high comorbidity with AUD. 
Mifepristone. In preclinical models, the GC-receptor antagonist, mifepristone, specifically affects ethanol-
dependence behaviors44, limiting ethanol self-administration45 and preventing ethanol seeking during 
abstinence46. Those results, in addition to our findings47, suggest that GC blockade may represent a promising 
pharmacotherapeutic approach for preventing future alcohol exposures48. Mifepristone is a FDA-approved oral 
medication for the termination of early pregnancy, and has a safe and tolerable profile. Due to its specific 
antagonism effect of GC function, mifepristone is used to treat disorders that occur when the body is exposed 
to high levels of cortisol (Cushing syndrome49 and psychological disorders50). Mifepristone may have the 
potential to “reset” a dysregulated HPA axis, as it upregulates GC receptor function, restores normal HPA 
feedback, decreases depression-like behavior, and attenuates relapse51. 


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Preclinical studies showed that in conditions without stress-induction, mifepristone has no effect on alcohol 
intake47,52-54, corroborating the hypothesis that GC receptors represent a key element in the 
preoccupation/anticipation (craving) stage of the addiction cycle. What remains unknown is the effect of 
mifepristone in acute stress precipitating alcohol craving and relapse in humans.  
Stress-induced models. One of the most challenging aspects in designing a human laboratory study is the 
inclusion of an acute stress condition intended to represent a comprehensive naturalistic environment in 
chronic alcohol-dependent individuals. Hence, testing pharmacotherapies in stress-induced relapse models in 
alcohol laboratory paradigms is critical for the identification and development of therapeutic interventions to 
prevent alcohol relapse. Because the level of stress experienced by individuals suffering from AUD in real life 
situations is far greater than one can apply to participants in the traditional alcohol laboratory setting, for this 
pharmacotherapy proposal, I will use a model that integrates a pharmacological stress-induction paradigm with 
cue-reactivity (CR session) and alcohol self-administration (ASA session) laboratory measures in non- 
treatment-seeking alcohol-dependent individuals. 
Pharmacological challenges such as yohimbine, an α-2 adrenoceptor antagonist, have been shown to activate 
the primary events of stress response (CRF/ACTH/cortisol) in addition to increasing sympathetic nervous 
system activity55, facilitating recall of traumatic memories56, and increasing alcohol craving correlated with 
alcoholism severity57. Although acute psychological stressors presented in the laboratory have the advantage 
of modeling stress-induced emotions (anxiety, frustration, and embarrassment) encountered by individuals in 
the real world, they do not create the cascade of neuroendocrine events that likely trigger the urge to drink and 
lead to relapse under naturalistic conditions. Physical stressors (cold presser test or isometric handgrip) induce 
cardiovascular activation and discomfort, but produce limited cortisol activation and no increase in craving in 
alcoholics58,59. Yohimbine provides a safe57,60 pharmacological opportunity to overcome methodological 
weaknesses in studying the impact of realistic mobilization of neuroendocrine processes during an acute, 
transient stress on human cognition. Yohimbine, being a FDA-approved oral medication, has the advantage of 
being directly applicable to an alcohol clinical setting and utilized in the translational efforts described in this 
application.  
Integration: psychoneuroendocrinology and trauma factors. In addition to acute life stressors, direct 
contributors to stress neuroendocrine dysregulation include early-61-63 and late-life64 trauma. Individuals who 
experienced life trauma may use alcohol to help cope with trauma-related symptoms. Recent investigations 
highlight the importance of assessing trauma among patients with alcohol use disorders65-67. This stress study 
will incorporate the life traumatic experiences to evaluate their association with neuroendocrine changes68,69 
and the later development of AUD65.  
Significance to the field and for NIAAA. This proposed study is consistent with the mission of National 
Institute on Alcohol Abuse and Alcoholism (NIAAA) to “promote the identification and prevention of alcohol and 
other drug use problems in our society through research.” This proposed study meets two of the needs of 
research on the field of alcoholism: 1) to develop new pharmacotherapies for alcoholism; and 2) to elucidate 
mechanisms by which the medications are likely to have beneficial effects. This research will add to the 
current knowledge about the potential benefits of mifepristone by examining its effects on cue-elicited urge, 
the effects of drinking, and its effects on alcohol-free choice during stressful events. Although it is a priority of 
NIAAA to develop new AUD therapeutic interventions, currently there are only four FDA-approved medications 
to treat AUD. All of these interventions exhibit limited efficacy 20, and none target the stress component. The 
stress system is ideally suited to develop a short-term therapeutic interventions with a long-enduring effect, as 
it can lessen acute distress, and promote stress resilience during long alcohol abstinence. Thus, blunting and 
resetting the stress system, in order to improve both physical and psychological factors in alcohol-dependent 
individuals, represents an effective and exciting novel pharmaceutical target for treating AUD. Finally, our 
approach builds from a network of sciences that may have the potential to target other mental disorders 
(posttraumatic stress disorder and psychotic major depression) that have high comorbidity with AUD.   
Innovation. This research is innovative in three ways.  First, it focuses on a novel target for the prevention of 
alcohol relapse, the stress system. The second major innovation of this proposal is the development of a 
translational research clinical model that integrates administration of pharmacological stressors with alcohol 


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laboratory study methods developed from personal neuroscience and neuropharmacology knowledge. As the 
design of this project has built logically on our prior work, it is our intent to translate our neuroscience safety 
results to clinical research, which includes examining the effects of pharmacokinetic (PK) interactions (alcohol, 
yohimbine, mifepristone) on Pharmacodynamics (PD) additive responses (CNS depressant properties of 
alcohol or increased sedation/depression of respiratory and/or cardiac functions). Although not observed in our 
preclinical models, possible negative outcomes may be observed in stress-induced conditions in alcohol-
dependent individuals, such as potentiation of the stimulant phase of alcohol, increase in behavioral effects of 
alcohol intoxication, or worsening alcohol withdrawal syndrome. Our strong team includes well-established 
clinicians in the fields of experimental pharmacotherapeutics in alcohol laboratory studies, psychiatry and 
neuropsychopharmacology, to ensure safety and answer additional clinical questions that may arise during or 
between alcohol laboratory sessions. This interdisciplinary-validated human laboratory protocol is critical to 
determine safety and tolerability of stress-induced pharmacological procedures before moving forward into a 
larger randomized clinical trial and to pave new hypotheses to be explored in alcohol and stress neuroscience 
research. Finally, by providing safety measures and PK/PD data, this proposed application will pave the way 
for new therapeutic targets that could be utilized in other stress/anxiety mental disorders that have high 
comorbidity with AUD.  
The Investigator Team. The PI, Dr. Haass-Koffler, is a T32-funded postdoctoral fellow at CAAS. This REA 
proposal represents a logical extension of her previous experimental pharmacology and preclinical work with 
mifepristone on alcoholism done at the Gallo Center at University of California San Francisco (UCSF) before 
moving to the Center for Alcohol Addiction Studies (CAAS) at Brown. As such, under the supervision of her 
mentor, Dr. Kenna, this application will allow Dr. Haass-Koffler to 1) conduct a translational clinical study, the 
rationale of which is directly driven from her preclinical work; 2) gain experience and receive mentorship on 
human behavioral pharmacology research; and 3) collect pilot data that will support the feasibility and 
background of her NIH R01 proposal.  
The qualified medical personnel during the laboratory sessions.  
Responsibilities for each visit for each member of the Research Staff are described in Appendix Z.   
The PI, Dr. Haass-Koffler has extensive experience in the PK/PD drug-drug interactions.  She obtained her 
PK/PD training during her doctorate at UCSF, and she applied her PK/PD knowledge at a clinical level in her 
postdoctoral training in the department of Pharmacology and Experimental Therapeutics in the School of 
Medicine at UCSF; she also taught drug-drug interaction lectures in the core PK course to UCSF Pharmacy 
students (for two years). Dr. Haass-Koffler is also familiar with possible physiological adverse events that may 
arise during the administration of mifepristone, yohimbine and alcohol, since she ran the same mifepristone-
yohimbine-alcohol study at a preclinical level. She also authored a drug-drug interaction book chapter in a 
medical Substance Abuse Textbook (please see CV, publications) and she was part of the Medication Use and 
Safety Subcommittee (MUSS), San Francisco General Hospital (SFGH) (please see CV, Hospital 
Committees). Dr. Haass-Koffler is a trained military officer nurse who served in Italian Army/Air Force Hospitals 
and International Relief Missions (Somalia, Rwanda and Ex-Yugoslavia) for four years. She was the Lieutenant 
in change of medical training for the nurses’ qualification in Air Mobile Search and Rescue, School of Medicine, 
Italian Air Force. The medical experience in military hospitals and in war zones professionally prepared Dr. 
Haass-Koffler to assess both physical and psychological human distress and determine situations that may 
trigger a call to the study physician (please see CV, military service). Furthermore, regarding specific training in 
addictive behaviors in the alcohol-dependent population, Dr. Haass-Koffler worked at the Department of Public 
Health, Community Behavioral Health Services, San Francisco General Hospital (SFGH) as a Drug Information 
intern for two years during her doctoral training (please see CV, Hospital appointment). She was responsible 
for researching and presenting scientific and clinical information that would provide recommendations intended 
to represent the best-practice guidelines for the use of medications for the treatment of alcohol dependence 
and other psychiatric disorders (please see CV, list of CBHS publications). To augment her formal training on 
addictive behaviors, Dr. Haass-Koffler also attended the University of Utah, School on Alcoholism and Other 
Drug Dependencies training. This program focuses on keeping pace with increased awareness of the health 
and social problems of alcoholism and other drug dependencies. Academically, Dr. Haass-Koffler received her 


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PharmD with the double track in Pharmaceutical Science at UCSF, School of Pharmacy (#1 Pharmacy School 
in the US). She performed research at the prestigious Ernest Gallo Clinical and Research Center in California 
under the mentorship of Dr. Antonello Bonci, now one of the top directors at NIH. This high selective doctoral 
program allowed her to receive a double concurrent appointment at UCSF in the Neuroscience Department 
(Gallo Center) and in the Department of Clinical Pharmacology and Experimental Therapeutics (School of 
Medicine).  
The study physician, either Dr. Swift, will be present during the screening visit. They will perform the physical 
exam and psychological assessments.  Dr. Swift, is a practicing physician and is Board Certified in Addiction 
Psychiatry. Dr. Swift is Staff Psychiatrist at the VA Medical Center at Roger Williams Medical Center and at 
CAAS; he has extensive alcohol laboratory experience and contributed to the advancement of knowledge in 
the AUD research field through several selected publications23,70-86. Dr. Haass-Koffler and the RA will 
immediately call the study physician if any safety issues arise during or between sessions (i.e. CIWA score ≥7). 
Dr. Haass-Koffler has the support of Research Associates (RA) who have been trained in administering 
psychological assessments (i.e. CIWA, SCID, HAM-D/A), conducted similar alcohol and pharmacological 
studies for many years at Brown and included in our peer-review.  They also will collect blood, saliva and urine 
samples and monitor blood pressure and heart rate using a Dinamap Adult Vital Signs Monitor.  
 
METHODS  
Overview of Proposed Research. The design will be a randomized within, crossover, double-blind, placebo-
controlled human study with mifepristone in non-treatment-seeking alcohol-dependent individuals. The study 
will be conducted in two consecutive phases with one month washout period (Figure 1): Visit #1, Screening; 
Visit #2: randomization and drug/placebo dispensed; Visit #3: first lab-session: single dose of yohimbine; Visit 
#4: After one-month washout period (30 days, plus or minus two days to accommodate the schedule of 
the next visit), follow-up and drug/placebo dispensed; Visit #5: second lab-session, single dose of yohimbine, 
motivational session (MET); Visit #6: follow-up (one month). END of STUDY.  
Figure 1 – Study Design 
 
Medications and doses: Participants receive an oral dose of 600 mg of mifepristone or matching placebo for 
approximately seven days (plus three extra pills). Participants will receive detailed information on the study 
medications, including their current use and possible side effects. Mifepristone treatment in clinical setting has 
shown to be safe, tolerable, and acceptable87-89, including in participants suffering from depression, anxiety, 
and PTSD90-92. On Days 7 and 44, all participants will receive a single oral dose of 32.4 mg yohimbine 
approximately one hour (tmax=1 hour) prior to the lab session. The oral dose of yohimbine for this study is 
based on prior studies in which yohimbine was administered to examine neuroendocrine probe in human 
studies57,93,94. Ample data support the safe use of yohimbine to induce craving in alcohol-dependent 
individuals57, and the safe induction of stress in PTSD veterans95 and gamblers60. We already obtained the 
Investigational New Drug (IND#121984) from FDA that determined that the clinical investigation of mifepristone 
and yohimbine while consuming alcohol is safe to proceed (see attaché letter form FDA). Our IND was also 
cross-referenced by the IND of Corcept Therapeutics (IND#059737) for chemistry, manufactory, 
pharmacological, and toxicology data of mifepristone (see attached letter form Corcept). Participants will 
receive detailed information on the study medications, including their current use and possible side effects. 
 


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STUDY PROCEDURES: 
Visit 1 (Screening). All procedures and responsibilities of each member of the research team are described in 
Appendix Z (page 1). Following a breath analyzer (BrAC) that must be 0.00, participants will then be assessed 
on demographics, medical history, physical examination, vital signs and ECG. Blood, urine, cortisol and clinical 
assessments are performed to screen individuals for inclusion/exclusion criteria and monitor adverse effects; 
we will collect a baseline salivary cortisol sample (three samples by spitting in a tube) and administer 
psychometric assessments. The salivary cortisol samples will be stored in Dr. Haass-Koffler’s lab. A study 
physician will administer the Brief Trauma Questionnaire (BTQ, Appendix J). After a study physician reviews 
and approves the medical history and lab results, the participants will be called with the results and scheduled 
for Visit 2.  When the RA or Dr. Haass-Koffler administers the SCID, Drs. Swift will review the SCID the 
screening day.  They will review the rest of the other blood, saliva and urine laboratory analysis before 
enrolling any participant in the study. Session will last approximately 3-4 hours. Randomization will be 
performed on Visit 2.  
 
Visit 2 (Randomization): All procedures and responsibilities of each member of the research team are 
described in Appendix Z (page 2). BrAC = 0.00 before initiating any procedure; participants in addition to the 
psychometric assessments (see complete list in Appendix Z) they will then be assessed for life trauma 
exposure. We will assess lifetime history of trauma exposure using Life Events (LEC) and Post Traumatic 
Stress Disorder (PTSD) (PCL) Checklists. The participants will then be randomized and we dispense the study 
medication (see Appendix Z). The overall descriptions of the measures and the specific questions and 
responses that may trigger a call to the licensed clinician are provided in the Protection of Human Subject 
section. Compensation: sessions will last approximately 3 hours, and subjects will receive $25 for participation. 
 
Visits 3 and 5 (Stress-induction and Alcohol Laboratory Session): All procedures and responsibilities of 
each member of the research team are described in Appendix Z (page 3 and 5). Participants will be instructed 
not to consume alcohol for 24 hours and must have a BrAC of 0.00 prior to any assessment. A sample of 
salivary cortisol will be collected and a single oral dose of 32.4 mg yohimbine will be administered to 
participants. The lab-session will begin one hour later in order to allow yohimbine to take effect96, at which time 
a second sample of cortisol will be collected. The CR will be run first, followed by the ASA (Assessments 
Schedule, Appendix Z). The PI will schedule Visit #3 and Visit #5 (alcohol laboratory sessions) only if Dr. Swift 
will be in proximity of CAAS laboratory.  The PI will not schedule Visit #3 and Visit #5 if both study physicians 
are traveling or not in Providence. 
Cue-reactivity (CR). The CR will be similar to previously published studies73,97-101. The entire procedure takes 
about 45 minutes. The water trial provides a controlled baseline that controls for all aspects of stimuli and 
movement, except for the nature of the beverage. Next, participants will undergo two 3-minute alcohol cue 
exposure trials that will be identical to the water trial except that the glass of water will be replaced with their 
preferred alcoholic beverage and the bottle of water will be replaced with the appropriate commercially-labeled 
alcohol bottle. After every 3-minute beverage exposure, participants will rate their urge to drink alcohol by 
completing the alcohol urge and craving questionnaire (ACQ) to assess attention to the sight and smell of 
water and alcohol cues. Saliva (weight in cotton rolls, mg), heart rate (HR; beats/min) and blood pressure 
(systolic, diastolic, and mean arterial pressure-MAP) will be monitored continuously using a Dinamap Adult 
Vital Signs Monitor. After the conclusion of the CR, participants will undergo the ASA. Consistent with 
recommendations102, participants will be informed they will receive alcohol following the CR. The last of 
salivary cortisol (by spitting in a tube) will be collected at the end of the CR. 
Alcohol Self-Administration (ASA). Participants are presented with a priming dose of alcohol designed to 
raise blood alcohol levels to 0.03 g/dl. Consistent with previous studies78,103,104, we will wait 40 minutes before 
presenting more alcohol. We will assess craving and whether stress-induced craving will modify responses to 
the priming drink using the ACQ. Stimulant and sedative effects of alcohol will be assessed using the Biphasic 
Alcohol Effects Scale (BAES)105. The ”free-choice” phase of the ASA lasts 120 min and the ACQ will be 


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administered every 30 min78,103,104,106. Each participant will get $3.00 per drink (max possible is $24), provided 
as an alternative reinforcer for not drinking. Each beverage is calculated to raise the blood alcohol levels by 
0.015g/dl. If the participant’s BrAC has reached 0.1, then the alcohol consumption period will stop. We will 
also collect multiple BrAC values in order to monitor the mifepristone effects on alcohol pharmacokinetic and 
pharmacodynamic levels. Participants wait until BrAC = 0.00 (repeated twice) before being discharged. At the 
end of Visit 5, a Motivational Enhancement Therapy (MET) will be performed to provide education about 
alcoholism and to explore participants’ desire to get treatment if they wish to receive it, and then we will 
assess at last follow-up to ascertain that drinking has not increased. 
Participants are strongly encouraged to remain in the lab until no longer intoxicated.  After the laboratory 
session, we will provide food and water and they can watch television.  If they want to leave, we will provide a 
taxi ride. 
Compensation: sessions will last approximately 6 hours, and subjects will receive $100 for participation plus 
another possible $3/drink as incentive for not drinking (max $24). 
 
Washout period: During the washout and follow up period (30 days, plus or minus two days to accommodate 
the schedule of the next visit) we will contact participants weekly by telephone to ensure that there are not 
unexpected side effects. We will alert the study physicians in the event of anxiety, depression and suicidality. 
We will also send a text reminder for the next visit (Visit #4 and Visit #6).  
 
Visits 4 and 6 (Follow-up): All procedures and responsibilities of each member of the research team are 
described in Appendix Z (page 4 and 6). After a one-month Washout period (30 days, plus or minus two days 
to accommodate the schedule of the next visit), participants will be asked to return for a follow-up and for 
dispensing of medication: mifepristone 600 mg/day or placebo for a week. The purpose of setting a month-
long follow-up is because mifepristone may have the potential to “reset” a dysregulated HPA axis. In this 
manner, we will assess if there is an enduring effect of mifepristone beyond when the drug is stopped. The 
follow-up after one month will exclude pharmacokinetic mechanisms and will assess if the mifepristone 
antagonism at GC-receptors is responsible for resetting the HPA axis feedback loop. Due to the distinct 
circadian rhythm of cortisol, we will schedule Visits 3 and 5 at the same time of day as Visit 1 in order to 
collect salivary samples to be measured both under natural (Visit 1) and induced-stress response (Visits 3 and 
5) conditions. At the follow-up visits, the participants will complete assessments, including a urine drug 
screening, as outlined in Appendix Z. As there is no medication or alcohol administration during the 
randomization (Visit #2), medication dispensing (Visit #2 and Visit #4), and follow-ups (Visit #4 and Visit #6), 
these visits may be conducted without the physical presence the of the study physicians in the CAAS 
laboratory, but preferably within the Providence area.  
. 
Compensation: sessions will last approximately 2 hours, and subjects will receive $25 for participation. 
 
Data analysis 
This study will represent the first intervention of mifepristone on yohimbine-induced alcohol craving and 
consumption in this population. As this is a safety and tolerability study, adverse events evaluation (AEE) will 
be reported as the number and their intensity. We will compare the number and intensity of AEE in the 
mifepristone vs. placebo groups weekly and during the alcohol laboratory sessions. These events will be rated 
as none, mild, moderate, and severe. Paired t-tests will be used to test for medication effects.  Generalized 
Estimating Equations (GEE) will be used for dichotomous data if events are rare. To guard against Type II 
errors, we will also report additional descriptive data on adverse events (the distribution of the maximum level 
of an adverse event collapsed across time points per condition). This study integrates self-reported and 
clinician-administered assessments with clinical laboratory analysis. A series of analyses of covariance 
(ANCOVA) will be conduct to test the effect of mifepristone on alcohol craving while controlling for variance 


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attributed to stress and anxiety level. The dependent variables will be baseline and post-laboratory session 
scores of Alcohol Urge and Craving Questionnaires (ACQ), Alcohol Visual Attention Scale (A-VAS) and 
Alcohol Attention Scale (AAS). The covariates will be trauma experienced as measured by Life Event 
Checklists (LEC), stress level measured by Perceived Stress Scale (PSS) and PTSD (PCL) Checklist scores, 
and anxiety level measured by Hamilton Anxiety Rating Scale (HAM-A), Self-Evaluation Questionnaire for state 
(STAI-y1) and Self-Evaluation Questionnaire for trait (STAI-y2). To examine the relationship between 
mifepristone compared to placebo on neuroendocrine fluctuations, we will use repeated measures ANCOVA 
with the cortisol baseline curve (three time-points: neutral, yohimbine challenge and after cue-reactivity) 
change during the laboratory sessions. Finally, to examine the effect of mifepristone compared to placebo in 
increasing the alcohol consumption during the alcohol self-administration, we will utilize an analysis of variance 
(ANOVA) with repeated measures. We will also attempt to establish an effect size for applying this paradigm 
on craving and drinking. These dependent measures will be operationalized by the ACQ and the ml of alcohol 
consumed during the drinking session, respectively. An effect size also will be obtained so that a target sample 
size to ensure adequate statistical power may be calculated for future proposed studies. Naturalistic drinking 
will be tracked via Alcohol Timeline Followback (TLFB) outside of the lab at each visit (by keeping track of the 
drinking behavior in the participants’ calendar). 
Alternative Design Considerations.  We considered (1) testing the stress-induced model by yohimbine in 
AUD populations before initiation of the mifepristone trial; however, yohimbine challenge demonstrated to (a) 
be safe57,60,93, (b) induce a robust cortisol response, (c) elevate alcohol craving correlated with alcoholism 
severity but (d) not anxiety57, demonstrating that yohimbine as a pharmacological challenge produces robust 
and reproducible responses that are well suited for medication development. Similarly, we considered (2) 
testing only mifepristone in AUD population; however, (a) this approach is already ongoing (NCT01548417) 
and our previous results47, aligned with other preclinical data52-54, showed that in conditions where stress is 
limited, mifepristone has modest effect on alcohol intake. In addition, we considered (3) inclusion criteria for 
women that were less stringent than our proposal by including women with childbearing potential willing to use 
double barrier methods of birth control; however, due to the FDA abortifacient indication of mifepristone, we 
opted for a more prudent approach that has been used by others (NCT01548417). We understand that the 
exclusion of pre-menopausal women in this study could be a source of variability in medication response since 
the age range for male and female participants could end up being different; therefore we considered (4) 
changing the age to 45-65. However, this approach would limit the field of participants, and furthermore, it will 
provide a source of variability in medication response in different age populations, which is a critical feature in 
AUDs 
 
 
PROTECTION OF HUMAN SUBJECTS  
The PI, Dr. Carolina Haass-Koffler, is a T32-funded postdoctoral fellow at CAAS. This study is an extension of 
her previous experimental pharmacology and preclinical work with mifepristone, yohimbine on alcoholism done 
at the Gallo Center at University California San Francisco (UCSF) before moving to the Center for Alcohol 
Addiction Studies (CAAS) at Brown.  She has previously tested these drugs with alcohol in preclinical models. 
To ensure participant safety, the investigator team includes well-established clinicians in the fields of 
experimental pharmacotherapeutic in alcohol laboratory studies, psychiatry and neuropsychopharmacology , to 
ensure safety and answer additional clinical questions that may arise during or between alcohol laboratory 
sessions. Research Assistant (RA) trained to administer psychological assessments (including SCID) or the PI 
(when completed her training at Butler Hospital) will assess the withdrawal syndrome by administering the 
CIWA (Appendix F). Self-report scales will provide the anxiety level by (STAY-y1/2, appendix R and S) and the 
stress level PSS (Appendix P) if there is need to call the study physician (Dr. Swift). Specific questions and 
responses during the psychological assessment that may trigger a call to the licensed clinician are included 
(page 13-15). When the RA or Dr. Haass-Koffler will administer the SCID, Dr. Swift will review the SCID the 
same day of screening.     


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Protections Against Risks: This human subject research meets the definition of Phase I Clinical Trial 
Research that has received an IND121984 from FDA to Dr. Haass-Koffler. This is a randomized within, 
crossover, double-blind, placebo-controlled human laboratory study with mifepristone (600 mg/ day for seven 
days) in a stress-induced condition triggered by yohimbine (32.4 mg, single dose) in non-treatment-seeking 
alcohol-dependent individuals. Participants will be recruited primarily through advertisements in the media. The 
participants will be 21 to 65 years (inclusive) in good physical health and competent to provide consent. 
Inclusion and Exclusion Criteria are outlined in Table 1. 
This study involves non-treatment-seeking alcohol-dependent individuals who are heavy drinkers but do not 
meet the threshold criteria for alcohol withdrawal (CIWA-Ar ≤7). This is first to ensure participants’ safety, and 
also because our study evaluates the neuroendocrine response to alcohol craving triggered by stress and 
anxiety-related negative emotions rather than withdrawal syndrome. If we identify individuals who meet the 
threshold criteria for clinically significant withdrawal syndrome during recruitment/eligibility process, we will 
follow a standard referral protocol (Potential Risks session, below), which includes calling the study physician 
(Dr. Swift). Regardless of eligibility, all screened participants will receive a local resource sheet of mental 
health and substance abuse services. Any unexpected ethical issues that arise with our study population will 
be discussed during weekly team meetings. Referrals and emergency protocols will be reviewed by mentors 
and Brown Research Protections Office (RPO)/Institutional Review Board (IRB).   
Recruitment and Informed Consent: Participants will be recruited through newspaper, TV and radio 
advertisements and screening efforts conducted at CAAS, Brown University, centrally located in Providence, 
Rhode Island. After routine screening involving telephone interviews and completion of a research initiated 
screening instrument, each participant will receive an explanation of the study protocol, its risks and potential 
benefits. In specific, each participant must acknowledge they understand that this is not a treatment study. 
Should participants want treatment, treatment program information will be provided. At baseline following a 
breath alcohol level (BrAC) = 0.00, participants will provide written informed consent that is approved by the 
Brown IRB/RPO. Following resolution of questions from interested participants, volunteers will be asked to 
read and initial each page of the informed consent, acknowledging their understanding of each page. An entire 
copy of the informed consent will be given to each participant. 
Participants will be enrolled based on inclusion and exclusion criteria (Table 1). Careful participant evaluation 
by trained staff will minimize the risk of including individuals with excluded medical and/or psychiatric 
conditions. The PI, Dr. Haass-Koffler will be responsible for administering the procedures described in the 
protocol. A RA, is also a phlebotomist, will be responsible for drawing blood, and collecting urine and salivary 
cortisol samples during the study. The risk of hematomas will be minimized by using single-use butterfly 
needles or BD vacuntaiers. Eligible volunteers will receive the Emergency card (Appendix T) for the study to 
keep in the wallet; they will be closely monitored during the entire study period. During the trial individuals’ 
substance use and psychiatric status will be monitored. Participants with positive BrAC levels or evidence of 
intoxication will be monitored until no longer intoxicated, or referred for appropriate treatment. Intoxicated 
individuals who drove to a visit and who refuse to stay for whatever reason will be sent home via taxi. 
Participants will be given a card (Appendix X) identifying themselves as participants in a research study, and 
containing emergency numbers of the PI and study physicians on call 24 hours a day. The blind will be broken 
if necessary for emergency assessment or treatment. Adverse events will be systematically evaluated and 
recorded. If adverse events are serious or intolerable, participants will be immediately withdrawn from the 
study and given treatment and or referral as the situation dictates.  Participants will be referred for treatment 
according to their needs and wishes if they show severe deterioration such as withdrawal syndrome (tremor, 
anxiety, and agitation) monitored by administering the CIWA (score ≥7 will call the study physician) (Appendix 
F), and continued evaluation of them will provide ongoing information concerning their clinical status. Given the 
nature of alcohol-dependent participants, we are aware that special consideration and safety precautions must 
be provided for our subjects. Our first precaution is the comprehensive assessment that we conduct on the 
subjects prior to initiating the study. Subjects are screened by interview, questionnaire, medical history, 
physical examination and laboratory testing to eliminate subjects with a personal history of current substance 
abuse or dependence or other psychiatric comorbidity whose symptomatology precludes participation in a 


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research study. A second precaution is the orientation to the procedures, conducted prior to the experimental 
sessions. Subjects will sit in the lab room and be acclimated to the blood pressure cuff. This will serve to 
diminish any anxiety and will identify subjects who are too anxious or paranoid to undergo subsequent testing, 
assessed by PSS (Appendix P) and STAY-y1/2 (Appendix R and S). A third precaution is the monitoring and 
medical backup present throughout the study. Finally, a follow-up visit will be performed at the end of the 
study. Finally, individuals should always carry their ID (appendix X) and Emergency card (Appendix T). 
Individuals will be referred for further evaluation and treatment should any medical or psychiatric conditions 
occur. 
Insuring Informed Consent and Comprehension: The Informed Consent Form will be written at 8th grade 
reading level. At the initial visit, participants will be provided with information about the study, its rationale, 
risks, and potential benefits. Participants will be informed that they are participating of their own free will and 
can withdraw their consent at any time during the study. Participants who elect to withdraw or are discontinued 
for any reason will be provided with information about places to receive treatment should they desire. All 
questions pertinent to the study raised by the potential subject will be answered before consent is requested. 
All participants will consent in writing.  The consent form will be dated and countersigned by a staff member. A 
copy of the consent form will be given to the subject, as is mandated by the Brown Institutional Review Board. 
The consent form will contain details of whom to contact in case of an adverse event, details of the principal 
investigator, and information on how to contact the Institutional Review Board to register a complaint. Another 
copy of the form will be kept on file. Participants who complete screening but who are not eligible for study 
inclusion will be provided with the self-help pamphlet on how to achieve alcohol cessation, as well as the 
address and telephone number of a local treatment center.   
Psychosocial assessments: This is a stress study; therefore, to minimize risks of assessments, participants 
who are distressed or who show clinical deterioration will be referred for further assessment or intervention as 
required. The baseline assessments can be conducted over more than one day if necessary to minimize 
participant fatigue.  These measures are utilized to establish clinical eligibility at screening and for 
safety during the course of the trial.   
 
- Structured Clinical Instrument for the Diagnostic and Statistical Manual of Mental Disorders-IV 
(SCID-I/P) is used for exclusion criteria such as current substance dependence (other than alcohol and 
nicotine), diagnosis of Major Depressive Disorder or anxiety disorder, schizophrenia, bipolar disorder, or 
other psychoses and life time of attempted suicide.   
 
- Clinical Institute Withdrawal Assessment Alcohol (CIWA) (please see Appendix F) is used to assess 
symptoms of alcohol withdrawal syndrome (Research studies require a score of <10 to participate, in this 
protocol we adopt a more conservative score, ≤7) and exclude potential participants who might 
experience withdrawal symptoms during the course of the study. This assessment is implemented at 
every session before initiating any procedure to ensure participants’ safety.   
Overall: For monitoring withdrawal syndrome.  
Specific questions and scores that will trigger a call to the study physician: 
#4 Anxiety: observation, moderately anxious (so anxiety is inferred), score >4 
#5 Agitation: observation, restless, Score >4 
#6 Tactile Disturbance: moderately, severe hallucinations, score >4 
#7 Auditory Disturbance:  moderately, severe hallucinations, score >4 
#8 Visual Disturbance:  moderately, severe hallucinations, score >4 
 
- Post traumatic Stress Disorder Check List (PCL) (please see Appendix H) 
Overall: To monitor stress. 
Specific questions: 
#9 Loss of interest in activities that you used to enjoy (so depression is inferred), score >4 
 
 


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- Perceived Stress Scale (PSS) (please see Appendix P) 
Overall: To monitor stress over ti13)me, we will adopt the Perceived Stress Scale (PSS) PSS-10 scores 
are obtained by reversing the scores on the four positive items, e.g., 0=4, 1=3, 2=2, etc. and then 
summing across all 10 items.  We will call the study physician with participants scoring >30.   
 
- Side Effects Report Form (please see Appendix Q) 
Specific questions and scores that will trigger a call to the study physician: 
#19 and 20 Restlessness and Nervousness (so anxiety is inferred), score >3 
 
- Drinking Inventory consequences, (DrInC) (please see Appendix L) 
Specific questions and scores that will trigger a call to the study physician: 
#34 I have lost interest in activities because of my drinking (so depression is inferred), score >3 
 
- Hamilton Anxiety and Depression Rating Scale (HAM-A; HAM-D) (please see Appendices O and O2) 
in addition to being utilized as research outcomes, in our proposed study, these measures are used to 
monitor participants’ anxiety and depression during the course of the trial. These assessments are critical 
to assess anxiety (HAM-A) — especially during yohimbine administration — and monitor for possible 
symptoms of depression that can lead to suicidality (HAM-D).  It is important to know the clinical state of 
each participant before initiating any procedure.  
Overall: To monitor for anxiety we will use the Hamilton Anxiety rating scale (HAM-A) and for depression 
we will use the Hamilton Depression Rating scale (HAM-D). Each item of the HAM-D is rated from 0 (not 
present) to 4 (severe) with a total score range from 0 to 56, where <17 (mild severity), 18-24 (mild to 
moderate) and 25-30 (moderate to severe). We will alert the study physician with a score of >24.   
Specific question in the HAM-D and score that will trigger a call to the study physician: 
#3 Suicide: Feel life is not worth living (so suicide may be considered), score >0 
 
- Self-Evaluation Questionnaire (STAI y1/2) (please see Appendix R and S) 
Overall: State-Trait Anxiety Inventory (STAI) -y1 and -y2, which are a commonly used measure of trait 
and state anxiety. The STAI has 40 items allocated to each of the State-anxiety and Trait-anxiety 
subscales.  Responses for the S-Anxiety scale assess intensity of current feelings “at this moment,” and 
the T-Anxiety scale assesses frequency of feelings “in general” from 1 (never) to 4 (always).  We will alert 
the study physician to a score of > 60 on each subscale.    
Specific question: 
#22 I feel nervous and restless (so anxiety is inferred), score >3 
 
NOTE - Suicidality: To assess the risk of suicidality we included the Suicide Assessment Five-Step Evaluation 
and Triage (Appendix K). It is a 5-step screening tool developed in collaboration with the Suicide Prevention 
Resource Center and Screening for Mental Health.  This assessment will be done by the study physician 
during screening (see Appendix Z for assessments schedule)..  Also, the HAM-D question # 3 is about suicide; 
if participants score >0 during the course of the trial, we will alert Dr. Swift iimmediately.  
 
Screening and Randomization: Potential participants will be screened by telephone using a standardized 
questionnaire, which includes alcohol use, personal medical/mental health history and the major 
inclusion/exclusion criteria for the study. Eligible participants will receive information of the logistics (duration, 
commitment, compensation, measures) and on the medications that will be administered in the study. 
Interested volunteers are asked to come for a comprehensive visit at CAAS. At screening, subjects must 
have their BrAC mesured (must be = 0.00), and  must be = 0.00 every time before initiating any 
procedure at every visit. During this visit, participants will be assessed using Inclusion/Exclusion criteria 
(Table 1), psychometric scales (Appendix Z), vital signs, ECG, blood (two tubes) and urine analysis; three 
samples of salivary cortisol will also be collected (by spitting tube) to measure cortisol level. All participants 


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will undergo careful medical and psychiatric assessment and must meet all inclusion and no exclusion criteria 
to qualify for this study.  
 
Table 1 – Inclusion and Exclusion Criteria 
Inclusion  
• Male or female, 21 to 65 years of age 
• Females must be postmenopausal for at least one year or surgically sterile (proven by medical record) 
• Meet criteria for Alcohol Use Disorders (AUD) DSM-5 diagnosis  
• Meet criteria for heavy drinking (≥35 drinks/week for men; ≥28 drinks/week for women)  
• Must be in good health as confirmed by medical history, physical examination, ECG, lab tests 
• Participants must be willing to take oral medication and adhere to the study procedures 
 
• Breath alcohol (BrAC) = 0.00 at each visit 
• Be able to understand informed consent and questionnaire in English at an 8th grade level 
Exclusion 
• Individuals expressing interest in treatment for alcoholism 
• Premenopausal women 
• Participants who have significant alcohol withdrawal symptoms, defined as a CIWA-Ar score ≥7  
• A repeated positive urine drug screen at baseline for any illegal substance except marijuana. 
• Individuals diagnosed with a current “severe” Substance Use Disorder (SUD) diagnosis, other than alcohol 
or nicotine 
• Meet DSM-5 criteria for a diagnosis of schizophrenia, bipolar disorder, or other psychoses 
• An active illness within the past six months of the screening visit that meets the DSM-5 criteria for a 
diagnosis of Major Depressive Disorder (MDD) or Anxiety Disorder, or history of attempted suicide 
• Clinically significant medical abnormalities: unstable hypertension, clinically significant abnormal ECG, 
bilirubin >150% of the upper normal limit, ALT/AST >300% the UNL, creatinine clearance ≤60 dl/min 
• Current use of psychotropic medications that may have an effect on alcohol consumption 
• Current use of any medication involved in the metabolism of alcohol such as aldehyde dehydrogenase 
(ALDH), alcohol dehydrogenase (ADH) and CYP2E1: Cefamandole, Cefotetan, Sulfamethoxazole, 
Nitroglycerin, Chlorpropamide, Glyburide. 
• Current use of any medication (CYP3A4 inhibitor and substrate) that may interact with mifepristone:  
cyclosporine, fentanyl, heparin, escitalopram, lovastatin, simvastatin, warfarin 
• Current use of any medication (CYP2D6 inhibitor and substrate) that may interact with yohimbine: 
amitriptyline, doxepin, nortriptyline, venlafaxine 
• Medical contraindications for use of mifepristone or yohimbine  
• A history of adverse reaction or hypersensitivity to mifepristone or yohimbine 
• History of suicide 
• History of seizure disorders 
• Hypokalemia (low potassium level)<3.5mEq/L 
• Participated in any behavioral and/or pharmacological study within the past 30 days 
• Neuroendocrine disorders 
• Taking corticosteroids 
• Bleeding disorders 
• Pre-existing QT prolongation on ECG 
• History of porphyria (Mifepristone progesterone receptor antagonist is an inducer of CYP-450 and 
therefore may have the ability to precipitate or exacerbate attacks of acute porphyria)  
• Not willing to engage in protected sex (condom). This risk includes both women and men. Mifepristone 
long half-life (t1/2 = 18 hrs) and its three main metabolites retain considerable affinity toward human 
progesterone and glucocorticoid receptors, with serum level similar to the parent mifepristone and there 


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are no studies on the presence of mifepristone or metabolites in semen 
 
Sources of materials: Research data include: interviews, self-reported and clinician-administered 
questionnaires, breath, saliva, blood, and urine samples. All data will be gathered and obtained exclusively for 
research purposes. Cortisol and other data will be obtained by physical examination, clinical laboratory 
evaluation, and data from observation of participants by study staff during the visits. Standardized diagnostic 
and psychological assessments and the time of research staff responsibilities are described in Appendix 
Z. To evaluate safety and tolerability data, we will assess adverse events and they will be reported as the 
number and their intensity. To assess pharmacological intervention efficacy, we will gather quantitative data at 
baseline, between alcohol sessions, and one month post-intervention. Subject numbers will be entered to code 
all data. To ensure participants’ privacy, only authorized persons will have access to the data.  
 
Description of Potential Risks. Participants will be carefully screened at the beginning and closely monitored 
during the study procedures. Eligible individuals will be informed of each study procedure and the associated 
potential risks. Risks include distress during assessments, breach of confidentiality, issues related to coercion, 
and effects of alcohol withdrawal syndrome (including tremor, agitation, anxiety). 
Assessments and Breach of Confidentiality: There is always some risk that participants will be identified 
as participants in a study or that clinical assessments will involve questions on illegal behaviors, or will 
adversely affect participants’ well-being; while this does present a confidentiality risk, studies have been 
performed in the open public without evidence of participant harm. Inadvertent breach of confidentiality 
concerning drinking behavior is also a risk. All data will be used for research purposes only, and will not be 
revealed without the participant’s written consent. Data will be kept in a secure locked file in the locked 
study office. Data will be entered into a computer database at the study site, which is password protected 
involving only numerical identifications that can only be linked with subjects’ identification locked in a 
cabinet known only to the research staff. Access to data will be available only to investigators involved in 
the study. The research staff is trained in confidentiality procedures. As an additional layer of security, we will 
use a “Subject Number” from a Log and keep contact information in a separate locked location.  
We will apply for a Certificate of Confidentiality issued by the National Institutes of Health to protect 
identifiable research information from forced disclosure. The certificate will allow those of us who have 
access to research records to refuse to disclose identifying information on research participants in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By 
protecting us and Brown University from being compelled to disclose information that would identify 
research subjects. A Certificate of Confidentiality helps achieve the research objectives and promote 
participation in studies by helping to assure confidentiality and privacy to our participants. 
Coercion: Risks of coercion are minimized by having participation payments be reasonable for the amount 
of time and effort required and comparable to other studies in this area. The likelihood of financial coercion 
is low because the compensation is commensurate with the amount of time and effort required for this 
study. There will be no cost(s) to participate in this study. The study medications and all procedures that are 
not part of routine care, but are required for the study, will be provided to the participant.  If eligible for the study, 
participants will receive $25 for the randomization visit (Visit# 2) and for the follow-up visits (Visits #4 and 
#6). During the laboratory phase, at each visit (Visits #3 and #5) participants are compensated $100 + 
another possible $3/drink as incentive for not drinking (max $24). Therefore, each participant may be 
compensated up to $323 during the entire study period. Participant will be also compensated for their travel 
costs. Participation fees and tasportation expenses will have been approved by the Brown University IRB. 
There will be no other inducements. 
 
Alcohol withdrawal: Since participants must have BrAC = 0.00 before initiating any procedure, there is risk 
of withdrawal syndrome. Our experience across numerous alcohol studies suggests that the risks for 
withdrawal from alcohol are minimal in this study as any potential participant with a CIWA ≥7 or having 


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significant hepatic dysfunction (by blood laboratory analysis) will be excluded during screening. As a result 
of our screening we can recruit people who drink enough to qualify for this study yet don’t drink at a level 
that would potentially put them at risk for withdrawal. Alcohol craving following yohimbine administrations 
are reported to be modest, but significantly higher than placebo, however with not increased anxiety ratings. 
Alcohol craving will be monitored by psychometric scales. However, it is still possible that some participants 
may experience some withdrawal symptoms if they stop or reduce their drinking on their own. These 
symptoms may become severe enough to require hospitalization in order to be managed safely. Again, any 
participant with a CIWA score ≥7(agitation, tremor, sweats) at any time will be excluded from the study and 
immediately referred for medical attention at a Hospital Emergency Room or mental health clinic. 
Compliance: We will use a modified Medical Management (MM) used by the COMBINE study that has been 
revised and tailored for this study107.The use of these components of MM in this study is aimed to facilitate 
participant adherence to pharmacotherapy. Sessions are conducted by trained research staff.. We will be 
dispensing the medication or placebo in blister packs to facilitate compliance. The initial session will be 30-
45 minutes in order to establish rapport and will include a discussion of how the medications work, 
discussion of potential side effects and what to do about them, and a motivational interviewing-oriented 
discussion related to medication adherence, including the participant’s experience with medications 
compliance, when and why they might miss doses, and what mechanisms could be useful to enhance 
medication adherence. Another important part of the MM is the focus on alcohol-related medical problems 
(such as liver panel exam).  
Medications and Drug-Drug Interactions: Corcept Therapeutics will provide mifepristone (600 mg, for seven 
days plus three extra day doses) or matching placebo. Participants will receive a blister pack containing 10 
capsules of mifepristone or placebo (7 days + three extra doses). Participants will return for the first follow-up 
visit and they will receive the additional blister pack. Bayview pharmacy will provide yohimbine (32.4 mg) 
formulated in a single capsule that will be administered at CAAS under team supervision prior to the alcohol 
laboratory session. Risks of medication side effects will be minimized through careful and detailed screening of 
participants by the PI (Dr. Haass-Koffler) to minimize recruitment of those who might be at higher risk for 
adverse events, as well as careful and detailed monitoring of adverse events and participant well-being during 
the study.  
Mifepristone: Since mifepristone is a FDA-approved oral medication for the termination of early pregnancy, 
we will exclude women with childbearing potential regarding the birth control methods used. The following 
complications or risks have been reported, are known, or may occur with mifepristone: the most commonly 
reported side effects associated with the use of mifepristone include: abdominal or stomach pain, back pain, 
diarrhea, dizziness, headache, nausea or vomiting. Other less common side effects associated with the use 
of mifepristone include: cough, fainting, fever, heartburn, indigestion, lack of strength, or stomach 
discomfort. Rare side effects associated with the use of mifepristone include: sleepiness, pain during sexual 
intercourse, pale skin, shaking chills, shortness of breath, stuffy or runny nose, and unusual bleeding or 
bruising. Mifepristone may cause low blood potassium (hypokalemia); symptoms may include muscle 
weakness, aches, or cramps, or abnormal palpitations. Subjects with low potassium levels at screening will 
be excluded. In eligible participants, hypokalemic symptoms will be monitored during the entire study. 
Mifepristone progesterone receptor antagonist is an inducer of CYP-450 and therefore may have the ability 
to precipitate or exacerbate attacks of acute porphyria (exclusion criteria).  
Because mifepristone has been used safely for termination of early pregnancy by the FDA since September 
2000 at doses of 600 mg (single dose), we considered mifepristone titration in our study (one week therapy); 
however, mifepristone has been used at 600 mg dose in other clinical research studies and is currently 
being evaluated by Corcept Therapeutics in conducting studies using a similar dose including: control of 
hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome who have type 
2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery. 
Additionally, Corcept Therapeutics is engaged in the discovery, development and commercialization of 
drugs for severe metabolic, psychiatric and oncologic disorders. Current trials include: Metastatic Triple 
Negative Breast Cancer (phase I), A Study of Mifepristone vs. Placebo for individuals With Major 


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Depression With Psychotic Features (phase III) and Mifepristone in Children With Refractory Cushing's 
Disease in collaboration with National Institute of Child Health and Human Development.  
It will be stated clearly in the consent form and to the participants verbally, that participants must engage in 
protected sex (i.e. wear a condom). This risk includes men and women. Mifepristone has a long half-life (t1/2 
= 18 hrs); its three main metabolites retain considerable affinity toward human progesterone and 
glucocorticoid receptors, with serum levels similar to the parent mifepristone and there are no studies on the 
presence of mifepristone or metabolites in semen. This will be clearly spelled out in the consent form 
document 
Yohimbine: The oral dose of yohimbine for this study is based on prior studies in which yohimbine was 
administered to examine neuroendocrine probe in human studies. Ample data support the safe use of 
yohimbine to induce craving in alcohol-dependent individuals, and the safe induction of stress in PTSD 
veterans and gamblers. In this study, yohimbine (32.4mg) is administered below the therapeutic index to a 
dose considered dangerous (>100mg). Furthermore, yohimbine will be administered only once, during the 
laboratory session and under direct supervision of the study personnel. It will be given at a safety-tested 
dose to increase noradrenergic activity already being evaluated in psychiatric individuals with clinically 
relevant stress conditions such as PTSD, anxiety, and depression. Finally, yohimbine’s short half-life (t1/2 = 
1-2 hour) provides a transient effect. The protocol includes close monitoring of blood pressure, heart rate, 
and cortisol levels by Dr. Haass-Koffler or research laboratory staff, and we have Dr. Swift on call. In 
addition, the Hamilton Anxiety Rating Scale (HAM-A) (Appendix O), Self-Evaluation Questionnaire for state 
(STAI-y1) and Self-Evaluation Questionnaire for trait (STAI-y2) (Appendix R and S) to assess and compare 
anxiety at baseline and prior to releasing the participants after laboratory session are included in the 
assessments (Appendix Z). If anxiety is higher at the end of the study we will call Dr. Swift to have him 
meet with the participant before release. The most common side effects reported by the use of yohimbine 
are:  an allergic reaction, irregular or fast heartbeat, confusion, dizziness, anxiety, irritability, or nervousness, 
tremor, headache, skin flushing. 
Drug-drug interactions: To reduce risk of drug-drug interactions, participants will be instructed to call our 
study team before taking any new prescription or over-the-counter medication. Participants will be asked to 
avoid taking medications that could interact with mifepristone and yohimbine. A wallet card identifying 
themselves as participants in a study receiving mifepristone and yohimbine (single dose) will be provided. 
This card will also contain the contact numbers of our study team, including emergency numbers of the PI 
and study physicians on call 24 hours a day (Appendix X). Participants will be asked to carry this card that 
will, in case of emergency, alert the medical personnel treating the participants that they may be taking 
mifepristone. This card, which should be kept at all times, will also include appropriate drug information and 
precautions.  
As this project is guided by Dr. Haass-Koffler’s neuroscience pre-clinical work, she did not observe any two-
way drug interactions in preclinical models when administering the combination of mifepristone 
(systematically and by brain microinfusion into the central nucleus of the amygdala) and yohimbine47. 
Moreover, pharmacokinetically, yohimbine and mifepristone do not share liver microsome metabolic 
pathways; yohimbine is metabolized by CYP2D6, and mifepristone via CYP3A4. In Dr. Haass-Koffler’s 
preclinical models, she did not observe any three-way drug interactions when administering the 
combination of mifepristone, yohimbine, and alcohol. The primary enzymes involved in the metabolism of 
alcohol 
are 
aldehyde 
dehydrogenase 
(ALDH), 
alcohol 
dehydrogenase 
(ADH) 
and 
CYP2E1. 
Pharmacodynamically, both mifepristone and yohimbine do not show the CNS depressant properties of 
alcohol and we should not expect increased sedation or depression of respiratory and/or cardiac functions. 
Dr Haass-Koffler has pharmacy background and they will include: 1) a search using Lexicomp, and 2) 
systematic symptom monitoring of drug-drug interactions between yohimbine, mifepristone and alcohol. 
While we recognize that both drugs, as well as alcohol, have indirect adverse effects, we note that Dr. Swift 
have experience in administering multiple drugs (aripiprazole with topiramate at clinical doses) and alcohol. 
Their experience suggests that without direct interactions, the side effects from both drugs may be broader 
but not additive with each other. Finally, we have already obtained the Investigational New Drug 


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(IND#121984) from FDA that determined that the clinical investigation of mifepristone and yohimbine while 
consuming alcohol is safe to proceed. In addition, our IND was cross-referenced by the IND of Corcept 
Therapeutics (IND#059737) for chemistry, manufactory, pharmacological, and toxicology data of 
mifepristone. Participants will receive detailed information on the study medication, including its current use 
and possible side effects. 
The following medications are contraindicated with mifepristone: antithrombin alfa, antithrombin iii, 
argatroban, aspirin, bemiparin, bivalirudin, budesonide, cisapride, clobetasone, cortisone, cyclosporine, 
dabigatran, dalteparin, deflazacort, dexamethasone, dihydroergotamine, dronedarone, enoxaparin, 
ergotamine, fentanyl, fludrocortisone, fondaparinux, heparin, hydrocortisone, lepirudin, lovastatin, 
methylprednisolone, phenindionem, pimozide, prednisolone, prednisone, protamine, quinidine, simvastatin, 
sirolimus, tacrolimus, thioridazine, tinzaparin, triamcinolone, warfarin. 
The following medications are contraindicated with yohimbine: amitriptyline, doxepin, nortriptyline, 
venlafaxine 
The 
following 
medications 
are 
contraindicated 
with 
alcohol: 
cefamandole, 
cefotetan, 
sulfamethoxazole, nitroglycerin, chlorpropamide, glyburide. 
The most common medications are listed in the emergency card and in the consent form.   
Drug Storage and Accountability. The investigator will ensure that all study drugs are stored in a secured 
area under recommended storage conditions and in accordance with applicable state regulatory requirements 
in a locked closet in a room accessible only by a card-activated lock.    
Mifepristone and yohimbine administration: The use of mifepristone and yohimbine in these studies will be 
under FDA-approval via IND#121984 (Dr. Haass-Koffler is the IND holder). Only healthy individuals will be 
eligible for enrollment. Medications will be prepared by Bayview Pharmacy. Females with childbearing potential 
are excluded regardless of the birth control method adopted, unless the woman has had a surgical sterilization. 
Participants will be monitored by Dr. Haass-Koffler or research laboratory staff for symptoms of adrenal 
insufficiency (weakness, nausea, fatigue, and hypotension) that may result by mifepristone administration and 
increasing BP and HR that may result from the adrenergic effect of yohimbine.  Dr. Swift will be alerted 
immediately if any adverse effect arises during the entire study duration. Dr. Swift will determine if a participant 
is in need of hospitalization or other mental health intervention.  
Alcohol Cue-reactivity (CR) and Alcohol Self-Administration (ASA) Sessions: The PI will schedule Visit 
#3 and Visit #5 (alcohol laboratory sessions) only if Dr. Swift will be in proximity of CAAS laboratory.  The PI 
will not schedule Visit #3 and Visit #5 if both study physicians are traveling or not in Providence. To assess for 
medical/psychiatric conditions requiring an intervention, all participants will be evaluated at the end of each 
laboratory session and at follow-up visits. Individuals will be referred for further evaluation and treatment 
should any medical/psychiatric conditions occur. Participants are selected for the study and monitored carefully 
throughout the alcohol laboratory session; should a participant display an adverse effect, Dr. Swift will be 
called immediately. Dr. Swift will determine if a participant is in need of hospitalization or other mental health 
intervention.  
 
Adverse Events 
We included the list of side effects and occurrence associated with the two study drugs administered 
separately.    
Side effects and occurrence with study medications 
Mifepristone 
Yohimbine 
Abdominal pain, cramping (96%) 
Uterine cramping (83%) 
Nausea (43-61%) 
Headache (2-31%) 
Vomiting (1-26%) 
Anxiety 
Irritability 
Headache 
Sweating 
Nausea 


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Diarrhea (12-20%) 
Dizziness (1-12%) 
Fatigue (48%) 
Nausea (48%) 
Headache (44%) 
Endometrial hypertrophy (38%) 
Hypokalemia (34%) 
Arthralgia (30%) 
Vomiting (26%) 
Peripheral edema (26%) 
Hypertension (24%) 
Dizziness (22%) 
Decreased appetite (20%) 
Abnormal thyroid test (18%) 
Xerostomia (18%) 
Back Pain (16%) 
Dyspnea (16%) 
Myalgia (14%) 
Pain (14%) 
Sinusitis (14%) 
Nasopharyngitis (12%) 
Extremity pain (12%) 
Diarrhea (12%) 
Tachycardia 
Priapism 
Worsening of panic attack 
 
The frequency not defined 
 
Adverse Effects: Adverse events (AEs) will be recorded and tracked for this protocol and will be reported to 
Brown University IRB and FDA.  At the follow-up visit, AEs will be recorded and followed to resolution only if 
they are serious or unexpected, or if the study physician assesses them to be clinically significant. In 
accordance with FDA reporting requirements, all AEs occurring during the course of the study will be collected, 
documented, and reported by the investigators. The occurrence of AEs will be assessed starting on the day of 
randomization. 
Unexpected Adverse Events: An unexpected AE is one that is not described with respect to nature, severity, 
or frequency in the current protocol. 
Serious Adverse Events (SAEs): Each adverse event or reaction will be classified by a study physician as 
being serious or non-serious. Based on the seriousness of the adverse event or reaction, appropriate reporting 
procedures will be followed. The Code of Federal Regulations Title 21 part 312.32 and International 
Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, ICH-E2A March 1995, as implemented by the U.S. Food and Drug 
Administration, defines a SAE or serious adverse drug experience as any untoward medical occurrence at any 
dose that: 
• results in death 
• is life-threatening;  (NOTE: The term "life-threatening" in the definition of "serious" refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• requires hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity; or 
• is a congenital anomaly/birth defect 
In addition, important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug reaction, when based on appropriate medical 


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judgment that may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in the above definition.  If a study subject withdraws from the study or if an investigator 
decides to discontinue the subject from the study because of an SAE (assessed by the Side Effect 
Reporting Form (Appendix Q), the subject must have appropriate follow-up medical monitoring including, if 
necessary, hospitalization. The research laboratory staff will continue to monitor by contacting the 
participant (phone) until the problem prompting hospitalization has been resolved or stabilized with no 
further change expected or is discovered to be clearly unrelated to study medication or progresses to death. 
Unexpected and Serious Adverse Events Reporting: Any Unexpected or SAE, including death due to any 
cause, which occurs to any subject from the time of admission through discharge whether or not related to the 
investigational product, will be reported within 24 hours of knowledge of the event to our local IRB and to the 
Project Officer of this project via fax or phone call. 
Detailed written documentation for all SAEs/unexpected AEs will be submitted within seven (7) days to our 
Brown IRB. Required documents that must be submitted include the following information: 
• title of protocol 
• description of the unanticipated adverse event 
• a determination of whether the event was related to the research study 
• name of the drug 
• where and when the event occurred 
• to whom else the event has been reported 
Upon receipt of a notification of an unanticipated adverse event or death, the IRB will determine whether 
further investigation of the event is required. Depending on the circumstances, the investigator may be 
required to suspend the study pending the outcome of an IRB review. Also, the IRB may require modification of 
the risks section of the consent form. These documents may be submitted by facsimile, as e-mail attachments, 
or via overnight courier.  
Reporting to FDA: In agreement with the IND regulations, the investigators will report SAEs/Unexpected AEs 
to the FDA as well as the Program Officer at NIAAA: 
• in 7 days if the SAE is unexpected, life-threatening or lethal, and at least possibly related to the 
investigational product, with a follow-up written report 8 days later 
• in 15 days if the SAE is unexpected, but not immediately life-threatening 
• in an annual report in all other cases 
Follow-Up of All AEs/SAEs: All adverse medical events must be followed until they are resolved, or until all 
attempts to determine the resolution of the AE/SAE are exhausted.  All outcomes and information regarding 
whether or not the subject was referred to their Primary Care Provider for additional follow-up must be 
recorded in the source document. Any SAEs and/or unexpected AEs among study participants during the 
follow-up period will be reported within 24 hours of knowledge of the event to the FDA, to our local IRB and to 
the Project Officer of this project via fax or phone call. All follow-up AEs will be recorded and followed to 
resolution only if they are serious, or if the study physician assesses them to be clinically significant. 
Periodic Review of the Safety Data: Drs. Haass-Koffler and Swift will meet prior to the enrollment of the first 
subject to review the research protocol, informed consent documents and plans for safety and data monitoring 
of the study. This review will determine the risks and benefits to research subjects, protection and safety of the 
subjects and offer suggestions for improving the study design. Moreover, Drs. Haass-Koffler and Swift will 
meet in a regular basis during the duration of the study. These meetings will take place every 10 weeks for the 
entire duration of the study. ‘Ad hoc’ and/or emergency meetings will take place if needed for specific and/or 
safety reasons. Minutes of these meetings will be taken and filed in the regulatory binder of this project. The 
goals of these meetings will be to: 
(1) determine adherence to research plan 
(2) review interim analysis, if applicable, and determine specific data to be analyzed 


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(3) evaluate end point/stop point rules 
(4) review protocol violations and deviations to assess adequacy of study 
(5) ensure documentation of informed consent 
(6) enrollment (followed eligibility criteria, enrollment numbers, visit compliance, screening failure information) 
(7) discuss investigator or key personnel changes 
(8) review completeness and quality of data collection forms, vital signs, clinical tests, and confidentiality 
(9) evaluate the aggregate analysis of adverse events/serious adverse events 
The major outcomes following data review include: 
(1) continuing the trial unchanged 
(2) modifying the protocol and/or consent form 
(3) terminating the study 
If the protocol and/or consent form should be changed, or the study should be terminated, Dr. Haass-Koffler 
will be responsible for all the necessary communications with the Project Officer, the FDA and the Brown 
University IRB.  
Potential Benefits of Proposed Research: There are no benefits of participating in this study. The level of 
risks and potential side effects are outweighed by the potential for benefits to be gained. However, we believe 
that the risk-benefit ratio justifies the conduct of this study, given the magnitude of alcohol dependence and the 
need to identify novel targets for alcoholism. 
Importance of the Knowledge to be Gained:  Alcohol abuse and dependence is a major public health 
problem for which treatment options are limited. This study provides an opportunity to explore a novel pathway 
that could represent a target for possible pharmacological approaches able to help problem drinkers to reduce 
or stop their alcohol consumption. On this point, this study provides much needed data necessary for potential 
future clinical trials testing other new possible compounds (glucocorticoid-receptor antagonists). 
 
Inclusion of Women and Minorities 
Women will be encouraged to participate in this research. Our experience is that between 29% and 33% of 
alcoholics in our research centers are women and that about 36% of subjects who enrol in similar studies are 
women. However, due to the FDA abortifacient indication of mifepristone, women with childbearing potential 
will be excluded regardless of the birth control methods adopted. Based on Dr Swift’s alcohol studies, between 
15% and 33% of the women enrolled are postmenopausal or surgically sterile; therefore, we expect about 24% 
of those enrolled in our study to be women. We will attempt to target women for recruitment by advertising in 
the women’s health section of the major state newspaper as well as sections that focus on women’s health in 
local newspapers and magazines.  In our radio ads we will target women and women of color who are typically 
underrepresented in studies of alcoholism. 
All ethnic and minority groups will be welcome to participate. Our experience suggests that involvement in 
studies reflects the most recent (2009) Rhode Island demographics with about 2.7% of participants Asian, 
5.5% African-American and about 11.4% Hispanic. That said, the Hispanic population makes up 36% of the 
Providence area; therefore, we will aim to enroll a greater amount than 11.4% Hispanic individuals. We will 
attempt to target minorities for recruitment by advertising in local newspapers in cities with significant minority 
populations.   
 
Inclusion of Children  
As this is an alcohol study, children are ineligible for enrollment. 
 


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SAP_001.pdf: 
 
 
 
Center Alcohol and Addiction Studies 
Brown University 
 
 
TITLE: A Pilot Study on the safety and efficacy of Mifepristone for the prevention of relapses of alcohol 
drinking 
PI: Carolina L. Haass-Koffler   
NCT02243709 
IND121984 
DATE: December 15 2014 
 
 
 
 


Statistical analysis  
Distributional characteristics of outcome measures were examined to evaluate similarity to the normal 
distribution, detailed descriptive analysis of demographics, substance use, and clinical characteristics 
were conducted. Comparisons with these characteristics, in relation to enrolled versus completer 
status, were performed using t-tests to analyze continuous variables (e.g., age) and Chi square (χ2) for 
categorical variables (e.g., sex, race, smoking status). Attrition rates between the screening visit and 
follow-up visit were examined descriptively to assess for potential bias. In addition, a logistic regression 
was performed to test for possible bias due to period (A/B: placebo first, then mifepristone and B/A: 
mifepristone first, then placebo) or medication carryover (1: placebo and 2: mifepristone), as done in 
our prior cross-over trial1. 
Primary outcomes: safety and tolerability of oral administration of mifepristone was assessed 
after 7 days in outpatient setting, and when it was administered with yohimbine and alcohol during the 
laboratory paradigms. These analyses included comparing the number of adverse events (AEs) 
between the mifepristone and placebo condition via a χ2 test. The results were presented using 
summary statistics such as number of subjects (n); mean (M); standard deviation (SEM) or frequency 
distributions (%).  
Primary outcomes: safety and tolerability assessed by the number of adverse events (AEs) of 
oral administration of mifepristone was assessed after 7 days in an outpatient setting, and when it was 
administered with yohimbine and alcohol during the laboratory paradigms. Additional safety and 
tolerability analysis included hemodynamic response, alcohol pharmacokinetics, and subjective effects 
of alcohol between the mifepristone and placebo condition (χ2 test). 
Secondary outcomes: Craving measures included alcohol craving questionnaire short form-
revised (ACQ-SF-R)2. Values of the water trials for each dependent variable were inserted as covariate 
in the model (allowed for the dependent variable to be specific for alcohol), time coded: t1=alcohol trial 
1 and t2=alcohol trial 2. In the bar laboratory, alcohol consumption was measured by number of drinks 
consumed (t-test). In the outpatient setting, alcohol consumption was measured by self-report using 
the timeline follow back method, reported as heavy drinking days and drinks per week.  
All statistical analysis was performed after participants had their follow-up visit and the study 
database had been locked. All the statistical procedures were performed by IBM SPSS Statistics for 
Windows, version 27 with Macro MEMORE extension9 (IBM Corp., Armonk, NY, USA) and GraphPad 
Prism (v.5) was used to generate figures (La Jolla, CA, USA). The effect sizes were calculated as դ2 
for GLM and Cohen d for t-test. All statistical tests were two-tailed, and statistical significance was 
accepted if an alpha value p<.05 was obtained. 
For all outcomes, we utilized an intention-to-treat (ITT) approach, where participants were examined 
based on their a priori randomized protocol and received at least one dose of the study medication 


(mifepristone or placebo)3. All analyses were conducted using Generalized Estimating Equations 
(GEE)4 with robust standard errors, and an unstructured correlation matrix, unless noted.  
 
Power  
This was a proof-of-concept trial to demonstrate the feasibility of the combined study design, the safety 
and tolerability of mifepristone and yohimbine while consuming alcohol, and the potential value of 
testing mifepristone in an appropriately-powered larger RCT. In selecting a target sample size, we 
balanced power considerations and feasibility given the translational nature of this trial. Because of the 
within-subjects design, power to test the effects of study drug is optimized for this modest sample size 
(originally N=20 then, after additional funding, increased to N=32). For the safety and tolerability 
outcomes (primary) adverse events difference was detected based on a judgement concerning the 
minimal effect which has clinical relevance in the management of patients. In a noninferiority trial, the 
exact sample size cannot be fixed in advance because it depends upon the chosen stopping guideline5.  
All statistical analysis was performed after participants had their follow-up visit and the study 
database locked. All the statistical procedures were performed by IBM SPSS Statistics for Windows, 
version 27 with Macro MEMORE extension (IBM Corp., Armonk, NY, USA) and GraphPad Prism (v.5) 
was used to generate figures (La Jolla, CA, USA). All statistical tests were two-tailed, and statistical 
significance was accepted if an  value p<.05 was obtained.  
 
1. 
Haass-Koffler CL, Perciballi R, Magill M, et al. An inpatient human laboratory study assessing 
the safety and tolerability, pharmacokinetics, and biobehavioral effect of GET 73 when co-administered 
with alcohol in individuals with alcohol use disorder. Psychopharmacology (Berl). Nov 3 
2021;doi:10.1007/s00213-021-06008-1 
2. 
Singleton E. Alcohol craving questionnaire, short-form (revised; ACQ-SF-R): background, 
scoring, and administration. Baltimore, MD, USA. 1995; 
3. 
Schulz K, Altman D, Moher D. Consolidated Standards of Reporting Trials Group CONSORT 
2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. Bmj. 
2010;340:c332.  
4. 
Zeger SL, Liang K-Y. Longitudinal data analysis for discrete and continuous outcomes. 
Biometrics. 1986:121-130.  
5. 
U.S. Department of Health and Human Services FDA. Guidance for Industry, E9 Statistical 
Principles for Clinical Trials. Center for Drug Evaluation and Research (CDER) CfBEaRC; 1998. E9. 
1998. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm0731
37.pdf