Clinical trial NCT00585780
Conditions: Alcohol Dependence
Sponsor: Yale University
Start date: 2009-09-01; Completion date: 2019-05-13
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To test the preliminary efficacy of 16.0 mg of Prazosin daily versus placebo in treatment seeking alcohol dependent individuals. This proposal is a laboratory and treatment outcome study to examine the effects of Prazosin on brief exposure to stress, drug cues and neutral situations on alcohol and drug craving, mood and neurobiological reactivity in a sample of cocaine and/or alcohol dependent individuals. Prazosin will be beneficial for reduction in stress and alcohol cue induced craving and related arousal. In a sample of treatment-seeking alcohol dependent men and women, we propose to examine (a) differences in measures of alcohol craving, emotion state, hypothalamic-pituitary-adrenal (HPA) activation, physiological arousal and plasma catecholamine response to stress imagery and to alcohol cue imagery as compared to neutral imagery; (b) reduction in alcohol abstinence symptoms; and (c) improvement in alcohol treatment outcomes as measured by reductions in heavy drinking days, any drinking days, secondarily on drinks/day, anxiety, mood and sleep.

Detailed description:
This is a proof-of-concept (POC) experimental therapeutics study with 2 arms. The first is a double-blind placebo controlled laboratory study with 40 individuals meeting current alcohol dependence criteria (DSM-IVTR) who are admitted to the Clinical Neuroscience Research Unit and initiated on Prazosin vs Placebo (16mg/day) after admission and initial detoxification (if required). Experimental laboratory sessions are conducted after subjects achieved full dose after the 2-week titration, in week 3-4 of inpatient stay. The laboratory outcomes included alcohol craving, anxiety, negative affect and neuroendocrine and sympathetic arousal measures. Individuals who wished to remain on study medication for the outpatient (Arm 2) were maintained on study medication throughout the outpatient phase for a total period of 12 weeks.

Arm 2 of the POC study is a 12-week randomized clinical trial (RCT) of Prazosin (16mg/day) versus Placebo in 100 treatment seeking alcohol dependent individuals, to assess whether high anxiety and distress, including alcohol craving, manifest as increased alcohol withdrawal symptoms at treatment entry moderates Prazosin effects on alcohol use outcomes. Primary alcohol use outcomes include heavy drinking days, any drinking days and secondarily drinks/day. Additional secondary outcomes include alcohol craving, anxiety and mood symptoms and sleep disturbances. Patients from Arm 1 who wished to continue on study medication for the outpatient phase were included in Arm 2. Arm 2 patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation.

Arms: arm 1: High AW was determined by those scoring at or above the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. High AW were randomized to Prazosin 16 mg/day (tid) administered for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner. arm 2: High AW was determined by those scoring at or above the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. High AW were randomized to Placebo tablets administered tid for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner. arm 3: Low AW was determined by those scoring below the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment. Low AW were randomized to Prazosin 16 mg/day (tid) administered for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner. arm 4: Low AW was determined by those scoring below the median on Clinical Institute of Withdrawal for Alcohol Revised (CIWA-Ar) assessment.Placebo tablets administered tid for 12 weeks with fish-bowl contingency management for weekly treatment attendance and manualized 12-Step relapse prevention counseling in a double blind manner.
Interventions: intervention 1: Prazosin Tablet intervention 2: Placebo Tablet
Intervention descriptions: intervention 1: Target medication dosing was three times/day (t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, followed by a 5-day taper in week 12, as in previous research.The titration schedule was as follows: 1 mg dose at bedtime for 2 nights, followed by a 1mg dose morning and night (8 AM/8 PM) on day 3, then 2 mg dose t.i.d., on days 4-6, 3 mg dose (2 pills each) morning and afternoon, and 4 mg dose (2 pills) at night for days 7-9, increased to 4 mg dosing t.i.d. on days 10-13, and from day 14 through week 11, 5 mg (1 pill) each in the morning and afternoon, and 6 mg for the night (2 pills) dose. This was followed by a 5-day taper in week 12. Patients were initiated on study medication upon presenting with a negative breathalyzer without any minimum pre-treatment alcohol abstinence period prior to medication initiation. intervention 2: Placebo tablets identical in appearance and dosing schedule as the active study medication was utilized

Protocol documents:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY 
 
                                  HUMAN INVESTIGATION COMMITTEE 
 
                                     Application to Involve Human Subjects in Biomedical Research 
100 FR1 (2013-1)  
 
 
 
 
SECTION I: ADMINISTRATIVE INFORMATION 
 
Title of Research Project:  
Prazosin to Reduce Stress-Induced Alcohol Craving and Relapse 
Principal Investigator: 
Rajita Sinha PhD 
Yale Academic Appointment: Professor 
Department: Psychiatry 
Campus Address: 2 Church Street South Suite 209 New Haven 
 
Campus Phone: 203-737-5805 
Fax: 203-737-1272 
E-mail: rajita.sinha@yale.edu 
Protocol Correspondent Name & Address (if different than PI):  
Julie Pinto, 2 Church Street South Suite 209, New Haven 
Campus Phone: 203-737-5489 
Fax: 203-737-1272 
E-mail: julie.pinto@yale.edu 
 
 
Investigator Interests: 
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.  
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI  
DATE STAMPED-RECEIVED 
PROTOCOL NUMBER 
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html  
Submit the original application and one (1) copy 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.   
HIC OFFICE USE ONLY 


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  Yes  
x No  
 
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol? 
  Yes  
x No  
 
 
 
If yes to either question above, list names of the investigator or responsible person: 
 
 
 
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the 
form:  http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center  
 
 Yale University PET Center 
     (MR-TAC)    
 
 
 
 
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU)  
 Yale Cancer Center/Smilow 
 
 
 YCCI/Keck Laboratories 
 Yale-New Haven Hospital  
 
 
 Yale-New Haven Hospital—Saint Raphael Campus 
 Cancer Data Repository/Tumor Registry 
 Specify Other Yale Location: 
 
 
 
 
 
b. External Location[s]: 
 APT Foundation, Inc. 
 
 
 
 Haskins Laboratories 
 Connecticut Mental Health Center 
 
 John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven 
 


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 Other Locations, Specify: Yale Stress Center, 2 Church Street South, Suite 209, New Haven 
 International Research Site (Specify location(s)): 
 
c. Additional Required Documents (check all that apply): 
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)  
Approval Date:  
*Pediatric Protocol Review Committee (PPRC) 
 
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC) 
 
Approval Date: 
 
*Dept. of Veterans Affairs, West Haven VA HSS 
 
Approval Date:  
*Radioactive Drug Research Committee (RDRC) 
 
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC) 
 
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) 
Approval Date:  
 YSM/YNHH Cancer Data Repository (CaDR)  
 
Approval Date:  
 Dept. of Lab Medicine request for services or specimens form 
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found 
at  http://radiology.yale.edu/research/ClinTrials.aspx) 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. April 2007 – June 2017 
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
   
 Single Center Study 
   
 Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes 
 
No 
 
  
 Coordinating Center/Data Management 
  
 Other:  
 
 
b. Study Phase 
 N/A 
    
 Pilot  
 Phase I 
 Phase II 
 Phase III 
 Phase IV 
    
 Other (Specify)  
 
 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c: 
 Clinical Research: Patient-Oriented 
   
 
 Clinical Research: Outcomes and  
 Clinical Research: Epidemiologic and Behavioral  
                 Health Services 
 Translational Research #1 (“Bench-to-Bedside”)      
 Interdisciplinary Research 
 Translational Research #2 (“Bedside-to-Community”)  
 Community-Based Research 
 
 
5.   Is this study a clinical trial? Yes 
 
No 
 


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NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events” 
  
If yes, where is it registered? 
  
 
Clinical Trials.gov registry 
 
  
 
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 
 
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used. 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx 
or  contact YCCI at 203.785.3482) 
 
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)?  
Yes 
 No
 
 
 
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study. 
 
Yes 
 No
 
If you answered "yes", this study will need to be set up in OnCore Support 
http://medicine.yale.edu/ymg/systems/ppm/index.aspx  
 
8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No X  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? 
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? 
  
c. Will a novel approach using existing equipment be applied? 
  
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol. 


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SECTION III: FUNDING, RESEARCH TEAM AND TRAINING 
 
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply. 
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).   
 
 
PI  
Title of Grant 
Name of Funding Source  
Funding 
Funding Mechanism 
 
Sinha, Rajita 
 
Prazosin to Decrease 
Alcohol Craving, 
Normalize Stress 
Dysregulation and 
Prevent Relapse 
 
NIAAA – 1R01-AA20504 
  Federal 
  State 
  Non Profit 
  Industry 
  Other For 
Profit  
  Other 
 
Grant- 1 R01 AA 20504-03   
Contract#  
Contract Pending 
  Investigator/Department 
Initiated 
  Sponsor Initiated 
  Other, Specify: 
 
 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
 
Send IRB Review Fee Invoice To: 
 
Name: 
 
Company: 
Address: 
  
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below. 
 
 
 


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NOTE: The HIC will remove from the protocol any personnel who have not completed required training. A 
personnel protocol amendment will need to be submitted when training is completed. 
 
 
Name 
Affiliation: Yale/Other 
Institution (Identify) 
 
NetID 
Principal Investigator  
Rajita Sinha PhD 
Yale 
Rs57 
Role: Co-PI 
Helen Fox PhD 
Yale 
 
Role: Co-Investigator 
Robert Beech MD PhD 
Yale 
 
Role: Co-Investigator/ MD 
Peter Morgan MD 
Yale 
 
Role: Co-Investigator/MD 
Gretchen Hermes MD 
Yale 
 
Role: MD 
Julia Shi MD 
Yale 
 
Role: Coordinator 
Rachel Hart 
Yale 
 
Role: Post Doc 
Verica Milivojevic 
Yale 
 
Role: Research Associate 
Gina Lombardi 
Yale 
 
Role: Research Assistant 
Christian Panier 
Yale 
 
Role: Research Nurse 
Mary Kurjanowicz 
Yale 
 
Role: Research Assistant 
Sheridan Finnie 
Yale 
 
Role: Staff Affiliate 
Nathan Grandpre 
Yale 
 
Role: Staff Affiliate 
Jennifer Weinberg 
Yale 
 
Role: Research Assistant 
Arielle Rabinowitz 
Yale 
 
Role: Correspondent 
Julie Pinto 
Yale 
Jg358 


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SECTION IV: 
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As the principal investigator of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 I assume full responsibility for the protection of human subjects and the proper conduct of the 
      research. 
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
      rights and welfare. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 All members of the research team will be kept apprised of research goals. 
 I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
      study or any change and I will obtain continuing approval of this study prior to the expiration date      
      of any approval period. 
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
      participants. 
 I am in compliance with the requirements set by the University and qualify to serve as the 
      principal investigator of this project or have acquired the appropriate approval from the  
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
      Yale-New Haven Hospital, or have a faculty advisor. 
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
 
_____ 
 
 
 
 
 
 
 
 
 
 
 
 
  
PI Name (PRINT) and Signature 
 
 
 
 
Date 
As the faculty advisor of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 This project has scientific value and merit and that the student or trainee investigator has the  
      necessary resources to complete the project and achieve the aims. 
 I will train the student investigator in matters of appropriate research compliance, protection of 
      human subjects and proper conduct of research. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 The student investigator will obtain approval for this research study and any subsequent revisions 
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
      of any approval period. 
 The student investigator will report to the HIC any serious injuries and/or other unanticipated  
      problems involving risk to participants.  
 I am in compliance with the requirements set forth by the University and qualify to serve as 
      the faculty advisor of this project. 
 
 
 
 
___________  
______ 
 
 
 
_____ 
    Advisor Name (PRINT) and Signature 
 
 
 
 
Date 


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Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
 No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
   ____________________________  
 
 
 
 
 
 
   Chair Name (PRINT) and Signature   
     
 
 
 Date 
 
   _________________________________ 
   Department 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
 I have read a copy of the protocol and approve it being conducted at YNHH. 
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
 The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
 
  ______________________________________ 
 
 
 
 
 
 
 
 
    YNHH HSPA Name (PRINT) and Signature         
 
 
Date 
 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.  
To test the preliminary efficacy of 16.0 mg of Prazosin daily versus placebo in treatment seeking 
alcohol dependent individuals.  This proposal is a laboratory and treatment outcome study to 
examine the effects of Prazosin on brief exposure to stress, alcohol cues and neutral situations on 
alcohol craving, mood and neurobiological reactivity in a sample of alcohol dependent 
individuals. Prazosin will be beneficial for reduction in stress and alcohol cue induced craving 


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and related neuroadaptations.  In a sample of 150 alcohol dependent men and women, we 
propose to examine (a) differences in measures of alcohol craving, emotion state, hypothalamic-
pituitary-adrenal (HPA) activation, physiological changes and plasma catecholamine response to 
stress imagery and to drug cue imagery as compared to neutral imagery; (b) reduction in alcohol 
abstinence symptoms; and (c) improvement in alcohol treatment outcomes as measured by 
increasing abstinence, reduction in alcohol use and increased treatment attendance. 
 
2. Background: Describe the background information that led to the plan for this project.  
Provide references to support the expectation of obtaining useful scientific data. 
 
 
 
Evidence from clinical surveys indicates that stress frequently leads to continued drug use and 
relapse (Marlatt and Gordon 1985; Bradley, Phillips et al. 1989; Wallace, 1989; Hodgins, el 
Guebaly, & Armstrong, 1995; Miller & Tonigan, 1996). Animal studies have shown that acute 
behavioral stress facilitates drug self-administration and reinstatement to drug seeking behavior 
in drug-addicted animals that have been drug-free for extended time periods (Shaham et al., 
1995). Previous work in our laboratory has shown that exposure to previous stressful experiences 
consistently increases alcohol craving and stress-related brain changes in alcohol dependent 
individuals (Fox et al., 2007; Sinha & O’Malley, 1999, Sinha et al, 2008). These data suggest 
that attenuation of stress-induced alcohol craving and related neuroadaptations may be a useful 
target in alcohol relapse prevention.  
 
 
Prazosin HCl (Prazosin) has an established history as an antihypertensive agent since it was first 
introduced by Pfizer in 1976. Prazosin is a lipophilic alpha-1 adrenergic antagonist making it 
also useful in treating behaviors linked to noradrenergic hyperresponsiveness. For example it has 
been shown to be effective in reducing the overall PTSD illness severity (Taylor et al.2006; 
Peskind et al 2003; Raskind et al.2000, 2002, 2003; Taylor & Raskind, 2002). Pre-clinical 
evidence has suggested that noradrenergic circuits may be involved in alcohol craving and 
relapse (Simpson et al., 2007). Prazosin therefore has been of particular interest as a potential 
pharmacologic treatment for alcohol dependence (Simpson et al., 2007; Walker et al, 2008). 
 
 
Alpha-2 adrenergic agonists, such as clonidine, lofexidine and guanfacine significantly reduce 
stress-induced drug seeking in drug addicted animals that are drug free for over 4 weeks (Erb et 
al., 2000; Shaham et al., 2002). Taylor et al. (2000) report that the postsynaptic blockade of 
alpha-1 receptors will have similar effects to those of alpha-2 receptors. 
 
 
On the basis of these data and previous preclinical research, we hypothesize that Prazosin will 
also decrease stress-induced and alcohol cue induced alcohol craving in laboratory sessions. We 
have developed a laboratory-based imagery induction method that reliably increases cocaine and 
alcohol craving after imagery of stressful and drug/alcohol cue events in cocaine dependent and 
in alcohol dependent individuals (Sinha et al., 1999; 2000; Fox et al., 2007). However, whether a 
medication suppresses stress and alcohol induced craving in alcohol dependent individuals has 
not been conclusively shown. In a sample of 150 alcohol dependent men and women, we will 
examine the effects of Prazosin on alcohol craving, subjective mood states, and neurobiological 
responses in personalized stressful imagery and drug cues imagery. All subjects will be exposed 
to three imagery sessions (neutral, stressful and drug cues) and the order of imagery conditions 
will be counterbalanced across subjects.  


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We expect that Prazosin will be easily tolerated as the effects are indirect. Unlike other less 
selective alpha blockers, which also block presynaptic alpha receptors, alpha-1 blockers do not 
prevent inhibition of noradrenaline release. Uninhibited noradrenaline release causes increased 
reflex tachycardia through the sympathetic baroreflex response that increases cardiac output. 
Prazosin therefore has a minimal effect on cardiac function due to its alpha-1 receptor selectivity 
(Arnsten et al., 1988). 
 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. Describe the setting in 
which the research will take place. 
 
One hundred and fifty treatment seeking alcohol dependent individuals (men and women) will be 
recruited to participate in this medication study. Subjects may or may not participate in 
laboratory sessions. Subjects will be recruited through flyers and advertisements in local 
newspapers and from community substance abuse treatment facilities. Subjects will participate in 
an initial screening and intake session to obtain informed consent, followed by physical 
examination and blood work to determine eligibility.  Subjects will be randomized to Prazosin 
(PRZ) or placebo (PLA) and medication will be dispensed in a three times daily dosing schedule 
(t.i.d. dosing) with 5 mg in the morning, 5 mg in the afternoon and 6 mg at night reached at the 
end of the 2-week period, and maintained at this or their highest tolerated dose until week 11, 
followed by a 5-day taper in week 12, as in previous research. The titration schedule was as 
follows: 1 mg dose at bedtime for 2 nights, followed by a 1mg dose morning and night (8 AM/8 
PM) on day 3, then 2 mg dose t.i.d., on days 4-6, 3 mg dose (2 pills each) morning and 
afternoon, and 4 mg dose (2 pills) at night for days 7-9, increased to 4 mg dosing t.i.d. on days 
10-13, and from day 14 through week 11, 5 mg (1 pill) each in the morning and afternoon, and 6 
mg for the night (2 pills) dose. Subjects will be maintained on this dose during the laboratory 
sessions (if completing the laboratory sessions) and until week 12 of the study at which point 
they will be tapered off the study medication over the course of five days. Some subjects may be 
tapered prior to completion of the 12 weeks. This taper is similar to what has been used with 
lofexidine in opiate withdrawal protocols (Bearn et al., 1996; Strang et al., 1997) and in our 
outpatient relapse prevention study of lofexidine with opiate dependent patients.  We expect 
most subjects will tolerate a daily dose of 16.0mg.  However, subjects who cannot tolerate a 
dosing schedule of 16.0 mg will meet with the study psychiatrist to discuss a reduction in dose 
down to 10mg/day.  Based on the Physician Desk Reference (2007), which reports that dosage 
may be as high as 40mg daily, we anticipate that 16.0mg per day will be well tolerated by 
subjects.  Subjects who cannot tolerate a minimum dose of 6mg/day will be removed from the 
study protocol.  
 
Subjects will complete a variety of diagnostic, cognitive and psychological assessments, a 
comprehensive physical examination and blood work. If completing the laboratory component as 
inpatients, subjects will also be involved in development of imagery scripts from personal stress, 
drug-related cue and neutral situations during the first 3 weeks of their stay. After subjects have 
been substance- free for 21+ days, they will participate in an imagery/relaxation training and 


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habituation session. Between weeks 3 – 4, subjects will participate in a 3-day experiment in 
which during a 2-hour laboratory session on three consecutive days, subjects will be exposed by 
guided imagery to a personal stressful situation, a drug cue related situation and a neutral 
relaxing situation, one exposure per day. Order of imagery type will be randomly assigned across 
subjects.  
 
Research Plan:   
 
Subjects will have the option of participating in either the inpatient–outpatient plan, or the 
outpatient plan. The inpatient–outpatient plan involves 3 - 4 weeks of inpatient treatment 
followed by 8 - 9 weeks of outpatient treatment. Subjects completing the inpatient-outpatient 
plan may or may not complete the laboratory sessions. The outpatient plan involves outpatient 
treatment with 12-Step Counseling for 12 weeks. Subjects enrolled in the outpatient plan also 
have the option to complete 4 days of inpatient laboratory sessions. The provision of an 
outpatient alternative is added to provide an opportunity for participation to those subjects who 
are not able to participate in longer inpatient treatment due to childcare, employment, or other 
related obligations. The three alternatives are described below: 
 
Inpatient-Outpatient Plan with laboratory sessions: 
 
Once a subject is deemed eligible, those who are interested in the inpatient option will be 
admitted to the Clinical Neuroscience Research Unit (CNRU) of the Connecticut Mental Health 
Center (CMHC) for the 3 - 4 week stay that will involve medication initiation and laboratory 
sessions where subjects will be exposed to stress, drug cues and neutral-relaxing cues on three 
separate consecutive days. Lab sessions will take place either on the Clinical Neuroscience 
Research Unit (CNRU) or at the Yale Stress Center.  
 
After completing the inpatient phase of the study, subjects will either taper off the study 
medication or participate in a 9-week outpatient medication trial. Those choosing to continue 
treatment will be seen 2 times per week in outpatient treatment at the Substance Abuse Center at 
CMHC, or at the Yale Stress Center at 2 Church Street South. Subjects will be maintained on 
16.0mg dose of PRZ/PLA until week 12. In week 12, subjects will undergo a 5-day taper similar 
to what has been used with Lofexidine in opiate withdrawal protocols (Bearn et al., 1996; 
Strange et al., 1997) and in our outpatient relapse prevention study of Lofexidine and Guanfacine 
with opiate and cocaine dependent patients respectively. Urine monitoring, assessment of 
craving, alcohol abstinence symptoms, self report of drug use and stress and craving scales, heart 
rate and blood pressure will be assessed weekly in the trial.  
 
Inpatient-Outpatient Plan without laboratory sessions: 
 
The plan for subjects completing the Inpatient-Outpatient Plan without laboratory sessions, will 
be identical to the plan for the Inpatient-Outpatient Plan with laboratory sessions, minus the 
laboratory sessions, and all procedures related to the laboratory sessions, such as participating in 
imagery script development sessions. Once a subject is deemed eligible, those who are interested 
in the inpatient option will be admitted to the Clinical Neuroscience Research Unit (CNRU) of 


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the Connecticut Mental Health Center (CMHC) for the 3 - 4 week stay that will involve 
medication initiation.   
 
After completing the inpatient phase of the study, subjects will either taper off the study 
medication or participate in a 9-week outpatient medication trial. Those choosing to continue 
treatment will be seen 2 times per week in outpatient treatment at the Substance Abuse Center at 
CMHC, or at the Yale Stress Center at 2 Church Street South. Subjects will be maintained on 
16.0mg dose of PRZ/PLA until week 12. 
 
 
Outpatient Plan:   
 
Subjects who are deemed eligible, but are unable to commit to 3 - 4 weeks of inpatient treatment 
will be seen 2 times per week in outpatient treatment at the Yale Stress Center at 2 Church Street 
South. Outpatient appointments will include motivational enhancement, urine drug screens, 
breathalyzers, blood pressure monitoring, and counseling. Daily interactive voice response (IVR) 
telephone monitoring, or the smartphone app MetricWire, will prompt subjects to take study 
medication, and assess their alcohol use, craving, craving resistance and mood states. Blood 
draws will be done at weeks 4-5 to measure Prazosin levels. These levels will allow staff to 
ensure subjects are taking medication as prescribed. Medication compliance will also be 
monitored through the use of riboflavin as a marker. Riboflavin produces a bright yellow 
discoloration of the urine when the medication is taken 2 to 8 hours prior. After the first week all 
subjects will be taking morning and bedtimes doses of the medication. After this time, staff will 
easily be able to visually inspect the subject’s urine to determine whether the morning dose has 
been taken. 25mg of riboflavin will be added to all doses of Prazosin and placebo by the 
pharmacist when capsules are made. Thirty-two cc’s of whole blood will be also collected from 
patients at intake for the purposes of understanding genetic factors that may affect craving. 
 
In the event that someone is unable to achieve any period of abstinence within a 4-week period, 
they will be offered inpatient treatment or referred to a higher level of care at another facility. In 
the event that someone achieves abstinence but has occasional relapses, outpatient treatment will 
continue until they either sustain abstinence or a higher level of care is clinically indicated.  
These clinical judgments will be made by the principle investigator.  Subjects will be provided 
with dollar amounts for kept appointments. Rewarding subjects for kept appointments, regardless 
of whether their urine is clean or not, will enable us to maintain treatment compliance while 
allowing for test of efficacy of medication in this trial.       
 
After a subject is able to abstain from substances for a period of 21+ days, they will have the 
option to complete a 3-night stay on the CNRU, where they will participate in imagery training 
and 3 laboratory sessions. After completion of the laboratory sessions, subjects will be 
discharged from the inpatient unit at least one day after the laboratory sessions.   
 
Subjects will undergo the same titration onto study medication as outlined above. If the subject 
decides to complete the laboratory component, they will be maintained on 16.0mg dose of 
PRZ/PLA medication during the week of the inpatient laboratory sessions, after which they will 
undergo the above mentioned taper or continue to take their medication for 9 weeks in outpatient 


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treatment. In the event that someone continues to use alcohol while in the study, they may be 
asked to come in for more frequent appointments to assess for adverse symptomatology and meet 
with the study psychiatrist.  Similar methods have been used in our outpatient lofexidine study 
and no adverse interaction events are anticipated.   
 
Table 1: PRZ/PLA Dosing 
 
 
 
Prazosin PRZ 
(N = 75) 
(Male  / Female) 
 
 
Placebo (PLA) 
(N = 75) 
(Male / Female) 
 
 
Week 1 
 
Days 1 -2 
(1mg / 1mg) 
 
Days 3 
(2mg /1mg) 
 
Days 4-6 
(6 mg/4mg) 
 
AM 
 
PM 
 
Evening 
 
AM 
 
PM 
 
Evening 
 
 
0mg / 0mg 
 
 
1mg / 0mg 
 
 
2mg/1mg 
 
0mg / 0mg 
 
 
0mg / 0mg 
 
 
2mg/1 mg 
 
1mg / 1mg 
 
 
1mg / 1mg 
 
 
2 mg/2mg 
 
0mg / 0mg 
 
 
1mg / 0mg 
 
 
2mg/1mg 
 
0mg / 0mg 
 
 
0mg / 0mg 
 
 
2mg/1 mg 
 
1mg / 1mg 
 
 
1mg / 1mg 
 
 
2mg/2mg 
 
Week 2 
 
Days 7-9 
(10mg /8mg) 
 
Days 10 – 13 
(12mg/12mg) 
 
Day 14 
(16mg/16mg) 
 
 
 
 
3mg / 2mg 
 
 
4mg /4mg 
 
 
5mg/5mg 
 
 
 
3mg / 2mg 
 
 
4mg/4mg 
 
 
5mg/5mg 
 
 
 
4mg /4mg 
 
 
4mg /4mg 
 
 
6mg/6mg 
 
 
 
3mg / 2mg 
 
 
4mg /4mg 
 
 
5mg/5mg 
 
 
 
3mg / 2mg 
 
 
4mg /4mg 
 
 
5mg/5mg 
 
 
 
4mg /4mg 
 
 
4mg /4mg 
 
 
6mg/6mg 
 
Follow-up: 
 
Upon completion of outpatient treatment, follow-up interviews will be scheduled with all 
subjects. If a subject decides to complete only the inpatient phase, follow-up appointments will 
be scheduled after the inpatient phase is complete. Follow up interviews will be scheduled at 30 
days. Urine monitoring, assessment of craving, cocaine abstinence symptoms, self report of drug 
use and stress and craving scales, will be assessed during the follow-up appointment.  
 


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Contact and collateral information will have been obtained from subjects at intake. We currently 
use procedures that make it possible to locate and re-interview more than 90% of the patients 
recruited into our treatment and laboratory research studies. Of note, in our recently completed 
stress study with cocaine dependent individuals we obtained a 92% completion rate. Our 
procedures include informing the patient of the importance of follow-up evaluations at the time 
of initial assessment, emphasizing the patient's role as a research subject, guaranteeing complete 
confidentiality of all information, obtaining permission, addresses and telephone numbers of 
three collaterals to be contacted in order to help us locate the subject, arranging for home visits 
and telephone interviews when subjects fail to keep appointments, mailing of appointment 
reminders that are followed by telephone calls, and provision of incentive payments for 
successful completion of follow-up evaluations.  All of these procedures will be incorporated 
into this study.   
 
 
Study Feasibility:  
 
The Chronic Alcohol and Brain Stress Circuit Relapse (#22015) for alcohol addiction currently 
screens approximately 15 subjects per month. On average, approximately 6-8 patients meet 
criteria for the proposed study (not on other medications and otherwise healthy) and will be 
offered participation in this study. Thus we anticipate that 3-4 patients can be enrolled into the 
pilot study monthly, leading to a 15-20 month recruitment phase for this study. The subjects will 
be recruited from treatment seeking individuals who are being evaluated for alcohol treatment at 
clinical programs and from those responding to advertisements and flyers for inpatient treatment 
and research.  
 
General Procedures: 
 
All subjects will be screened and recruited into the study by the research assistant coordinator. 
Potential subjects will meet with the research assistant coordinator who will, after an initial 
screening over the telephone/in person, determine eligibility based on inclusion/exclusion 
criteria. The initial screening will collect basic demographic information and ask questions 
specific to the inclusion/exclusion criteria.  The initial screening will take approximately 5-10 
minutes. She will explain all study procedures and risk/benefits and obtain informed consent. 
Subjects will undergo breath alcohol testing/urine toxicology screens at each in-person 
appointment to confirm self-report of drug and alcohol use information.  
 
 
Admission: 
 
Subjects will then be scheduled for admission at the CNRU for inpatient treatment, or the SAC 
for outpatient treatment and participation in research procedures.  Subject will participate in a 
comprehensive physical examination conducted at the Clinical Neuroscience Research Unit 
(CNRU) of the CMHC to rule out any subjects who may be medically or psychiatrically unfit to 
participate in the study. Routine laboratory studies will include CBC, ESR, glucose, 
BUN/creatinine, electrolytes, liver and thyroid function tests, and EKG. Abnormal findings will 
be further evaluated by the physician on staff at the CNRU and appropriate medical advice will 
be provided. Subjects who report any specific current medical conditions and require, or are 


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currently on medications for treatment of their medical condition will be excluded from the 
study. Subjects will participate in standard substance abuse treatment.  
 
Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scores will be taken at admission 
to monitor alcohol withdrawal symptoms. Librium 50mg, Ativan 2mg or other treatment will be 
given as appropriate for clinical evidence of alcohol withdrawal symptoms. CIWA scores will be 
assessed every four hours for at least the first 48 hours and longer if clinically appropriate. In 
addition to assessing CIWA scores for PRN medication, subjects who have a history of major 
alcohol withdrawal symptoms (e.g. withdrawal seizures or delirium tremens) will be placed on a 
standing dose of Librium 50mg tid for the first 24 hours with continued treatment as clinically 
appropriate.  
 
Baseline assessments will be completed over the course of the first week. If participating in the 
laboratory sessions, subjects will participate in an imagery script development session to provide 
descriptions of recent stressful, drug cue related and neutral relaxing situations to the research 
assistant, in the second week. At the start of week 3 or day 15, if participating in the laboratory 
sessions, subjects will participate in a relaxation and imagery training and habituation session 
(STUDY DAY 1), followed by three laboratory sessions on each consecutive day (STUDY DAY 
2, 3, 4). Subjects will be offered Nicotine Replacement Therapy (NRT) if needed. 
 
Subjects will participate in lab sessions after maintaining at least 14 days of sobriety.  After 
completion of laboratory sessions, subjects will be discharged from the inpatient unit at least one 
day after the laboratory sessions. All subjects will be maintained on a dose up to 16.0mg of 
Prazosin/PLA until week 12. In week 12, subjects will undergo a 5-day taper similar to what has 
been used with lofexidine in opiate withdrawal protocols (Bearn et al., 1996; Strange et al., 
1997) and in our outpatient relapse prevention study of lofexidine with opiate dependent patients. 
Some subjects may be tapered prior to week 12.  
 
Subjects will be seen two times per week by research staff for urine monitoring, assessment of 
craving, alcohol abstinence symptoms, self report of alcohol use and stress and craving scales, 
heart rate and blood pressure in the trial.  Subjects will be administered the first dose of study 
medication at the clinic and will remain at the clinic for 1-2 hours to assess side effects. 
Remaining medication at the same dose will be provided as take home to self-administer daily.  
 
All subjects will also be seen two times per week in outpatient treatment at the Yale Stress 
Center. All subjects will participate in 1x per week standard individual drug counseling as 
outlined in the Individual Drug Counseling Manual (IDC, Mercer & Woody, 1998) during the 
outpatient trial. Each subject will be assigned a counselor with expertise in IDC .The general 
purpose of the counseling sessions as described in the manual are to: (1) acquire information 
about important concepts and aspects of recovery from addiction; (2) increase self-awareness of 
specific problems and issues in relation to addiction and recovery, and (3) learn new coping 
skills to deal with problems contributing to or resulting from the addiction and to improve 
functioning. The focus of this psycho-educational approach is on providing patients with 
frequent supportive contact, introduce them to key concepts about the recovery approach, and 
develop a sense of personal responsibility for recovery. 
 


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Relapse in the pilot study will be defined as the first day of any alcohol use as documented by 
self-report and/or positive urine and positive breathalyzer for alcohol. Treatment drop-out is 
defined as four consecutive missed research appointments for medication self-administration.  
Relapse to alcohol will be recorded in the data and subjects will continue in the protocol. 
Furthermore, it will be addressed by their counselor and doctor in therapy appointments. If 
subjects have missed four consecutive appointments, all attempts will be made to bring the 
subject back and after a full assessment of the subject’s need, a formal referral will be made to 
appropriate residential, inpatient or intensive outpatient care. Subjects will be maintained in 
regular treatment until they have entered treatment at the next appropriate level of care. Other 
clinical deterioration such as exacerbation of psychiatric or withdrawal symptoms will be 
assessed on a case-by-case basis by the study investigators. When clinically indicated and 
necessary, psychotropic medication or discontinuation of study medication will be initiated 
and/or a referral will be made to intensive outpatient, residential or inpatient care.  
 
 
 
 
Physiological Assessments 
 
During the physical, 8ml of whole blood will also be drawn to analyze molecular adaptations.  
Microarray profiling will be used to detect these molecular changes by comparing the molecular 
profile of the blood drawn during the physical to another 8ml of blood drawn during one of the 
laboratory sessions. A total of 16ml of whole blood will be drawn to examine molecular changes 
in the blood.    
 
During the physical, all female subjects will have 8ml of whole blood drawn to determine 
estradiol levels. Estradiol levels drawn during the physical will be compared to another 8ml of 
blood drawn during one of the laboratory sessions. A total of 16ml of whole blood will be drawn 
to measure estradiol levels.    
 
 
Laboratory Sessions:  
 
Rationale for Use of Personalized Imagery Procedures. Emotional imagery paradigms have been 
widely used in behavioral research studies examining the pathophysiology of anxiety disorders, 
including panic disorder, obsessive compulsive disorder and PTSD (Cook, Melamed, Cuthbert, 
McNeil, & Lang, 1988; Foa & Kozak, 1986; McNeil, Vrana, Melamed, Cuthbert, & Lang, 1993; 
Pitman, Orr, Forgue, de Jong, & Claiborn, 1987; Shalev, Orr, & Pitman, 1993; Orr et al., 1998; 
Orr, Pitman, Lasko, & Herz, 1993). These procedures are known to activate the same 
physiological, subjective and behavioral components as the emotion trigger situations, thus being 
a useful clinical research procedure for inducing stress/emotional states. Similar imagery 
induction procedures have been successfully adapted by our group in previous studies to induce 
specific emotion states in normal volunteers and stress and alcohol cues in alcohol dependent 
individuals (Sinha, Lovallo, & Parsons, 1992; Sinha & Parsons, 1996; Sinha, Catapano, & 
O'Malley, 1999a; see Preliminary Studies section C1, C2, C6).  
 


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Imagery procedures have also been used in the alcohol abuse literature to induce alcohol cue-
induced alcohol craving and stress/negative mood induced alcohol craving in the laboratory 
(Cooney, Litt, Morse, & Bauer, 1997; Payne, Rychtarik, Rappaport, & Smith, 1992; Rubonis et 
al., 1994; Sinha et al., 1999a). Tiffany and colleagues compared imagery induction vs. in-vivo 
exposure to cues, and found that while both methods were equally effective in eliciting high 
levels of self-reported craving, physiological reactivity was greater with the imagery 
manipulation. Furthermore, our previous work in cocaine dependent individuals showing 
activation of the HPA axis and increases in plasma catecholamines with stress and with drug cue 
imagery indicates that the method is effective in inducing drug craving and in activating brain 
stress circuits (Sinha et al., 1999a). Thus, the imagery procedure includes the following 
distinctive components based on prior experience:  
 
(i) Personal stressful, drug cue and neutral situations rather than standard situations will 
be selected because personal events show greater physiological reactivity and generate more 
intense emotional reactions than imagery of standardized non-personal emotions (Cook et al., 
1988; McNeil et al., 1993; Miller et al., 1987).  
 
(ii) Based on Lang's network theory on emotion processing and Tiffany’s cognitive 
model of drug use and urges (Tiffany, 1990; Tiffany & Drobes, 1990) and our previous work, the 
addition of physiological, subjective and behavioral response descriptors are included in the 
imagery script so as to produce stronger activation of the experience.  
 
(iii) To minimize subject variability in the imagery induction procedure, we include an 
imagery training session, in which each subject receives training on how to generate and 
maintain a mental image for 2-3 minutes. The imagery training procedures have been extensively 
used in previous studies by Lang and his colleagues and by the PI in her previous work on 
emotions and stress work with cocaine abusing samples. 
  
Imagery Script Development Session: In a session prior to the laboratory sessions, scripts for the 
guided imagery induction will be developed. The stress imagery script will be based on subjects’ 
description of a recent personal stressful event that they had been experienced as "most 
stressful". “Most stressful” is determined by having the subjects rate the perceived stress 
experienced by them on a 10-point Likert scale where “1=not at all stressful” and “10=the most 
stress they felt recently in their life”. Only situations rated as 8 or above on this scale are 
accepted as appropriate for script development. Stressful situations that involved drug-related 
stimuli, such as being arrested for possession of drugs or being caught in a police chase, are not 
allowed. Examples of acceptable stressful situations include breakup with significant other, a 
verbal argument with a significant other or family member or unemployment-related stress, such 
as being fired or laid off from work. As stressful situations often occur in the context of alcohol 
use, these situations are thought to be associated with alcohol use and therefore elicit alcohol 
craving.   
 
The alcohol-related script will be developed by having subjects identify a recent situation that 
included alcohol-related stimuli and served as a trigger for subsequent alcohol use (e.g. buying 
alcohol, being at a bar and watching others drink alcohol; getting together with alcohol drinking 
buddies). Alcohol-related situations that occurred in the context of negative affect or 
psychological distress will not be allowed, i.e., going to a bar after a marital conflict, or feeling 
depressed and calling an alcohol drinking buddy.  A neutral-relaxing script will be developed 
from the subjects’ commonly experienced neutral-relaxing situations. Neutral-relaxing events 


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that involve drug cues will not be allowed.  A ‘script’ or description of each situation will be 
developed using Scene Development Questionnaires which obtain specific stimulus and response 
details, including specific physical and interpersonal context details, verbal/cognitive attributions 
regarding the people involved, and physiological and bodily sensations experienced for the 
situation being described. The three scripts for each subject will then be recorded on an audio-
tape for guided imagery in the laboratory sessions. The order of stress, neutral and drug cue 
scripts will be assigned randomly, and counterbalanced across subjects. Detailed procedures are 
outlined in the Imagery Development Procedures Manual (Sinha, 2001b). 
 
Interview sessions may be videotaped. Subjects will be asked for their signed permission to 
videotape their interview sessions and will be paid an additional $20 for each interview session 
we videotape. Subjects are informed of the possibility of videotaping in the consent form, in 
additional to a separate videotaping consent form. Subjects will know when they are being 
videotaped. Videotapes will be used to evaluate the interviewer, train new staff, and rate the 
subject using a behavioral observation scale. Videotaping will not affect the subject’s study 
participation or treatment in any way. 
 
Manipulation Check for Script Development: All three scripts will be rated on a Likert scale 
from 1 to 10 on a standard rating form (Independent Rating Scale) by two objective independent 
raters for stressful and emotional content. If a script scores below a rating of 8 for stressful 
content on a five-point rating scale the subject will be asked to develop a new script at the next 
appointment prior to the laboratory sessions. These procedures ensure that the stress and drug 
cue scripts of all subjects are equated in intensity and content. It further ensures that differences 
in stress reactivity are not due to differences in intensity and emotional content of the stressor. 
The procedures for development of imagery scripts, rating of scripts for content and 
physiological activation are similar to those used by Miller et al. (Miller et al., 1987) and have 
been successfully used in our previous work on emotions (Sinha et al., 1992; Sinha & Parsons, 
1996) and on stress reactivity with cocaine dependent individuals (Sinha et al., 1999a).  
 
Imagery and Relaxation Training and IV Habituation Day- STUDY DAY 1. On the afternoon of 
DAY 1, an indwelling catheter will be inserted in the subject’s arm for one hour, so that subjects 
can habituate to the stress of an IV insertion. We have found that this period of adaptation is 
critical for stable baseline measurements on testing days. No blood will be drawn on the training 
day. After insertion of IV catheter, the subject will be provided with relaxation training followed 
by general imagery and physiological response training, as described in the imagery training 
procedures manual (Lang, Levin, Miller, & Kozak, 1983). The imagery training involves 
subjects' visualizing some commonplace scenes as they are presented to them. The scenes are 
neutral and non-emotional in content, such as reading a popular magazine. Following the 
imagery, the subject is asked questions about the visualization and given pointers regarding the 
process of imagining the scene. The subject also imagines scenes that are non-emotional but 
physically arousing in nature, such as doing sit-ups in gym class. With these scenes subjects are 
asked whether they notice any changes in their physiological response, such as change in heart 
rate or change in breathing. Once again, pointers with regard to imagining the situation "as if" 
they were really present in the situation are presented. This session takes approximately one hour 
and was developed to insure that all subjects are trained on the method of generating an image 
and maintaining it for 2-3 minutes.  


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Laboratory Sessions.  On DAY 2, 3, and 4 of the study, subjects will be brought into the research 
testing rooms of the CNRU at 8:00 AM after a smoke break at 7:30 AM. Breakfast will be 
withheld from the subject until after the laboratory session. The subject will then be prepared for 
physiological assessments.  An indwelling intravenous (IV) catheter will be inserted by the 
research nurse specialist in the antecubital region of the subject's non-preferred arm for blood 
sampling. Blood samples will be obtained periodically for assessment of ACTH, cortisol, 
prolactin, NE and EPI levels. A blood pressure cuff will be placed on the subject's preferred arm 
to monitor blood pressure (BP) periodically. On-line assessment of physiological measures will 
be obtained at specified time periods during the laboratory sessions. Self-reports of emotional 
state, anxiety and alcohol craving will also be assessed periodically. 
  
After preparation of assessments and a 40 minute adaptation period, a –20 minutes and –5 
minutes blood draw will be conducted. After the –5 blood draw, a 5-minute baseline period will 
follow to assess continuous pulse rate and BP assessments. Following the baseline period, 
instructions for conducting imagery will be provided. The order and content of the imagery 
condition will not be revealed to the subject or to the research staff conducting the sessions. In 
the imagery task the subjects will be asked to imagine the situation being described vividly, 'as if' 
he/she is in the specific situation and actively participating in it, until asked to stop. The imagery 
script will be played to the subject over headphones and the subject will be required to imagine 
the situation for 5 minutes. A tape recording for each subject's script will be developed prior to 
the testing situation and read by the same person for each subject. Timeline for assessments are 
summarized in Table 3.  
 
 
TABLE 3: Schedule for Laboratory Sessions 
 
DAY 1: 
Imagery and Relaxation and Habituation Session (1 hour) 
DAY 2, 3 and 4: IMAGERY SESSIONS 
8:00 AM 
Set-up for plasma (IV insert) measures; physiological setup - HR, BP 
8:10 AM 
Stabilization and Adaptation period, BP reading 
8:40 AM (-20) Initial Blood Draw, craving/DES ratings, physiological assessments 
8:50 (-10) 
BASELINE Period; on-line physiological recordings 
8:55 (-5)  
Baseline blood draws; craving/DES ratings, BP assessments 
9:00   
IMAGE Period (Stress/Drug Cues/Neutral); physiological assessments 
9:05 (0) 
Post-Image blood draw; craving/DES ratings; Imagery Vividness ratings  
9:10  (+5)  
RECOVERY Period; 5-min physiological assessments; craving/DES ratings; 
9:20 (+15) 
Recovery1: Blood draws, craving/DES ratings; 5 minute physiological 
assessments  
9:35 (+30) 
Recovery2: Blood draws, craving/DES ratings; physiological assessments 
9:50 (+45) 
Recovery3: Blood draws, craving/DES ratings; physiological assessments 
10:05 (+60) 
Recovery4: Blood draws, craving/DES ratings;  
10:20 (+75) 
Recovery5: Blood draws, craving/DES ratings; physiological assessments 
10:30 AM  
Relaxation tape; assess physiological levels and subjective state for return to 
baseline 
 
 


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Relaxation instructions will be provided to ameliorate any residual effects of imagining personal 
stressful and drug cue situations. Subjects will then be free to leave the testing room and eat 
breakfast on the unit. Relaxation instructions have been found to be effective in reducing alcohol 
cue-induced craving (Margolin, Avants, & Kosten, 1994; Sinha et al., 1999a) in the laboratory 
and we will use these instructions to reduce any residual alcohol craving. All subjects will also 
remain on the inpatient unit for at least one more day after the laboratory sessions. Previous 
research and our clinical research experience indicates that laboratory induced drug craving 
returns to baseline after the laboratory sessions with little impact after laboratory exposure.  
 
Laboratory Assessments. 
 
a. Self-Reports   (a) Differential Emotion Scale (DES; 246). Subjects will be asked to rate their 
current emotional state for the following: anger, fear, sadness, anxiety, joy, neutral-relaxed 
feelings. These ratings will be conducted for each assessment period during the imagery session 
(as indicated in Table 3). An abbreviated version of the DES (Izard, 1972) includes five 
adjectives (a total of 30 items) are used to describe each affect state and subjects are required to 
rate on a 5-point scale the extent to which each word describes the way she feels at the present 
time. The DES has been used in human laboratory studies to assess subjective states after 
induction of moods either via imagery or other standard tasks such as mental arithmetic, Stroop 
test or in a confederate situation (Schwartz & Weinberger, 1980; Schwartz, Weinberger, & 
Singer, 1981). It has provided useful emotion state data for alcohol dependent individuals during 
stress exposure and in alcohol craving (Sinha et al., 1999a; Sinha, Fuse, Aubin, & O'Malley, 
2000; Sinha et al., 2002a; a copy of the abbreviated DES is provided in Appendix A2.3).  (a) 
Alcohol Craving: All subjects will be asked to rate alcohol craving during the laboratory sessions 
at time-points specified in Table 3. Alcohol craving will be measured using the Alcohol Urge 
Questionnaire (Bohn, Krahn et al., 1995), which is a brief 8-item self-report craving scale, and is 
designed so that it can be used in laboratory studies that require repeated assessments of alcohol 
craving such as in cue-reactivity studies (AUQ). The AUQ has high test-retest reliability (0.84) 
and was found to be a valid measure of alcohol urges that was significantly associated with 
drinking measures and dependence severity. We have previously used the AUQ in our laboratory 
study assessing the effects of naltrexone on craving and ad-lib drinking in alcoholics (O'Malley, 
Krishnan-Sarin et al, 2002). 
 
 b. Physiological Measures.  
 
A pulse sensor will be attached to the subject’s forefinger to obtain a measure of pulse rate. 
Blood pressure will be measured using the IBS dynamap.  
 
c. HPA and Catecholamine Measures.  
To assess plasma levels of ACTH, prolactin, cortisol, norepinephrine (NE) and epinephrine 
(EPI), 5ml of plasma (15 ml of whole blood) will be collected at each time point (total of 360 ml 
over 3 days). The samples will be split into five heparinized tubes (.15 ul of heparin) and the 
tubes will be placed on ice immediately after blood drawing. Within 30 minutes of collection, the 
blood will be centrifuged at 4C and the serum removed into separate test tubes, 1 ml of plasma 
each for ACTH, cortisol, prolactin, NE and EPI. Similar blood drawing procedures have been 
established successfully on the CNRU for previous studies with psychiatric and substance 


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abusing populations and in our previous studies with alcohol dependent individuals. All tubes 
will be stored at -70C until they are ready for shipping to the Kreek laboratories. ACTH, 
prolactin and cortisol will be measured using standard radioimmunoassay procedures.   
 
In addition, saliva samples will be collected at the same time points as the plasma samples. 
Saliva samples will be processed by the YCCI core laboratories.  This will be done to compare 
salivary cortisol measurements with the plasma cortisol assessments. 
 
Catecholamine samples will be analyzed by Dr. Anderson’s laboratory at the Yale University 
Medical School. These samples will be labeled with a serial number and will not have any 
identifying information.  These samples will be used to determine adreno-medullary and 
sympathetic response to the challenges employed.  Although both plasma norepinephrine (NE) 
and epinephrine (EPI) levels increase rapidly with a range of stressors, differential response is 
often seen (Goldstein, 1998). The plasma concentrations of NE and EPI will be determined in 
serial blood samples using high performance liquid chromatography (HPLC). Catecholamines 
will be alumina-extracted from 1.0 ml plasma samples, separated by reverse phase ion pair 
chromatography and detected using coulometry (Coulochem II, ESA, Inc.). Concentration 
detection limits of 1-2 pg/ml are observed; typical baseline plasma NE and EPI levels are 150 
pg/ml and 20 pg/ml, respectively. Within-day and day-to-day coefficients of variation are less 
than 10%. 
 
For both HPA and catecholamine assays, data will be analyzed for the time-points outlined in 
Table 3. In addition, as each measure may show different response profiles over time, we will 
also assess maximal or peak response and area under the curve (AUC) for each measure. Peak 
and AUC assessments of these measures are commonly used methods to reduce variability in 
responses and have been used in several studies (Kirschbaum, Wust, Faig, & Hellhammer, 1992; 
O'Malley, Krishnan-Sarin et al. 2002).   
 
Standard Individual Drug Counseling: All subjects will participate in weekly standard individual 
drug counseling as outlined in the Individual Drug Counseling Manual (IDC, Mercer & Woody, 
1994) during the outpatient trial.  Each subject will be assigned a counselor with expertise in 
IDC who will see the patient for the 9 or 12 week outpatient trial. The general purpose of the 
counseling sessions as described in the manual are to: (1) acquire information about important 
concepts and aspects of recovery from alcohol addiction; (2) increase self-awareness of specific 
problems and issues in relation to addiction and recovery, and (3) learn new coping skills to deal 
with problems contributing to or resulting from the addiction and to improve functioning. The 
focus of this psycho-educational approach is on providing patients with frequent supportive 
contact, introduce them to key concepts about the recovery approach, and develop a sense of 
personal responsibility for recovery.  
 
Assessments: A trained research assistant will meet with the client at various time-points to 
assess the client on selected substance use and psychological functioning measures using 
structured interviews, self-report assessments and to obtain urine samples for toxicology screens.  
A description of the assessment battery follows, and Table 1 lists the schedule of administration 
of assessments.  
 


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Screening Assessments: 
Sociodemographic/general patient information.  Demographic data, medical history, and 
family psychiatric history will be assessed with interviews and self-report forms that provide 
data on age, race, socioeconomic status, marital status, psychiatric family history, educational 
and occupational levels, and significant medical history. 
The Structured Clinical Interview for DSM-IVTR (SCID, First et al., 1995) will be used to 
obtain DSM-IVTR Alcohol Dependence and other substance use disorder diagnoses. The SCID's 
reliability and validity among substance-using populations has been established in large-scale 
surveys (Kranzler et al., 1996). The number of dependence syndrome elements endorsed from 
the DSM-IVTR substance abuse/dependence criteria will assess severity of alcohol and other 
drug dependence. The SCID will also be used to obtain previous psychiatric diagnoses.  
Medical History and Physical Examination: All patients will be required to participate in a 
physical examination including a medical history, electrocardiogram (EKG), blood and urine 
laboratory assessments prior to initiation of Prazosin to ensure eligibility for Prazosin study 
protocol. These will be conducted at the CNRU. 
Short Form 36 Health Survey (SF-36) is a 36-Item questionnaire used in to assess the 
subjective quality of life of respondents.  
 
Drug and Alcohol Use Measures:  
Addiction Severity Index (ASI: McLellan et al., 1992) is a structured interview that assesses the 
severity of substance use and substance-related problems in the areas of medical, employment, 
legal, family/social and psychiatric functioning. The ASI is the most widely used instrument for 
assessment of substance use and related problems and its psychometric properties are well-
established (Cacciola et al., 1997).  The ASI will be used at pre-treatment and week 9. Follow-up 
ASI interviews will be conducted at  30 days post-treatment.  
The Substance Use Calendar was developed by Miller and DelBoca (1994) and is based on the 
Time-Line Follow-Back Method (TLFB) (Sobell, Maisto et al. 1980). The SUC uses a calendar 
prompt and a number of other memory aids (e.g., holiday, payday, and other personally relevant 
dates) to facilitate accurate recall of daily drug use during the targeted period.  It has 
demonstrated adequate levels of reliability and validity when administered as an in-person 
interview, over the telephone, and when administered via computer (e.g. Carey, 1997; Sobell, 
Brown, Leo, & Sobell, 1996; Sobell, Sobell, Leo & Cancilla, 1988). It’s reliability and validity in 
drug abusing samples has also been established (Fals-Stewart, et al., 2000). In the current study 
we will use to obtain self-report of day to day use of alcohol and drugs, for the 60 days prior to 
treatment, weekly during treatment, and at the 30 day follow-up interviews. 
Alcohol Dependence Scale (ADS) is a 25 item to measure severity of alcohol dependence; the 
Alcohol Use Questionnaire (AUQ) consists of 8 items to determine the respondent’s alcohol 
craving; Smoking History Questionnaire 
 
Abstinence Measures: 
 
Clinical Institute Withdrawal Assessment-Alcohol Revised (CIWA-Ar) is a 13 item scale 
that measures alcohol withdrawal signs and symptoms.  The assessment will be administered at 
intake and weekly. 
 


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Urine Toxicology and Breathalyzer Screening: A urine toxicology screen will be conducted at 
intake to confirm alcohol use. During treatment, urines will be collected 3 times weekly to 
confirm sobriety during inpatient stay using the CNRU laboratory. In addition, urine samples 
will be taken 2 times weekly during outpatient treatment and at follow-up appointments using 
on-site TESTCUP5 Drug Screen (Roche Diagnostics Inc., Totowa, NJ) to monitor opiate and 
other drug use. The TestCup5 kit provides results for opioids, cocaine, THC, PCP and 
barbiturates. In addition, breath alcohol levels will also be assessed with the Alcosensor III 
Intoximeter at each face-to-face contact, 2 times weekly. 
  
Assessment of Psychological Symptoms:  
A number of self report measures of psychological functioning will be obtained weekly to 
examine Prazosin’s effects on psychological functioning. The following well-established and 
reliable instruments will be used:  
The Hamilton Anxiety Scale is a widely used anxiety rating scale comprised of 14 symptom-
oriented questions; The Center for Epidemiologic Studies Depression Scale (CES-D) a screening 
test for depression and depressive disorder; Childhood trauma Questionnaire (CTQ) is a 28-item 
self-report inventory that provides a brief screening for histories of abuse and neglect; The 
Emotion Regulation Scale (ERS) is a 36-item questionnaire to provide a comprehensive measure 
of the difficulties in emotion regulation; Global Perceived Early Life Stress Scale (GPELS) 
measures the occurrence of stressors in early life ; Interpersonal Support Evaluation Lists (ISEL) 
is a 40 item assessment to measure the perceived availability of four relatively independent 
social support resources; Positive and Negative Affective States (PANAS) is a 20 item 
assessment comprised of two mood scales, one measuring positive affect and the other 
measuring negative affect. Obsessive Compulsive Disorder Scale (OCDS) is a 14 item test to 
measure obsessionality and compulsion; Pittsburgh Sleep Quality Index (PSQI) measures the 
quality and patterns of seven areas of sleep; Stanford Sleepiness Scale uses a 7 point scale to 
measure the degree of sleepiness   
 
Stress-Related Assessments:  
Perceived Stress Scale (PSS; Cohen et al., 1983) assesses the degree to which situations are 
appraised as threatening or otherwise demanding and that there are insufficient resources to cope 
with the situation. This global measure of perceived stress has been widely used in the behavioral 
medicine literature to examine the effects of stress on disease and treatment outcome. The PSS is 
a 14 item self-report measure with adequate reliability and both predictive and construct validity. 
It has been shown to predict smoking reduction in a smoking cessation treatment program 
(Cohen et al., 1983; Cohen & Lichtenstein, 1990). It will be used to assess stress levels weekly in 
study patients during treatment and at follow-up appointments.(copy included in Appendix B).  
Chronic Stress Checklist  
 
 
Cognitive assessments 
All tasks are administered at baseline (day 4 of inpatient admission) and following three weeks 
of prazosin treatment.  All CANTAB tasks incorporate testing modes suitable for use across 
multiple time-points and are presented on a touch-screen computer. 
 


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1) Motor Screening: familiarizes subjects with the equipment and provides an index of motor 
performance.  Ten flashing crosses are presented (one at a time) on the screen and subjects are 
required to place their index finger on the center point of each cross to stop it flashing (2 min) 
 
2) Pattern and Spatial Recognition: Pattern recognition: participants are shown 12 colored 
abstract patterns, one at a time, for three seconds.  A recognition phase follows where the 12 
"target" patterns are shown in reverse order and paired with a novel pattern.  Participants must 
touch the pattern they recognized from the presentation phase. Spatial recognition: five white 
boxes are presented, one at a time for three seconds, in different locations on the screen.  In the 
recognition phase, five "target" boxes are shown again in reverse order and paired with a second 
box, located in a novel location. Participants must touch the box that is in the same location as 
the one shown in the presentation phase. Response latency and errors are recorded in both tasks 
(5 min each). 
 
3) Paired Associates Learning: Six white boxes are presented in a circle around the screen. Each 
of the boxes open up in a random sequence revealing an abstract pattern "inside". The patterns 
are then displayed individually in the center of the screen and participants are requested to touch 
the box in which they had seen each of the patterns. Participants perform 2-trials of one pattern-
location association, 2-trials of two pattern-locations and 2-trials of three pattern-locations. One-
trial of six pattern-locations and 1-trial of eight pattern-locations is then presented.  If an error is 
made, a "reminder" phase is shown.  Participants are allowed nine "reminder" phases for each 
trial, making a total of 10 attempts prior to the task being terminated. Number of presentations 
required on each trial; total number of patterns successfully located on initial presentation and 
total number of errors made on each trial are recorded (10 mins) 
 
4) Spatial working memory: Participants must search through a display of boxes to find "hidden" 
blue tokens. Only one token is hidden at any one time, and once a token is found in a particular 
box, that box is not used again to conceal other counters. There are two types of search error: a) 
returning to a box in which a blue token has already been found ("Between Search Error") and b) 
returning to a box (in the same search sequence) that is empty ("Within Search Error").  Each 
participant is required to attempt four 3-box trials, four 4-box trials, four 6-box trials and four 8-
box trials. In addition, participants receive a "search strategy" score reflecting ability to employ 
an optimal strategy to minimize errors. (8 mins) 
 
5) Three-Dimensional IDED: The ability to form, maintain and shift attentional set is assessed 
through learning a series of two alternative forced choice discriminations and their reversals. 
Stimuli vary along three possible dimensions (color, shape, number).  In the "intra-dimensional 
shift" stage, the relevant dimension (color) remains unchanged despite the introduction of two 
completely novel stimuli.  In the final "extra-dimensional shift" stage participants are required to 
"shift" response set to a previously irrelevant dimension (shape).  Participants must achieve 6 
correct successive discriminations.  If these discriminations are not achieved following 50 
attempts, the task is terminated.  Errors and response latencies are recorded. (10 min) 
 
6) Affective Go/No Go:  A series of words appearing rapidly on the center of the screen.  All 
words are taken from two of three different affective categories: Positive (joyful), Negative 
(hopeless), and Neutral (element). The subject is given a target category, and is asked to press 


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the pad only when they see a word matching this category. Commission and omission errors 
latency are recorded. (10 min) 
 
7) Stop/Signal Task:  In the first part of this test, participants are required to press the left hand 
button when they see a left-pointing arrow and the right hand button when they see a right-
pointing arrow. Sixteen practice trials are presented. In the second part, participants are told to 
continue pressing the buttons when they see the arrows, as before, but, if they hear an auditory 
signal (a beep), they should withhold their response. Direction errors, proportion of successful 
stops, and relevant reaction times are recorded. (20 min) 
 
8) Stroop Color Word Test (Golden, 1976).  On the initial trial participants are given 45 seconds 
to read as quickly as possible a list of 100 color words (red, green, blue) randomly arranged and 
printed in black ink. On the second trial participants have 45 seconds to identify as quickly as 
possible the color of 100 “XXXX” printed in either red, green or blue ink. The final trial consists 
of the 100 words presented in the initial trial in the colors presented in the second trial. In all 
cases, the word (i.e. red) is different from the color it is printed in (i.e. blue. (e.g. “red”). Subjects 
are given 45 seconds to name the color of the ink as quickly as possible. The number of raw 
items read for each trial is recorded and converted to standardized T scores. (5 min) 
 
9) RAVLT (Rey, 1964). This involves the repeated administration of a word list (List A) across 
five learning trials.  Free recall immediately follows each presentation. After the last learning 
trial a second “interference” list (List B) is presented prior to the free-recall of List B. 
Immediately following recall of List B, participants are again required to recall List A, without 
additional presentation. After a 40 minute delay, they are again asked to recall List A without 
presentation. No time limit is applied to the recall trials and participants are prompted to recall 
words in any order. Both stimulus word lists (A and B) are presented to the participants on tape, 
at a rate of one word per second.  Following the delayed recall trial, a recognition word list is 
presented comprising 45 words, (15 target words from List A; 15 from List B; 15 phonologically 
or semantically similar to those in List A).  Recall, recognition and error scores are recorded as 
well as interference, learning rate and forgetting (10 min) 
 
Other Relevant Measures:  
(q) Safety and Side Effects Measures:  The following safety measures will be assessed at each 
contact with the patient: (i) Sitting vital signs: including heart rate, systolic and diastolic blood 
pressure will be assessed daily for inpatient subjects, and 2 times a week for outpatient subjects. 
(ii) Laboratory chemistry will be assessed upon treatment entry and during the week of labs. 
(iii) Adverse Events/Side Effects:  A Systematic Assessment of Treatment Emergent Events 
(SAFTEE) will be assessed at each visit to assess any adverse events of side effects that may 
have occurred in patients during the treatment study. The scale will assess physical or health 
problems since the last visit, including changes in physical appearance and changes in 
functioning due to physical condition (see Appendix B, SAFTEE assessment page 1). If the 
subject describes any changes a detailed assessed of the symptom or complaint will be conducted 
using the SAFTEE form pages 2-4. An adverse events form developed by our group will be 
completed for the event according to the criteria outlined in the Data Safety Monitoring Plan in 
the Human Subjects section. Thus, study staff and investigators will evaluate all adverse events, 
and an adverse event report will be completed and the Yale HIC, the CMHC pharmacy, and the 


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YCCI Research Subject Advocate, will be notified (see Data Safety Monitoring Plan for 
procedures for safety monitoring and reporting of adverse events). Adverse events/side effects 
will be assessed weekly throughout the study.    
(r) The Commitment to Abstinence Scale adapted by Hall, Havassay and Weissman (1990) from 
Marlatt, Curry & Gordon (1980) will be included at baseline and monthly. Commitment to 
abstinence is assessed by asking subjects to endorse one of six abstinence goals: (a) total 
abstinence, never use again; (b) total abstinence but realized that a slip is possible; (c) occasional 
use when urge strongly felt; (d) temporary abstinence; (e) controlled use; (f) no goal.  Ratings are 
also made of desire to abstain, expected success in abstaining and the expected difficulty of 
abstaining using 10-point scales. 
(s) The Change Assessment Scale, a 32-item self-report, was developed to assess readiness for 
change according to Prochaska and DiClemente's model (Prochaska & DiClemente, 1982). It 
will be used at baseline and monthly to assess motivation to change alcohol use behaviors. 
 
 
 
 
 
 
TABLE 1: Schedule of Assessments 
_______________________________________________________________________ 
 
 
 
 
 
 
 
Timing of Assessments 
Purpose/Measure 
             Rater       Baseline      2-3x/wk  
Weekly 
       Monthly
 
Post-Tx 
   Follow-up    
______________________________________________________________________________
____________ 
Screening, Inclusion/Exclusion Criteria 
Socio-demographic Info 
RA 
 
X 
Physical Examination Phy 
   
X 
 
Medical History 
 
Phy/PSY 
  
X 
 
SF-36  
 
 
P 
 
X 
Laboratory chemistry Phy/PSY 
   
X 
 
      
             
 
 
Psychiatric        
Psychiatric Evaluation 
PSY 
  
 X 
SCID -I & II  
PC 
  
 X 
 
 
 
          
 
Assessment of Outcome 
Vital signs 
 
N/PSY  
X 
X 
 
 
 
X 
        
X 
 
 
Withdrawal Ass (CIWA) 
P/N 
   
X 
X 
 
 
X 
        
X 
 
Adverse Events/Safety 
N/PSY  
X 
X 
 
 
X 
        
X 
Substance Use: 
ASI 
 
 
 
RA 
  
X 
 
   
 
 
        
X 
 
 
ADS  
 
 
P 
 
X 
 
 
 
X 
 
X 
AUQ  
 
 
P 
 
X 
     X  
 
X 
 
X 


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Urinalysis  
 
RA 
  
X 
X 
 
 
 
X 
        
X 
 
 
Substance Use Cal. 
RA 
   
X 
 
     X  
X 
X 
        
X 
 
Treatment Services Rev. 
RA 
 
X 
 
 
 
X 
        
X 
 
 
Smoking History Q            RA                       X          
 
 
X 
 
X 
Psychological Symptoms 
Hamilton Anxiety Scale 
P 
 
X 
    X 
 
 
X 
        
X 
 
CESD  
 
 
P 
 
X 
    X 
 
 
X 
        
X 
 
CPI-SO 
 
 
P 
 
X 
CTQ  
 
 
P 
 
X 
ERS 
 
 
 
P 
 
X 
ISEL  
 
 
P 
 
X 
NPAS  
 
 
P 
 
X 
 
OCDS  
 
 
P 
 
X 
Stanford Sleepiness Sc 
P 
 
 
 
    X 
Stress Measures 
Perceived Stress Sc. P 
  
 
 
    X 
 
 
X 
        
X 
 
Chronic Stress Checklist     
P 
 
X 
 
 
 
 
 
 
GPELS 
 
 
P 
 
X 
Cognitive Measures 
Motor Screening 
 
RA 
 
X 
 
 
 
 
X 
Pattern & Spatial Recog 
RA 
 
X 
 
 
 
 
X 
Paired Associates Learning 
RA 
 
X 
 
 
 
 
X 
Spatial Working Memory 
RA 
 
X 
 
 
 
 
X 
IDED  
 
               RA  
X 
 
 
 
 
X 
RAVLT 
 
 
RA  
 
X 
 
 
 
 
X 
Stroop  
 
               RA  
X 
 
 
 
 
X 
Stop/Signal Test 
 
RA 
 
X 
 
 
 
 
X 
Go /NoGo 
 
 
 
Other Measures 
SAFTEE 
 
P 
 
 
 
  X 
¬_¬____ 
Note:  N/PC: Study Nurse/Project Coordinator; Phy: CMU Physician; PSY: Study Psychiatrist;  
RA=Research Assistant; P=Patient; 
 
 
4. Genetic Testing    N/A 
 
 
A. Describe 
i. the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned 
ii. the plan for the collection of material or the conditions under which material will 
be received 


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iii. the types of information about the donor/individual contributors that will be 
entered into a database 
iv. the methods to uphold confidentiality 
 
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects? 
C. Is widespread sharing of materials planned? 
D. When and under what conditions will materials be stripped of all identifiers? 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials? 
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? 
F. Describe the provisions for protection of participant privacy 
G. Describe the methods for the security of storage and sharing of materials  
 
Thirty-two cc’s of whole blood will be collected from patients during day 1 of the laboratory 
sessions for the purposes of understanding genetic factors that may influence the way in which 
the subject behaves/feels in response to alcohol. For subjects completing the outpatient plan, this 
blood draw will be done at their intake appointment. Samples will be marked only by study ID 
numbers and no other personal identifying information will be sent to the laboratory. Once 
genetic analysis are conducted the data will be sent back to our laboratory and the genetic data 
will be stored in computerized research records that will then be analyzed by group analysis. 
There is no plan to return specimens back. If the subject chooses to withdraw their sample, the 
subject will be informed that the genetic blood sample will be stripped of all identifiers  
(anonymized) including study id number. 
 
No immortalization of cell lines, animal studies or whole exome or genome sequencing is/are 
currently planned. Samples are stored in a de-identified sense, and candidate genes will be 
explored to assess treatment response to prazosin. We have no current funding to conduct genetic 
analysis. All treatment outcome data are de-identified and there is no way to link subject PHI to 
genetic or clinical outcome data. Samples may also be contributed to the NIH data bank for 
analysis of treatment response. Individual level donor’s personal health information will not be 
included; race, gender, age and education level are the only variables included but these do not 
provide individual level information, but rather are aggregated as group level data.  
 
The sharing of materials and/or distributing for future research projects is limited to contributing 
to the NIH data bank, as NIH is the funding source. Individual level donor’s personal health 
information will not be included; race, gender, age and education level are the only variables 
included but these do not provide individual level information. Widespread sharing of materials 
is not planned. 
 
The MetricWire smartphone app, has been designed to be compliant with HIPAA regulations. 
The app encrypts data on participants’ phones and while data is wirelessly transferred. The app 
randomly generates a 24-digit identification code that contains numbers and letters, and remains 
consistent for each subject throughout the smartphone assessment phase. This identification code 


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will be linked by the research team with the numerical Subject ID that is assigned to subjects 
upon their initial laboratory visit.  
 
 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study. 
 
One hundred and fifty treatment seeking alcohol dependent individuals (men and women) will be 
recruited to participate in this laboratory and medication study.  Subjects will be recruited from 
the community without regard to sex, racial, or ethnic background. We expect a representative 
sample will drawn from the community. 
 
 
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement. 
 
 Children 
 
 
 Healthy  
 
Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners  
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees  
 Pregnant women and/or fetuses 
 Yale Students  
 
Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements) 
 
 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion? 
 
One hundred and fifty subjects who meet current DSM-IV criteria for alcohol dependence and 
are seeking treatment will be recruited to participate in this study. The following inclusion and 
exclusion criteria will be followed: 
 
Inclusion Criteria: 
i. Male or female individuals, ages 18 and above, meeting current DSM-IV criteria for alcohol 
dependence. 
ii. Meet current DSM-IV criteria for alcohol dependence  
iii. Subject has voluntarily given informed consent and signed the informed consent document. 
iv. Able to read English and complete study evaluations.  
 
Exclusion Criteria: 
i. Meet current criteria for abuse or dependence on another psychoactive substance, excluding 
cannabis, nicotine and caffeine; 


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ii. Current use of any psychoactive drugs, including anxiolytics, antidepressants (except SSRIs), 
naltrexone or antabuse;  
iii. Any psychotic disorder or current Axis I psychiatric symptoms requiring specific attention, 
including need for psychiatric medications for current major depression and anxiety disorders 
iv. Significant underlying medical conditions such as cerebral, renal, thyroid, hepatic, or cardiac 
pathology which in the opinion of study physician would preclude patient from fully cooperating 
or be of potential harm during the course of the study; 
v. Hypotensive individuals with sitting blood pressure below 90/60 mmHG. 
 
 
8. How will eligibility be determined, and by whom?  
 
All subjects will be screened and recruited into the study by the research assistant coordinator. 
Potential subjects will meet with the research assistant coordinator who will, after an initial 
screening over the telephone/in person, determine eligibility based on inclusion/exclusion 
criteria. The initial screening will collect basic demographic information and ask questions 
specific to the inclusion/exclusion criteria.  The initial screening will take approximately 5-10 
minutes. She will explain all study procedures and risk/benefits and obtain informed consent. 
After obtaining written informed consent for participation in the study, one of the study 
physicians will interview the subject and review all medical and psychiatric data prior to 
enrolling the subject and beginning medication. 
 
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.  
 
i) Alcohol Detoxification:  
 
The risks associated with stopping drinking may include: anxiety, shakiness, confusion, rapid 
heart rate, fever and in rare cases, life-threatening seizures. To achieve abstinence from alcohol 
dependence, participants are reinforced for abstinence using the fishbowl and monitored three 
times weekly. The Clinical Institute Withdrawal Assessment – Alcohol Revised (CIWA-Ar) will 
be used during this period to assess withdrawal symptoms. In the case of moderate symptoms of 
alcohol withdrawal (CIWA score between 8-12), study physician, Dr Gretchen Hermes will 
provide initial treatment and monitoring and we will facilitate referral for detoxification at 
Southern Connecticut Rehabilitation Center (SCRC), with whom the study PI and the Stress 
Center research staff have a good working relationship for such transfers. Please note that the 
SCRC facility is only 2 blocks away from the Yale Stress Center.  In cases of severe alcohol 
withdrawal (CIWA-Ar scores at 13 or above), the subject will be immediately transported to the 
Yale New Haven Hospital Emergency Room (Yale ER) for full medical assessment and 
treatment of alcohol withdrawal. After the subject completes detoxification he/she will be 
allowed to return to the study for enrollment and participation. We will continue to monitor for 
alcohol withdrawal throughout the study period and facilitate referral to higher level of care such 
as inpatient treatment, as needed. If the subject is unable to stay abstinent from alcohol, he will 
be withdrawn from the study and also referred to inpatient and intensive outpatient treatment for 
alcohol use disorders. 


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Alcohol Detoxification in the Inpatient Unit:  To achieve abstinence from alcohol dependence, 
participants that are recruited into the inpatient portion of the study are simultaneously admitted 
to a clinical inpatient unit (the CNRU) for clinical treatment. This is separate from the research 
protocol which begins after detoxification (please see consent form) and does not guarantee 
participation into the research study.  However, following clinical admission to the CNRU a few 
participants may be required to go through medicated detoxification which, in rare case, may 
result in life-threatening seizures. The risks of stopping drinking and the medical care provided 
for these possible risks will be thoroughly reviewed upon entry into the CNRU by the qualified 
medical staff. Detoxification medications will be administered by medical staff on the CNRU 
based on need in order to ensure a safe withdrawal. Clinical Institute Withdrawal Assessment for 
Alcohol (CIWA) scores will be taken at admission by CNRU staff to monitor alcohol withdrawal 
symptoms. Librium 50mg, Ativan 2mg or other treatment will be provided as appropriate for 
clinical evidence of alcohol withdrawal symptoms. If CIWA scores are greater than 13, 
monitoring will occur every two hours around the clock. If CIWA scores are less than 8, 
monitoring will occur every 6 hours while awake.  In addition to assessing CIWA scores for 
PRN medication, subjects who have a history of major alcohol withdrawal symptoms (e.g. 
withdrawal seizures or delirium tremens) will be placed on a standing dose of Librium 50mg tid 
for the first 24 hours with continued treatment as clinically appropriate. 
 
ii)   Prazosin Treatment: 
 
Prazosin (marketed by Pfizer) is an alpha-1-adrenergic agonist, that is known to preferentially 
bind to post-synaptic alpha1-adrenergic receptors that are highly concentrated in the prefrontal 
cortical regions (Taylor & Raskind, 2002). It has been shown to have beneficial effects on PTSD 
symptoms (Taylor et al., 2006; Taylor & Raskind, 2000) and recent data has supported it’s use in 
alcohol/cocaine dependence (Simpson et al., in press; Zhang & Kosten, 2005). The major 
advantage that Prazosin has over clonidine is that it is less sedating and with less hypotensive 
effects than clonidine. More specifically, Clonidine is a non-selective agonist of alpha 2a, 2 b 
and 2c receptors, which accounts for its sedative and hypotensive effects. Conversely, Prazosin 
and guanfacine are preferential for the alpha-1 and alpha-2a receptors respectively; thus, limiting 
sedative and hypotensive effects (Arnsten et al., 1988). Additionally, the plasma half life of 
Prazosin is 2-3 hours, compared to 4-10 hours for clonidine (Physician Desk Reference, 2007), 
allowing rapid titration and limiting accumulation of the drug. 
Studies using Prazosin in patients with PTSD and alcohol dependence have used doses ranging 
from 2 to 16 mg/day. Commonly reported side effects with Prazosin have been fatigue, sedation 
and light-headedness, which are generally rated as mild in intensity. Possible side effects 
commonly associated with Prazosin include: low blood pressure, some drowsiness, dryness of 
mouth and/or throat and dizziness. No serious side effects have been noted in adult populations. 
There is no evidence that Prazosin will pose a greater risk to the pilot study population.  Subjects 
will not be started on the study medication until no alcohol is present in their system. Throughout 
the study, subjects will be monitored for alcohol consumption. If a subject were to resume using 
alcohol, study medication will be discontinued.  
 
iii) Laboratory Sessions: 
 


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(a) Intravenous (IV) Catheter: When an IV is started, there is some risk that subjects may 
develop a bruise or bleeding where the vein is punctured. If this occurs, appropriate treatment 
will be instituted immediately. On extremely rare occasions, fainting, blood clot or infection may 
occur. 
 
 
(b) Drawing of Blood: During each laboratory session, about 120ml of blood will be drawn to 
measure stress hormone levels that may change during the session. The amount of blood drawn 
for each of the five tests over three laboratory sessions is equal to a little over one-half the blood 
obtained during a regular blood donation. The total amount of blood drawn over the entire study 
period is 424 ml of blood (360ml total for laboratory sessions, 32 ml for genetic measures, 16 ml 
to measure molecular changes, and 16ml to measure estradiol levels). The total amount of blood 
drawn is within HHS guidelines of 450 ml within 8 research weeks. People who are in good 
health are not usually affected by this kind of blood loss. However, to be safe, subjects will be 
warned against donating blood for at least eight weeks after completing this study.   
 
(c) The Imagery Procedures: The imagery method involves reliving a personal stressful event 
and can be somewhat anxiety provoking at the time of the task. Our previous experience has 
shown that once the task is over, there is very little anxiety that carries over, thus posing minimal 
risk. The alcohol cue imagery involves reliving a personal experience involving alcohol-related 
stimuli associated with alcohol use. While subjects may feel aroused by the alcohol cue imagery, 
relaxation procedures have been shown to be successful in reducing the physiological changes 
associated with cue exposure and stressful imagery.  It is likely that moderate craving for 
alcohol, may occur due to subjects' imagining and reliving stressful events and alcohol cue 
related events. It is also possible that craving for alcohol may linger even after the task.  
 
iv) Breath and urine collections 
Breath screening and urine collections are performed primarily as safeguards to contamination of 
data and should add no risks other than those normally associated with these procedures.  
 
v) Rating Scales and Questionnaires 
These are all noninvasive and should add no risk.  The major disadvantages are the time taken to 
complete them, and possible breach of confidentiality.  Our past experience with these measures 
indicates that they are acceptable to subjects.  Careful efforts aimed at maintaining 
confidentiality have been effective in previous research, and only patients’ code numbers will be 
recorded on the forms themselves to protect confidentiality. 
 
vi) Nonspecific Risks. Other risks from the counseling, rating scales and urine collections are not 
beyond usual clinical procedures in a substance abuse treatment program.  Confidentiality of 
these results are specifically protected by Federal laws, and all records will be identified by code 
number only, with the master file kept under lock by the Principal Investigator or Data Manager. 
 
 
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized. 
 
i) Alcohol Detoxification 


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As this protocol includes patients with alcohol use disorders and requires abstinence from 
alcohol, some patients may require medical detoxification from alcohol and thus this protocol 
has been deemed a greater than minimal risk protocol. Detoxification from alcohol typically lasts 
between 1 to 4 days and in some rare cases up to a week.  While detoxification from alcohol 
presents greater than minimal risks, including the possibility of life-threatening seizures, clinical 
staff and assessments are in place at the Yale Stress Center to ensure that the risks are minimized 
to the greatest extent possible. The risks of all treatment procedures including acute medical 
detoxification are thoroughly explained to all patients by the trained clinical research staff at the 
YSC. Research staff are fully trained in administering the Clinical Institute Withdrawal 
Assessment for Alcohol (CIWA-Ar) and protocols are in include the PI, and medical staff, Dr 
Gretchen Hermes and research nurse Mary Kurjanowicz for consultation and referral to the 
YNHH –ER and/or to SCRC for medical detoxification if required. 
 
ii) Prazosin treatment:   
Inclusion criteria and the use of trained research assistants in the initial screening will help to 
avoid the acceptance of subjects that are inappropriate for the study.  There are no known serious 
adverse effects of Prazosin. The following precautions will be taken: 1. Vital signs (heart rate, 
blood pressure, body temperature) will be assessed daily during the inpatient phase of the study, 
and 2 times weekly during the outpatient phase of the study. Additional vital sign readings will 
be taken if subjects report symptoms and when medication dosage is changed. 2. Any clinically 
significant cardiac signs or other adverse symptoms will be monitored closely at each visit to the 
clinic. 
 
iii) Laboratory Procedures: 
The laboratory sessions will be conducted while subjects are hospitalized in the treatment and 
research inpatient unit (CNRU). Since subjects will be treatment-seeking individuals, they will 
participate in inpatient treatment during their stay on the CNRU. For subjects who have 
difficulty reducing their craving levels, relaxation procedures will be conducted to return craving 
levels to baseline after the imagery sessions. We have found that relaxation procedures are 
particularly effective in reducing craving levels after alcohol cue exposure (Margolin et al., 
1994; Sinha et al., 1999a).   
 
To enhance their response to relaxation procedures, subjects will also be trained on relaxation 
procedures in a session prior to the laboratory sessions.  
 
Any subject that reports residual alcohol craving or emotional discomfort after completion of 
laboratory sessions will receive an individual counseling session by a licensed psychologist (the 
PI or her designee) who are experienced in relapse prevention therapy. The focus of this session 
will be coping with high-risk situations and cravings. 
 
 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24. 


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a.  
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? This protocol has been deemed a greater than minimal/ 
moderate risk protocol. 
b. 
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  N/A 
c. 
Copy, paste, and then tailor an appropriate Data and Safety Monitoring Plan  
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for 
i. Minimal risk 
ii. Greater than minimal/moderate risk 
iii. High risk 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A 
 
Greater Than Minimal Risk DSMP 
 
1. Personnel responsible for the safety review and its frequency: 
 
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency, which must be 
conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought).  During the review process, the principal investigator (monitor) will evaluate whether 
the study should continue unchanged, require modification/amendment, or close to enrollment. 
Either the principal investigator, the IRB or DSM, have the authority to stop or suspend the 
study or require modifications. 
 
2. The risks associated with the current study are deemed greater than minimal for the 
following reasons:  
We do not view the risks associated with the withdrawal of alcohol as minimal risks. 
Although we have assessed the proposed study as one of greater than minimal risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or otherwise, to 
occur since it is not possible to predict with certainty the absolute risk in any given individual 
or in advance of first-hand experience with the proposed study methods. Therefore, we 
provide a plan for monitoring the data and safety of the proposed study as follows: 
 
3. Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and attributed to 
the study procedures / design by the principal investigator, Dr Rajita Sinha according to the 
following categories: 
 
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s). 
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s). 
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s). 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s). 
 


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4. Plan for Grading Adverse Events: 
 
The following scale will be used in grading the severity of adverse events noted during the 
study: 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe  
 
5. Plan for Determining Seriousness of Adverse Events: 
Serious Adverse Events: 
In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it 
results in any of the following outcomes: 
 
1. Death; 
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization;  
3. A persistent or significant disability or incapacity;  
4. A congenital anomaly or birth defect; OR 
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition.  
 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRB is necessary. 
 
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB 
 
 
The principal investigator will report the following types of events to the IRB:  
Any incident, experience or outcome that meets ALL 3 of the following criteria: 
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol 
and informed consent document and (b) the characteristics of the subject population being 
studied; AND  
2. Is related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or 
recognized. 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or 
non-medical in nature, and include – but are not limited to – serious, unexpected, and related 
adverse events and unanticipated adverse device effects.  Please note that adverse events are 
reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above. 


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These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using 
the appropriate forms found on the website. All related events involving risk but not meeting 
the prompt reporting requirements described in IRB Policy 710 should be reported to the IRB 
in summary form at the time of continuing review. If appropriate, such summary may be a 
simple brief statement that events have occurred at the expected frequency and level of severity 
as previously documented.  In lieu of a summary of external events, a current DSMB report 
can be submitted for research studies that are subject to oversight by a DSMB (or other 
monitoring entity that is monitoring the study on behalf of an industry sponsor). 
 
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies. 
 
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified: 
x All Co-Investigators listed on the protocol. 
□ Yale Cancer Center Data and Safety Monitoring Committee (DSMC) 
x National Institutes of Health 
□ Food and Drug Administration (Physician-Sponsored IND #_______) 
□ Medical Research Foundation (Grant______) 
□ Study Sponsor 
x DSM 
 
The principal investigator, Dr Rajita Sinha, will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form 
are required. 
 
As participants are not enrolled into the research study until they are in good medical health 
this study does not require a data safety monitoring board. However, as this protocol includes 
patients with alcohol use disorders and requires abstinence from alcohol, some patients may 
require medical detoxification from alcohol and thus this protocol has been deemed a greater 
than minimal risk protocol. Detoxification from alcohol typically lasts between 1 to 4 days and 
in some rare cases up to a week.  While detoxification from alcohol presents greater than 
minimal risks, including the possibility of life-threatening seizures, clinical staff and 
assessments are in place at the Yale Stress Center to ensure that the risks are minimized to the 
greatest extent possible.  
 
a) The risks of all treatment procedures including acute medical detoxification are thoroughly 
explained to all patients by the trained clinical research staff at the YSC.    
 
b) Research staff are fully trained in administering the Clinical Institute Withdrawal 
Assessment for Alcohol (CIWA-Ar) and protocols are in include the PI, and medical staff, Dr 


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Gretchen Hermes and research nurse Mary Kurjanowicz for consultation and referral to the 
YNHH –ER and/or to SCRC for medical detoxification if required. 
 
As this is a phase II clinical efficacy study, we have established a  data safety monitoring board.  
The DSMB for this trial is composed of the following three clinical investigators as listed below 
who are not affiliated with this study, and do not have an interest in the outcomes of this study. 
1). Dr. Gerard Sanacora is Professor at the Department of Psychiatry at Yale University. He is an 
experienced clinical researcher who is familiar with the population under study. He is PI on 
several pharmacological and behavioral treatment and laboratory studies and is extremely 
familiar with the NIH requirements for data safety monitoring. He is also a member of the Yale 
Human Investigation Committee and is therefore very familiar with safety monitoring 
procedures.  
2). Dr. Graeme Mason is an Associate Professor jointly appointed at the Department of 
Diagnostic Radiology in the Division of Bioimaging Sciences and the Department of Psychiatry 
at Yale University.  He is the Director of Psychiatric MRS and the Director of Metabolic 
Modeling.  He is PI on several imaging studies, including studies related to addiction.  
3). Dr. Suchitra Krishnan-Sarin is an Associate Professor at the Department of Psychiatry at Yale 
University.  She is PI and Co-PI on several NIH funded studies examining at risk adolescents, 
addiction treatment and the neuroscience of addiction. 
 
The DSMB members will evaluate all Adverse and Serious Adverse Events, and will assist the PI 
in preparing and sending the pertinent expedited reports to the appropriate persons as outlined 
below. They will monitor the study quarterly and review all adverse event sheets completed during 
that period. They will assist the PI in making critical decisions regarding a particular subject 
continuing in a study for safety reasons. They will review the summary of all Adverse Events for 
this study, which will be reported annually to the Yale Human Investigation Committee (HIC) and 
study sponsors. 
 
12. Statistical Considerations: Describe the statistical analyses that support the study design.  
 
Power Analysis: Sample size estimates for the laboratory study is based on our preliminary 
study of Prazosin (Fox et al., 2011) and previous pilot trials of Prazosin (Simpson et al., 2009).  
Moderate to large effect sizes were obtained for significant interaction effects in alcohol craving 
(2-way: f =.44; 3-way: .81), anxiety (2-way: f=1.16; 3-way: .87) and Cortisol/ACTH ratio (2-
way: f=.83 and f=.71; 3-way: f=.65). A conservative effect size of f =.44 for detection of 
significant interactions, and with power=.80, with p<.05, sample size estimates (Cohen, 1988, 
p.384) indicated that we would require 18 subjects per cell to detect the specified interaction 
hypotheses of the laboratory study. Including a 5-10% attrition rate, we estimated that 20 
subjects per cell would provide adequate power to test the laboratory aims.  
Sample size estimates for the clinical trial outcomes were determined from effect sizes derived 
from Simpson et al (2009). In this study, 6/7 PZ subjects remained abstinent and drank an 
average of 3.2 drinking days/wk after achieving full dose compared to the PL group where 4/10 
were abstinent and drank on 5.5 drinking days/wk. These data yielded large effect sizes (d=1.26 
for mean drinking days; and w=1.23 for proportion abstinent). As we proposed a 2X 2 design 


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with medication and alcohol withdrawal/anxiety, we used a conservative effect size of d= .60 for 
detection of significant main effects and possible interactions in the clinical trial. At this effect 
size and power=.80, with p<.05, sample size estimates from Cohen (1988, p.258) indicated that 
we would require 25 subjects per cell to adequately assess the proposed hypotheses for the 
clinical trial (total N =100). Including a 15-20% drop-out after enrollment, we estimated 
recruitment of 120 AD patients into the trial to ensure adequate power for the trial.  
 
Data Analysis for Laboratory Study: Repeated measures ANOVA and mixed model procedures 
to assess treatment group differences in alcohol craving and stress related changes (heart rate, 
blood pressure, HPA and catecholamine responses) during laboratory exposure to stress and drug 
cues as compared to neutral imagery conditions. Non-parametric tests will be used to assess 
occurrence of side effects, treatment retention rates, alcohol use measures, CIWA scores and 
perceived stress scores during the outpatient treatment phase. The number and type of AE’s for 
the two treatment groups will be conducted using t-tests, chi-square tests and ANOVAs as 
appropriate. Findings will be used to estimate effect sizes for the medication and guide the larger 
randomized clinical trial.   
 
Data Analysis for the 12-week clinical trial Study: For this phase, the following moderator and 
primary and secondary outcomes are specified: 
 
Primary Moderator Measure: Alcohol withdrawal symptoms, as measured by the CIWA 
alcohol withdrawal scale, 
 
Primary Outcome Measures in the outpatient treatment phase: These are: (1) Heavy drinking 
days (5 or more for men, 4 or more for women) during the 12 week period, and (2) Any drinking 
days. Both will be assessed daily using smartphone or interactive voice recording surveys 
completed by the patients and also with weekly urine drug screens/breathalyzer reports and self 
report of drug use on the Substance Use Calendar. 
 
Secondary Outcome Measures in the outpatient treatment phase:  Secondary outcome measures 
will include alcohol craving scales, anxiety (Hamilton Anxiety Scale) and depression (CES-D) 
and sleep quality using the Pittsburgh Sleep Quality Index – PSQI). 
  
Data Analytic Procedures: Since patients will be randomly assigned to the Prazosin and PLA 
treatment groups and Intent-to-Treat (ITT) analyses will be conducted for the clinical outcomes. 
We do not expect the groups to be different on demographic, prior drug use history or other 
predictor variables.  Nevertheless, prior to undertaking the specific analysis for each aim, we will 
compare the treatment groups on demographic variables, substance use characteristics and 
previous psychiatric history/predictor variables using t-tests/chi-square analyses as appropriate. 
If any group differences are found, the specific variable will be entered as a covariate in all of the 
specific analyses.  As there are no established thresholds for AW effects on drinking outcomes in 
outpatient treatment, baseline AW will be assessed as continuous measure in all overall analyses. 
Thus, intent-to-treat (ITT) analyses with baseline AW severity (mean-centered continuous 
CIWA-Ar scores) as a moderator of Time (Pre-Full Dose(FD): weeks 1-2; Post FD: weeks 3-12) 
were conducted with linear or generalized linear mixed effect (LME/GLME) piecewise growth 
models for continuous and binary outcomes. Due to a positive skew, number of drinks per day 


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(AvgD) will be log-transformed. Control variables in all analyses will be gender (0=male), 
inpatient (0=outpatient), and dropout (0=completer, 1=dropout/withdrawn prior to 4 weeks, 
2=dropout/withdrawn after 4 weeks). For secondary outcomes linear mixed models with random 
intercepts will be used to assess the effect of AW, Treatment and Week (factor 1-12, or Weeks 4, 
8 and 12) on the secondary outcome variables. All control variables from the main outcome 
analyses are included in the secondary outcome analyses. If significant interactions with AW are 
observed for primary or secondary outcome analyses, a median split of AW scores will be 
conducted to obtain Low and High AW groups and assess contrasts by treatment.   
 
Aims and Hypotheses for Laboratory and Treatment Outcome Components: All analyses of the 
laboratory and the treatment components will be based on the following specific aims and 
hypotheses: 
 
Specific Aim 1: To evaluate the effects of Prazosin on stress-induced alcohol craving and 
associated neuroadaptations in alcohol dependent individuals. Hypothesis 1: Prazosin will 
decrease stress-induced alcohol  craving and negative emotions in the laboratory as compared to 
placebo. 
  
This aim will be tested using mixed model analysis of variance procedures for each of the 
following dependent measures: VAS alcohol craving scale; VAS anxiety scale; brief CCQ; DES 
emotions of anger, sadness and fear; heart rate, blood pressure and HPA measures o ACTH and 
cortisol and NE and EPI.  
 
Specific Aim 2: To evaluate the efficacy of Prazosin versus Placebo in high alcohol withdrawal 
individuals on primary outcomes of: (a) heavy drinking days (HDD) over 12 week period; (b) 
Any drinking days (DD%). 
 
Hypothesis 2: In high alcohol withdrawal individuals, Prazosin group will show significant 
reductions in HDD% and DD% during the 12 week treatment period as compared to Placebo 
group. No differences between medication treatment groups in the Low alcohol withdrawal 
individuals will be observed.  
 
Secondary outcome measures such as alcohol craving, Anxiety, depression and sleep quality will 
be assessed. Findings PSS, COPE and LES scores will be examined.   
 
 
 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES 
 
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section. 
 
A.  DRUGS, BIOLOGICS and RADIOTRACERS 
 


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1. 
Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the 
drug(s) biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been 
granted and for what indication(s).  
 
Prazosin (marketed by Pfizer Inc) is an alpha-1-adrenergic agonist that is known to preferentially 
bind to post-synaptic alpha1-adrenergic receptors. Walker et al (2008) found that Prozaosin was 
effective in suppressing excessive alcohol consumption in rats, suggesting the involvement of the 
noradrenergic system in alcohol dependence. Sinpson et al. (2007) found similar findings in a 
pilot trial using prozosin for treatment of alcohol dependent  men and women. Prazosin therefore 
is an excellent candidate for treating alcohol seeking behaviors. It  may also be more easily 
tolerated than those medications which directly modulate these transmissions. 
 
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the 
FDA, or a radiotracer regulated by the RDRC, must provide the following information:   
a. What is the Investigational New Drug (IND) number assigned by the FDA? N/A 
b. Who holds the IND?  
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________ 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________ 
 
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step) 
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.      
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND 
and an exemption is being sought, review the following categories and complete the category 
that applies (and delete the inapplicable categories): 
 
Exempt Category 1 
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes: 
 
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in 
support of a new indication for use or to be used to support any other significant change in the 
labeling for the drug.  
 Yes  
 No 
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, 
and the intention of the investigation is NOT to support a significant change in the advertising 
for the product. 
 Yes  
 No 
iii.  The investigation does NOT involve a route of administration or dosage level or use in 
populations or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of the drug product. 
 Yes  
 No 


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iv. The investigation will be conducted in compliance with the requirements for institutional 
(HIC) review and with the requirements for informed consent of the FDA regulations (21 CFR 
Part 50  and 21 CFR Part 56). 
 Yes  
 No 
v.   The investigation will be conducted in compliance with the requirements regarding 
promotion and charging for investigational drugs. 
 Yes  
 No 
 
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption) 
 
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one 
or 
more of the following (check all that apply): 
 Blood grouping serum 
 Reagent red blood cells  
 Anti-human globulin 
 
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and 
 
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160. 
 
Exempt Category 3 
 
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60 
 
Exempt Category 4 
 
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND. 
 
 
2.  Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.  
 
 
 
Prazosin has been an approved medication by the FDA as a treatment for hypertension.  This pilot 
study is designed to examine the potential effect of Prazosin on alcohol cravings.  Prazosin has 
been used extensively off-label.  Prazosin does not pose any greater risk with the proposed study 
subjects than in subjects previously administered this medication.  As it is advised that alcohol 
should not be consumed while taking Prazosin, subjects will be closely monitored to ensure they 
are not drinking alcohol while taking the study medication. 
 
 
Studies using Prazosin in adults with PTSD or alcohol dependence have used doses ranging from 
2.0 to 20 mg/day (Raskind et al., 2002; Peskind et al., 2003; Raskind, 2003, 2002; Simpson et al, 
2007, July; Raskind et al., 2007). Prazosin was well tolerated with no reported serious adverse 


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effects both in research and in clinical use (PDR, 2007). Commonly reported side effects have 
been dizziness and light-headedness, drowsiness, headaches, lack of energy, and dryness of mouth. 
All side effects reported have been mild in nature and simple remedial action such as withholding 
a dose or adjusting the dose to a lower tolerated dose has been shown to reduce such side effects 
(Taylor et al, 2002).  
 
 
 
Simpson et al (2007) report that when administering 16mg per day of the drug, blood pressure 
changes were more evident in the prazosin group; however, the drop was still within the normal 
range.  Raskind et al. 2002, prescribed up to 20mg a day of the study medication. Three of the 36 
subjects reported orthostatic dizziness, headache, and lethargy, however no subject experienced 
syncope or a fall. The researchers report that previous administration of Prazosin for hypertension 
and benign prostate hypertrophy has shown that adverse effects tend to occur at initial lower does 
rather than at higher doses. Raskind et al, 2007 used a maximum dosage of 15mg which was 
maintained for 8 weeks. No significant differences in supine or standing blood pressure were found 
between the placebo and Prazosin groups. Transient dizziness was reported by some subjects, 
however, most of these subjects were also receiving concurrent antihypertensive or psychotropic 
medication, and was also reported by subjects in the placebo group. Therefore, it appears that a 
maximum maintenance dosage of 16mg of prazosin will be generally tolerable and safe for use in 
the proposed adult sample of subjects. 
 
 
3.  Source:  a) Identify the source of the drug or biologic to be used.  
 
 
Commercially available Prazosin capsules will be used. Prazosin HCl (generic) is marketed by 
Mylan Pharmaceuticals Inc in capsules containing 1mg,  2mg, or 5mg  of prazosin as the 
hydrochloride. The placebo medication will be prepared by the CMHC pharmacist. Both the 
Prazosin and the placebo will be dispensed by the CMHC pharmacist / YNHH IDS.      
 
 
Prazosin pills will be purchased through the CMHC pharmacy / YNHH IDS, and the research 
pharmacist will make up identical active and placebo capsules for medication administration. 
Subjects will be randomly assigned to three times daily dosing of Prazosin/placebo (with the 
exception of day 1 which is once daily, and days 2-3 twice daily).  
 
 
During weeks 1-4, inpatient subjects will self-administer study medication three times daily under 
supervision by nursing staff on the CNRU who will also monitor vital signs three times daily and 
side effects. Urines, alcohol craving, abstinence symptoms, mood and perceived stress scale and 
side effects will be assessed three times weekly.  
 
 
Outpatient subjects will come in for 2x weekly appointments and complete motivational 
enhancement, urine drug screens, breathalyzers, blood pressure monitoring, and counseling. 
Medication compliance will be monitored by blood draws done at week 4-5, to measure Prazosin 
levels, and through the monitoring of riboflavin as a urine marker. Riboflavin produces a bright 
yellow discoloration of the urine when the medication is taken 2 to 8 hours prior. After the first 
week all subjects will be taking morning and bedtimes doses of the medication. After this time, 
staff will easily be able to visually inspect the subject’s urine to determine whether the morning 


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dose has been taken. 25mg of riboflavin will be added to all doses of Prazosin and placebo by the 
pharmacist when capsules are made.   
 
 
Outpatient subjects will self-administer study medication, and will be reminded via daily 
interactive voice response (IVR) telephone monitoring or through the smartphone app MetricWire. 
Daily IVR telephone monitoring or MetricWire will be used to prompt patients to take study 
medication, and also to assess alcohol use, craving, craving resistance and mood states. 
Concordance between daily IVR or MetricWrire reports and alcohol positive urines will be 
evaluated for daily versus retrospective reporting. 
 
 
The MetricWire app (developed and owned by MetricWire Inc), has previously been utilized in 
clinical and academic research, and is HIPPA compliant. Subjects will complete a training session 
where we will assist them in installing the app on their smartphone device. At the end of the study, 
we will assist subjects in removing the app from their smartphone. If a subject does not own a 
smartphone, one will be supplied for their use, for the duration of the study, once a separate 
smartphone agreement is understood and signed. 
 
 
We expect most subjects will tolerate a dose of 16mg.  However, subjects who cannot tolerate a 
dosing schedule of 16mg will meet with the study psychiatrist to discuss a lower dose.  Subjects 
who cannot tolerate a minimum dose of 16mg will be maintained on maximum tolerated dose of 
Prazosin (up to 16.0 mg/day) and during week 12 the medication will be tapered down to 0 over 
the course of seven days. Some patients may be tapered prior to week 12.  
 
 
All study staff will remain blind to medication condition. Randomization will be conducted by the 
CMHC Pharmacy / YNHH IDS, which have extensive experience in random assignment of 
patients in medication trials. 
 
  
 
 
b) Is the drug provided free of charge to subjects? 
 Yes  
 No 
 
  
    If yes, by whom?  
 
4.  Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.  
 
Check applicable Investigational Drug Service utilized: 
     
   YNHH IDS                                                                      
  Yale Cancer Center  
     
   CMHC Pharmacy                                                           
  West Haven VA 
     
   PET Center                                                       
    None       
     
    Other:  
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
   
 
5.  Use of Placebo: 
 Not applicable to this research project 
 
If use of a placebo is planned, provide a justification which addresses the following: 
a. Describe the safety and efficacy of other available therapies. If there are no other 
available therapies, state this.  


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No other available therapies 
 
 
b.   State the maximum total length of time a participant may receive placebo while on the study.  
 
Subjects may receive placebo for 12 weeks.  
 
 
c.   Address the greatest potential harm that may come to a participant as a result of  receiving     
       placebo.  
 
No known risks. 
 
 
d.   Describe the procedures that are in place to safeguard participants receiving placebo.  
 
N/A 
 
6. Use of Controlled Substances: 
 
Will this research project involve the use of controlled substances in human subjects? 
 
 Yes  
 No  See HIC Application Instructions to view controlled substance listings.  
 
 
If yes, is the use of the controlled substance considered: 
 
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant. 
 
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information. 
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project 
 
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended? 
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access.  
 
 
 
 No    If no, explain why this is acceptable. 
 
 B.  DEVICES 
 
1. Are there any investigational devices used or investigational procedures performed at YNHH, e.g., 
YNHH Operating Room or YNHH Heart and Vascular Center?  Yes 
  No 
 
 
 
 
 
 
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES  
1. Targeted Enrollment: Give the number of subjects: 
a.   targeted for enrollment at Yale for this protocol   
150 alcohol dependent men and women 
b.    If this is a multi-site study, give the total number of subjects targeted across all sites      


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       N/A  
 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used. 
 
 Flyers 
 
 
 
 
 Internet/Web Postings 
 
 
 Radio 
 Posters  
 
 
 
 Mass E-mail Solicitation  
 
 Telephone 
 Letter 
 
 
 
  
 Departmental/Center Website 
 
 Television 
 Medical Record Review  
 
 Departmental/Center Research Boards 
 Newspaper 
 Departmental/Center Newsletters 
 Web-Based Clinical Trial Registries 
 
  YCCI Recruitment database 
 
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe): 
 
 
3.  Recruitment Procedures:  
a. Describe how potential subjects will be identified. 
b. Describe how potential subjects are contacted.  
c. Who is recruiting potential subjects?  
 
Subjects will be recruited through flyers and advertisements in local newspapers, internet/web 
postings, through YCCI’s recruitment systems: Epic’s Enterprise electronic medical record (EMR), 
OnCore, Yale’s clinical research management system (CRMS), and from community substance abuse 
treatment facilities. Subjects will participate in an initial phone screening and intake session to obtain 
informed consent with the research coordinator or research assistant, followed by physical 
examination and blood work to determine eligibility. 
 
 
4. Screening Procedures 
a. Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes  
 No 
b.  If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process.  
 
HEALTH INFORMATION TO BE COLLECTED: 
 
HIPAA identifiers:  
 Names  
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000.  
  Telephone numbers 
 Fax numbers  
 E-mail addresses 
 Social Security numbers  
 Medical record numbers 
 Health plan beneficiary numbers  
 Account numbers  


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  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older  
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers  
 Device identifiers and serial numbers  
 Web Universal Resource Locators (URLs)  
 Internet Protocol (IP) address numbers  
 Biometric identifiers, including finger and voice prints  
 Full face photographic images and any comparable images  
 Any other unique identifying numbers, characteristics, or codes  
 
 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  
 Yes, all subjects 
 Yes, some of the subjects 
 No 
 
If yes, describe the nature of this relationship. 
 
 
 
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
 
Choose one: For entire study: ______ For recruitment purposes only: X 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; N/A 
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data; Signed authorization is impracticable as subjects are screened over the phone 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 


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7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
 
  
 Compound Consent and Authorization form 
 
  
 HIPAA Research Authorization Form 
 
 
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent.  
 
Rachel Hart, Gina Lombardi, Nathan Grandpre, Jennifer Weinberg, Verica Milivojevic, Christian 
Panier, Arielle Rabinowitz 
 
 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making.  
 
Alcohol-dependent, treatment-seeking subjects will be interviewed by a research assistant to 
determine interest in participating in this inpatient/outpatient trial.  After obtaining written 
informed consent for participation in the study, one of the study physicians will interview the 
subject and review all medical and psychiatric data prior to admitting the subject and beginning 
medication. 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.  
 
The Investigator will not enroll subjects in the study who are determined to have limited decision-
making capacity.  Prior to consent procedures, breathalyzers will be conducted.  Subjects whose 
breathalyzer registers above the legal limit will not be consented for the study.  Subjects will be 
assessed throughout the consent process to ensure their understanding of consent procedures. 
 
 
11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects.  
 
4 Consents: 
Inpatient consent 
Inpatient with outpatient option consent 
Outpatient consent 
Inpatient no labs 
1 smartphone agreement 
 
 


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12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use.  
 
Non-English speaking subjects are not enrolled into this study 
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.   
 
 Not Requesting a consent waiver  
 
 Requesting a waiver of signed consent 
       
 Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity   
 No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.) 
 
  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
 
 
 
 
OR 
 
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No  
AND 


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d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No 
 
  
 B. Full waiver of consent: (No consent from subjects will be obtained for the activity.)  
 Requesting a waiver of consent for Recruitment/Screening only  
a. Does the research activity pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.) 
 
  
 
If requesting a full waiver of consent, please address the following: 
 
 
  
a. Does the research pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted.   
 No 
 
  
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No 
 
  
c. Why would the research be impracticable to conduct without the waiver?  
 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
         Confidentiality & Security of Data: 
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?    
 
Results of the physical examination, psychological assessments, self-reports, and data collected 
during the lab session will be collected and used for research. The proposed study will be 
conducted by specialized and trained research staff using standardized biophysiological and 
psychosocial assessments. Data collected and analyzed in the study will be derived from three 
main sources (1) semi-structured clinical interviews and self-rating scales: psychiatric history, 
medical history, levels of alcohol and substance use and demographic self-reports of age, race, 
socioeconomic status, marital status, educational and occupational levels. (2)  Biophysiological 
data: includes heart rate, blood pressure, saliva, prazosin levels, and plasma HPA axis markers 
(cortisol and ACTH). Additionally, health checks prior to  enrollment will comprise a physical 
examination and blood work. (3) Urine and breathalyzer data: will be used to confirm alcohol and 


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substance use.  It will be collected at intake, during 2x weekly appointments, and at follow-up 
interviews.   
        
b.    How will the research data be collected, recorded and stored?  
 
Research data is collected on paper assessments, and then scanned using the Teleform system. All 
research data is stored in two places--one as a hardcopy in a locked file, with records identified 
only by the participants study number, and the second in computerized databases protected by two-
level password systems on Yale encrypted desktop computers. 
 
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard    
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other 
 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study? 
 
Upon enrollment, all study subjects will be assigned a unique study number. The study number—
and no personal identifiers—will be used as labels for study records, samples and any other related 
research documentation. All electronic and digital files will be stored on the secure Yale network, 
and the PC accessing the network will be password protected and encrypted. All paper files, such 
as consent forms, will be stored in a locked file cabinet in a locked office and access is limited to 
members of the study research team. 
 
Do all portable devices contain encryption software? 
 Yes   
 No 
         If no, see http://hipaa.yale.edu/guidance/policy.html 
  
e. What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured. 
 
Upon completion of study and data analysis, a professional information protection, storage, and 
disposal company will be retained to dispose of research files and informed consent 
documentation. 
 
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data)  
 
All de-identified data will be available to the research investigator PI, Co-Investigator, 
statistician, DSMB, research staff responsible for entering data, NIAAA, Yale HRRP, and Yale’s 
HIC. Protected Health Information will be available to the research physician, and research staff 
only when deemed necessary.  De-identified data may also be shared with Governmental 
agencies to whom certain diseases (reportable diseases) must be reported. 
 


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g.   If appropriate, has a Certificate of Confidentiality been obtained? Yes, a Certificate of 
Confidentiality has been obtained from the National Institutes of Health.   
 
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported.  
 
Mandatory reporting of incidents of abuse or neglect of a child or elderly person as required by 
Connecticut State law will be complied with. Additionally, certain reportable infectious diseases 
such as HIV and Hepatitis B and C will be reported to the appropriate state agency. We may also 
need to intervene and report information regarding threat of injury to self or others to the proper 
authorities. All of these requirements will be complied with. 
 
 
SECTION IX: POTENTIAL BENEFITS 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.)  
 
There are no known potential benefits.  There may be benefits to society which would result 
from increased knowledge about treatments for alcohol addiction. 
 
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
 
Subjects need not participate in this study to receive treatment for substance dependence. 
 
2.  
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  
 
 
Subjects completing the Inpatient-Outpatient Study with laboratory sessions, will be paid $25 for 
the interview session, $25 for the imagery and relaxation training session, and $100 for each of 
the 3 laboratory sessions. Subjects will be paid a $50 bonus for completing the inpatient phase. 
Research interview sessions and study medication will be free of charge.  If subjects are only 
completing the inpatient phase, follow-up appointments will be scheduled after the inpatient 
phase is complete. Subjects will receive $50 for the 30-day follow-up interview. If a subject 
decides to complete only the inpatient phase, they will receive a total of $450.  
 
 
Subjects completing the Inpatient-Outpatient Study without the laboratory sessions, will be paid 
$20 for each intake appointment (2- 3), and $25 for each week that they are inpatient. Subjects 
will be paid a $50 bonus for completing the inpatient phase. Research interview sessions and 
study medication will be free of charge.  If subjects are only completing the inpatient phase, 


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follow-up appointments will be scheduled after the inpatient phase is complete. Subjects will 
receive $50 for the 30-day follow-up interview. If a subject decides to complete only the 
inpatient phase, they will receive a total of $235. 
 
 
If a subject continues on to complete the outpatient phase, they will earn chances to win dollar 
prizes for kept appointments to encourage appointment attendance. The prizes are in increments 
of $1, $5, $20, and $100. For every two biweekly appointments they attend, the chance will 
increase by one. Subjects will participate in this at every biweekly appointment they attend. If 
they miss any appointment, or fail to take study medication, the chances will be reset back to 
one. For example, if no appointment are missed the subject will have a total of 12 chances at the 
last appointment. Each prize increment that is won from the 12 attempts is then added together 
into a lump sum. There is no limit on the amounts that can be won. Subjects participating in IVR  
or MetricWire will be reimbursed at $2 a day, or $20 a week, for the duration of the outpatient 
phase. In addition, subjects will receive $25 for week 4, $25 for week 8, $25 for week 12, and a 
$25 bonus for completing the outpatient phase. Subjects completing both the inpatient and 
outpatient phases, will have follow-up appointments scheduled after the outpatient phase is 
complete. The total that subjects may be reimbursed if they complete all aspects of the Inpatient–
Outpatient study with the laboratory sessions, and the follow-up interviews will be $730 plus the 
various amounts won for keeping appointments during the outpatient phase. The total that 
subjects may be reimbursed if they complete all aspects of the Inpatient–Outpatient study 
without the laboratory sessions, and the follow-up interviews will be $515 plus the various 
amounts won for keeping appointments during the outpatient phase. 
  
 
Subjects completing the Outpatient Study will earn chances to win dollar prizes for kept 
appointments. The prizes are in increments of $1, $5, $20, and $100. For every two biweekly 
appointments they attend, the chance will increase by one. Subjects will participate in this at 
every biweekly appointment they attend. If they miss any appointment, or fail to take 
medication, the chances will be reset back to one. For example, if no appointments are missed 
the subject will have a total of 12 chances at the last appointment. Each prize increment that is 
won from the 12 attempts is then added together into a lump sum. There is no limit on the 
amounts that can be won. In addition, subjects will receive $20 for each  intake appointment, $25 
for week 4, $25 for week 8, $25 for week 12, and a $25 bonus for completing the study. Subjects 
will also receive $50 for the 30-day follow-up interview. Subjects participating in IVR or 
MetricWire will be reimbursed at $2 a day, or $20 a week. The maximum amount that subjects 
will receive for completing all aspects of the outpatient study, without completing the laboratory 
sessions, is $415, plus various amounts won for keeping appointments. If a subject decides to 
complete the laboratory sessions, they will receive an additional $25 for the imagery and 
relaxation training session, and $100 for each of the 3 laboratory sessions. They will also receive 
a $50 bonus for completing all aspects of the inpatient laboratory study. The total that will be 
paid if all aspects of the outpatient study are completed, including the laboratory sessions, is 
$825 plus the various amounts won for keeping appointments. 
 
 
Subjects will incur no costs for participation in this research outside of potential costs for parking 
or transportation that may be reimbursed. 
 


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If subjects are asked to have any of their interview sessions videotaped, they will be paid $20 per 
videotaped session. 
 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.      
 
 
There will be no costs charged to subjects who participate in this study.  All evaluations 
including interviews, physical exams, diagnostic tests will be provided at no cost to the subjects. 
 
4. 
In Case of Injury: This section is required for any research involving more than minimal risk. 
 
a.     Will medical treatment be available if research-related injury occurs?  
 
b.     Where and from whom may treatment be obtained?  
 
c.     Are there any limits to the treatment being provided?  
 
d.     Who will pay for this treatment?  
 
e.     How will the medical treatment be accessed by subjects?  
 
 
While medical therapy will be offered for any physical injuries sustained as a consequence of 
participation in this research, the subject and their insurance carrier will be responsible for the 
cost of such treatment. Financial compensation for injury is not available.   
 
 
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