Fyn Kinase Inhibitors and Alcohol Drinking
Phase: PHASE2
Conditions: Alcohol Drinking
Sponsor: Yale University

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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     
Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: 
Fyn Kinase Inhibitors and Alcohol Drinking
Principal Investigator:
Suchitra Krishnan-Sarin, PhD
Yale Academic Appointment:
Professor
Department: Psychiatry
Campus Address: 
34 Park Street, Suite S-208, New Haven, CT  06519
Campus Phone: 974-7595
Fax: 974-7606
Pager: 
E-mail: 
suchitra.krishnansarin@yale.edu
Protocol Correspondent Name & Address (if different than PI):  
Tricia Dahl, 34 Park Street, Suite S-215, New Haven, CT  06519
Campus Phone: 974-7599
Fax: 974-7606
E-mail: tricia.dahl@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)           
 NA
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail: 
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. 
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See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
Yes
  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
  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 co-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.
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 Clinical Neuroscience Research Unit (CNRU) Veterans Affairs Hospital, West Haven  Other 
Locations, Specify: SATU 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: 
 Yale University RSC (YU-RSC)Approval Date:  Magnetic Resonance Research 
Center PRC (MRRC-PRC)
Approval Date:  *Nursing Research Committee
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 
followup and data analysis activities. 3 years
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
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 Translational Research #2 (“Bedside-to-Community”)  Community-Based Research 5.   Is 
this study a clinical trial? Yes 
No 
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 
processof-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.
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)
1. 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 any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
YaleNew Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The service 
may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-
rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. 
There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects. 
Yes 
 No
 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
8.
Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes X   No ___ 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? Yes
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b. Will you be using any new equipment or equipment that you have not used in the past for this 
procedure? No
 
c. Will a novel approach using existing equipment be applied? No
 
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet the 
criteria, please telephone the Physician Services Department at 203-688-2615. By signing this 
protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
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 
grantfunded).  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
John Krystal 
Center PI); 
(
Suchitra 
Krishnan-Sarin 
(Project PI) 
Center for 
Translational 
Neuroscience on 
Alcoholism
NIAAA
 Federal
 State
 Non 
Profit
 Industry
 Other 
For Profit 
 Other
Grant-M#  
P50AA12870         
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:
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Name:
Company: 
Address:
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.   *See IRES for the list
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APPROVED BY THE YALE UNIVERSITY IRB 7/18/2018 VALID THROUGH 2/9/2019
APPROVED BY THE YALE UNIVERSITY IRB 7/18/2018 VALID THROUGH 2/9/2019
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.
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. 

I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
___________
______
_____
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    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.
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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. 
Alcoholism is a disorder that is mediated by multiple genes and environmental factors.  Existing 
medications like naltrexone and acamprosate are not efficacious in all drinkers.  Therefore, we 
need to develop new and effective strategies to treat alcoholism.  Development of medications for 
this disorder should be based on our understanding of the behavioral and neurochemical 
mechanisms mediating alcohol reward and drinking.  There is extensive preclinical evidence 
suggesting that glutamatergic circuits are involved in the acute behavioral effects of alcohol as well 
as in alcohol tolerance and withdrawal.  This project will evaluate the effect of an agent that 
indirectly modulates NMDA-R signaling without directly antagonizing NMDA-Rs on alcohol 
drinking. Specifically, we will test the influence of Saracatinib, a Src/Fyn protein tyrosine kinase 
inhibitor that modulates NMDA-R signaling via Fyn inhibition.
Primary Aim 1: To evaluate the effects of Saracatinib (125 mg/day) versus placebo on alcohol 
craving.
Primary hypothesis 1a:  Saracatinib (125 mg/day) will reduce craving for alcohol after exposure to 
the priming drink of alcohol, and during the free-choice drinking period, when compared with 
placebo.   
Primary Aim 2: To evaluate the effects Saracatinib (125 mg/day) versus placebo on alcohol 
drinking
Primary hypothesis 1b:  Saracatinib (125 mg/day) will reduce number of drinks consumed during 
the free-choice drinking period, when compared with placebo.  
Secondary Aim 1: To evaluate the effects of Saracatinib (125 mg/day), versus placebo, on 
alcohol-induced stimulation and sedation during the ADP. 
Secondary Aim 2:  To examine the tolerability of Saracatinib (125 mg/day) in heavy drinkers. 
Exploratory Aims:  To explore predictors of Saracatinib response.  The predictors have been 
selected based on findings from our earlier work and include behavioral outcomes like impulsivity, 
habit and deficiency in loss-avoidance learning, genetic markers related to alcohol drinking or 
glutamate and Src/Fyn systems, and neural networks/markers identified using multimodal 
neuroimaging. 
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.
This novel project will conduct the first test of whether human alcohol consumption may be altered 
by targeting an intracellular signaling protein implicated in alcohol dependence, Fyn kinase. 
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Alcohol-seeking behaviors involve complex interactions between neurotransmitters like dopamine 
and opioids that underlie reward in the nucleus accumbens and engage habits in the dorsal 
striatum, and glutamatergic pathways from the prefrontal cortex and basolateral amygdala to the 
nucleus accumbens that are involved in the reinstatement of alcohol drinking (e.g. Koob and 
Volkow, 2010).  
Using the alcohol drinking paradigm (ADP) that is being used in the current study, we showed in 
our earlier studies that naltrexone reduced drinking in FHP heavy drinkers (Krishnan-Sarin et al., 
2007) but did not reduce alcohol craving.  In subsequent studies we observed that a low dose (20 
mg) of the NMDA receptor (NMDA-R) antagonist, memantine, reduced alcohol craving, but not 
drinking (Krishnan-Sarin et al., in press). Further, the higher dose of memantine (40 mg) reduced 
alcohol craving, but increased drinking and alcohol-induced stimulation among those who were 
more behaviorally impulsive.  Therefore, we hypothesized that a more nuanced approach of 
altering NMDA-R signaling, that reduces alcohol drinking and craving without increasing positive 
alcohol effects, might be needed. In an ongoing project, we are studying the potential synergy of 
low dose memantine (which reduced craving) with 50 mg naltrexone (which reduced drinking; HIC 
protocol 1005006779).  In this project, we propose to examine the effects of an agent that indirectly 
modulates NMDA-R signaling without directly antagonizing NMDA-Rs. Specifically, we will test the 
influence of Saracatinib on drinking behaviors. 
Saracatinib is a Src/Fyn protein tyrosine kinase inhibitor that modulates NMDA-R signaling via Fyn 
inhibition. Importantly, this agent could target pathways in the corticostriatal circuitry where NMDA- 
upregulation may emerge as a consequence of heritable or alcohol-induced (Martinez et al 2005) 
reductions in dopamine D2 receptor signaling and subsequent upregulation of Fyn (Hattori et al 
2006). Saracatnib or AZD0530 is an inhibitor of Src Family kinases, blocking Src, Fyn, Yes and 
Lyn, with 2- 10 nM potency. At 10-100 fold higher concentrations the compound also inhibits Abl 
family kinases, but there is no detectable activity in this concentration range against other kinase 
families, including c-kit, Csk and PDGFR. An in vitro screen of AZD0530 against 307 different 
pharmacological targets, showed ≥50% inhibition of binding or function of only 9 targets at 10 µM 
and one additional enzyme at 100 µM (unpublished data from Astra Zeneca). It is estimated that 
the IC50 values for all 10 non-SFK targets are likely to be in the region of at least 3-100 µM 
(compared to a Fyn IC50 of 0.005 µM), and so any inhibition is unlikely to be clinically significant.
AZD0530’s specific inhibition of Fyn and SFKs have led to its development as therapy for solid 
tumors, because Src family kinases regulate tumor cell adhesion, migration and invasion, and also 
regulate proliferation. Clinical tolerability and oral bioavailablity have been demonstrated, but Phase 
II studies have demonstrated limited benefit as a single agent in specific oncological indications. For 
tumor cell migration and for oncological applications, it is estimated that >98% kinase inhibition is 
required so clinical doses have targeted concentrations >20-fold above the kinase IC50, in the 200-
1000 nM concentration.  Saracatinib has been studied in healthy individuals and patients with solid 
tumors (Dalton et al., 2010; Baselga et al., 2010; Fujisaka et al., 2013; Hannon et al., 2012) and in 
older patients with mild-moderate Alzheimers disease.  Steve Strittmatter and colleagues from Yale 
recently conducted a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-
controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores 
ranging from 16 to 26 (Nygaard et al., 2015).  They observed that the 100 and 125 m doses of AZD 
were generally safe and well tolerated that these doses achieved CSF drug levels corresponding to 
brain levels that rescued memory deficits in transgenic mouse models.  Moreover, one-month 
treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral 
glucose metabolism. 
We recently completed a pilot study to evaluate the preliminary safety, tolerability and effects of the 
combined administration of AZD0530 (125 mg/day) and alcohol (HIC# 0602001068). Five heavy 
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social drinkers (mean age = 26 + 2.2) completed a baseline inpatient alcohol administration 
session and a second alcohol administration session after taking AZD0530 for 8 days (to reach 
steady state levels).  During each alcohol administration session, subjects received successive 
doses of alcohol designed to raise their blood alcohol levels to 80 mg/dl. We observed the drug 
was safe and tolerable over the 8-day outpatient administration period.  Only mild adverse events 
were reported by two subjects and no other adverse events were reported. Complete blood counts 
and serum chemistries were similar across all pre- and post- drug and alcohol time points, with all 
values within the appropriate reference range, with only glucose and calcium slightly elevated. As 
expected, given the acute effects of alcohol, changes in heart rate and systolic blood pressure 
were seen within each drinking session, as were changes in blood alcohol levels and urine alcohol 
levels.  No session related differences were observed indicating no effect of AZD0530 on these 
parameters.  Furthermore, the results of the cognitive measures suggest that AZD0530 does not 
have an independent effect on cognitive performance or in combination with alcohol, but that 
alcohol affects these measures as expected. We also observed a promising signal on the alcohol 
intoxication assessment (reduced stimulation, intoxication, feel good drug effects) following 
exposure to alcohol. Thus, this study of 125 mg of AZD0530 given to healthy social drinking 
controls over 8 days in an alcohol administration session, raising blood alcohol to 80 mg/dl, did not 
result in any concerning changes in physiological or behavioral outcome measures and showed 
some promise for reducing alcohol related positive effects after exposure to alcohol. 
The current proof-of-concept trial will test the effects of 125 mg dose of Saracatinib versus placebo 
on alcohol drinking behaviors using the ADP. We have determined that there is a need to focus on 
the 125 mg dose and that there is no advantage to testing a lower dose (50 mg) of the drug as 
proposed in the grant.  The 50 mg dose is known to be inferior to the 125 mg in terms of Src family 
target coverage both peripherally and centrally and therefore the pharmacologic effect of the 50 
mg dose should not be superior to the 125 mg dose.  In addition, this will also allow Astra Zeneca 
to provide us with the 125 mg and matching placebo over a 3-year period without having to 
conduct additional stability testing over an extended period of time.  Therefore, with the goal of 
getting this proof of principle trial done in an efficient manner, we will now focus on an adequately 
powered examination of the 125 mg dose, the dose we believe will be effective based on our 
preliminary data and knowledge of target engagement. Specifically, in the first three years of the 
grant, we will recruit 60 subjects and randomize 40 subjects to the 125 mg Saracatinib dose and 
20 subjects to placebo. We anticipate a 10% drop out, leaving a final sample of 50 completers.
Thus, 60 non-treatment seeking, heavy drinkers will receive Saracatinib (0 or 125 mg/day), 
stratified by gender(to achieve 50 completers). Subjects will participate in a baseline ADP, followed 
by seven days of treatment with the study medication, and then a second ADP when they will take 
their last dose of study medication. Drinking behavior, alcohol craving and alcohol-induced 
stimulation/sedation will be measured in each ADP. Adverse events and drinking will be monitored 
during the treatment period, and at follow up. Potential behavioral predictors of Saracatinib 
response will obtained at baseline and post-treatment ADP, and the CTNA core assessment 
battery will be obtained at baseline. 
2. 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. 
A between subjects design will be used to examine the effects of Saracatinib on alcohol craving, 
drinking and subjective responses in heavy drinkers.  Non-treatment seeking heavy drinkers will 
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participate in two ADP sessions, occurring prior to and after eight days of medication treatment, 
and will complete one-week and 1-month follow up appointments (see below). 
Baseline 
1st ADP
Day 0
Study Medication: Saracatinib (0 or 
 mg/day) 
125
Daily medications, AE/Vitals 
2nd 
ADP 
Day 8
1 wk FU
MET
1 mo. 
FU
Day 1- Outpatient
Last Dose of Study 
Medication 
 
60 heavy drinkers, drinking on at least 4 days per week (20-65 weekly standard drinks for women 
and 30-70 for men) will complete this study. All subjects will be 21-50 years of age, physically 
healthy non-treatment-seeking heavy drinkers.  Volunteers will be recruited through 
advertisements in local newspapers, postings in community locations (bars, coffee shops, grocery 
stores) and advertisements on free community TV channels. Subjects who do not meet the 
inclusion/exclusion criteria described below will be excluded.  
The study will consist of six phases: 1) recruit subjects, obtain informed consent and evaluate 
eligibility for the study, 2) potentially eligible subjects will then receive a full physical examination to 
further determine eligibility.  3) If eligible they will participate in the baseline ADP in the Hospital 
Research Unit (HRU) of Yale New Haven hospital (YNHH), 4) they will be randomized to receive 0 
mg or 125 mg/day of Saracatinib for a 7-10 day outpatient medication treatment period (depending 
on ADP scheduling) with daily medication/adverse event recording appts 5) they will complete the 
second ADP on the last medication day in the Hospital Research Unit (HRU) of Yale New Haven 
hospital (YNHH), after taking the last dose of study medication, 6) they will be scheduled for one-
week and one-month follow up appointments. At the one week follow up, adverse events and 
drinking will be recorded and a clinical psychologist or social worker will provide a motivational 
enhancement session to motivate these non-treatment seeking drinkers to consider treatment.  
They will also be given the option to participate in an fMRI at the one-month follow-up appointment.
Justification for choice of Saracatinib dose: Saracatinib has been extensively studied in healthy 
individuals and patients with solid tumors (Dalton et al., 2010; Baselga et al., 2010; Fujisaka et al., 
2013; Hannon et al., 2012) and more recently in patients with Alzheimers disease. For our “proof-
of-concept” trial, we chose to use a higher dose of 125 mg, which have most commonly been 
tested in most trials (including those by our collaborator Dr. Strittmatter with AD patients) and 
shown to be safe. AZ has completed 7 Phase I studies in healthy volunteers and 5 Phase I 
studies in patients with solid tumors and advanced solid malignancies. AZD0530 doses of 60 mg 
to 185 mg were well tolerated, and although adverse events were more frequent at and above 250 
mg, no major safety issues were identified at any of the doses studied. In patients with advanced 
cancer, the MTD was 175mg. In clinical oncology, the duration of AZD0530 treatment has been 2-
12+ weeks in most trials. Importantly, with AZD0530 monotherapy no serious hematologic 
adverse events have been documented in doses lower than 175 mg.  In the phase 1 trials, no 
major safety issues were identified in any of the doses studied, up to 250 mg daily.  There is a 
potential for mild decreases in values for both white cell count and platelets at doses of above 125 
mg, but these abnormalities never fell below reference levels, and levels normalized while patients 
remained on the drug. Thus, the dose proposed in this study, 125 mg, has not only been used 
safely in healthy volunteers and patients with cancer and AD, but have also been used for longer 
periods than the six days proposed in the current project.  
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We have completed a pilot trial (HIC # 0602001068) to examine if there any interactions between 
AZD0530 (at the highest dose proposed in the current project i.e. 125 mg/day) and a moderate 
dose of alcohol (0.08 mg/dl; similar to the blood alcohol levels usually achieved by drinkers in our 
ADP paradigms) following 8 days of AZD0530 treatment (similar to the current protocol) in social 
drinkers. Five subjects have participated and no unanticipated adverse effects have been noted; 
findings were presented to the FDA, and HIC. 
Justification for length of treatment phase: We chose to study the effect of Saracatinib on alcohol 
drinking following eight days’ pretreatment to allow sufficient drug to accumulate. Per information in 
the AZ brochure, the PK profile of Saracatinib supports once-daily oral administration, with peak 
levels seen 3-4 hours after administration, and a mean t1/2 of about 40 hours. This treatment 
period also allows us to generate clinically relevant information on adverse events observed 
beyond an acute dose in heavy drinkers.     
Eligibility Determination, Physical Exam, Baseline Assessments
Intake appointments will be scheduled at the Substance Abuse Center in the Connecticut Mental 
Health Center, New Haven, CT.  After informed consent, the intake battery will be administered to 
assess study eligibility. This appointment should approximately 1 ½ hours. The research assistant 
(RA) will schedule potentially eligible participants a physical exam with an APRN which will include 
a detailed medical history, EKG’s, blood draws for routine CBC tests and hepatic, kidney and 
thyroid function tests as well as pregnancy tests from female participants (50cc).  This appointment 
will last approximately 1 ½ hours. All tests and medical history will be reviewed by the PI and the 
study physician (Dr. Julia Shi). All participants will complete the core battery of assessments (See 
CTNA Clinical Core for details) and if they have consented for genetic studies, then blood samples 
will be drawn (30cc). 
Medication Treatment Period and Blood Sample for Drug Levels
Participants will be randomized to receive Saracatinib 125 mg/day or placebo.  Study medication 
will be dispensed by the Investigational Pharmacy of YNHH.  During the first seven outpatient 
treatment days, participants will be asked to come in daily to take their medication.  Adverse 
events, vitals, alcohol drinking and craving will also be monitored by the RA and study APRN. On 
the ADP day, participants will take their 8th dose of medication upon arrival to the Hospital 
Research Unit (HRU). 
Alcohol Drinking Paradigm (ADP)
The procedures for both ADP’s will be similar and will follow the NIAAA guidelines for administering 
alcohol to humans (http://www.niaaa.nih.gov/research/guidelines-andresources/administering-
alcohol-human-studies).  Participants will arrive at the HRU of YNHH at 10 am for ADP1 and 
10:30am for ADP2.  They will be told not to consume any alcohol after 10 pm on the earlier 
evening.  We will assess breath alcohol levels and urine drug tests. If the breath alcohol levels are 
positive but below 0.05 and decreasing, the participant will be allowed to continue.  If the urine 
drug tests are positive and/or breath alcohol levels are 0.05 or greater, the session will be 
rescheduled. The drinking sessions will be conducted in a private room in the HRU. Because 
caffeine is a weak phosphodiesterase inhibitor (Nehlig et al., 1992), caffeine users will be limited to 
one serving of their usual caffeinated beverage with lunch at 12 pm. This will also help to avoid 
caffeine withdrawal.  
The ADP will start at 3 pm with the priming dose period, which will be followed by 3, 1 hour drinking 
periods (4-5 pm, 5-6 pm and 6-7pm) and will conclude at 7 pm (see Table 1 for detailed list of 
procedures).
a.
Exposure to Alcohol Cue: Ten minutes prior to the start of the priming dose period (i.e. 
2:50 pm), the RA will enter the participant’s room with the alcohol dose and the preferred 
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mixer. The RA will then proceed to mix the priming drink in front of the participant.  When 
done, he/she will leave the drink on the table, instruct the participant not to drink the 
priming drink yet, and leave the room.  At 2:59 pm the RA will reenter the room, ask the 
subject to report on how much they are craving alcohol, and then tell the participant that 
they have five minutes to consume the priming drink and will then again leave the room.
b.
Priming Dose (PD) Period: This dose provided at 3 pm will raise blood alcohol levels to 
0.03mg% and subjects will have 5 minutes to drink it. The purpose of the PD is to 
provide a standard dose for evaluating the effects of medications and to model a “lapse” 
situation. A 40-minute absorption period will follow during which the subjective and 
physiological effects of this priming dose of alcohol in combination with Saracatinib will 
be monitored. Using this procedure, we will be able to closely monitor changes in 
subjective effects of alcohol during the rising and falling limbs of the blood alcohol curve. 
c.
Alcohol Self-Administration (SA) Periods: Following the PD, there will be 3, 1-hour SA 
periods.  During each SA period, participants will be offered a choice between 4 
alcoholic drinks designed to raise BALS by 0.015 mg% of alcohol), or cash (equivalent to 
the price of each drink that is not consumed). The first SA period will begin at 4:00 pm 
when the RA will take 4 prepared drinks into the room along with a "tab" sheet worth 
$12. The participant will be informed that these 4 drinks will be available to him/her for 
the next 60 minutes (i.e. until 5 p.m.). S/he can either choose to drink or keep the 
money; each drink will cost $3. The money will be given to them the next morning before 
they leave the hospital. The second and third SA period will begin at 5 p.m. and 6 p.m. 
respectively will be similar to the SA period. Thus, participants can choose to consume 
up to 12 additional drinks over these 3 SA periods or receive up to $36. Given the 
possibility that a participant could consume more alcohol during the ADP than what they 
might normally consume, all subjects will be closely monitored and the ADP will be 
stopped if 1) The subjects requests to stop, 2) In the judgment of trained research 
personnel conducting the study and monitoring subject behavior the study needs to be 
stopped, or 3) If the subject’s heart rate exceeds their maximum heart rate (220 minus 
age).
d.
Beverage Content and Mixers: The YNHH Investigational Pharmacy will calculate the 
alcohol dose based on the age, weight and gender of the participant (Watson, 1989) and 
deliver the doses to the HRU. The PD will raise blood alcohol levels to 0.03 mg% and 
each drink in the SA periods will raise BAL by 0.015 mg%.  Alcoholic beverages 
administered during this study will consist of 1 part 80 proof liquor of the subject's 
choosing to 3 parts mixer chosen from a selection of equicaloric noncaffeinated 
noncarbonated beverages.  The RA will prepare the drinks using the alcohol doses 
prepared by the YNHH pharmacy.  Participants would have already chosen their mixers 
on an earlier day, thereby providing a closer approximation to their own drinking 
experiences.  Frozen plastic cubes will be used to chill each drink without diluting them 
and the prepared drinks will be covered with saran wrap to avoid any evaporation of 
alcohol.   
Assessments during and after the three choice periods:  
During the second, third and fourth hour of the laboratory session, drinking behavior will be 
videotaped for later analysis, and craving and stimulation/sedation will be assessed every thirty 
minutes. The frequency of assessments is limited to avoid interfering with the evaluation 
of drinking behavior.  
Blood samples to monitor blood alcohol levels will be obtained every 10 minutes during the 
PD and every 60 minutes thereafter (total of 5cc). On the morning after the second ADP, all of 
the laboratory tests that were completed at baseline will be repeated.  
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End of ADP and overnight stay in HRU
After the end of the ADP, breath alcohol levels will be assessed until they fall below 0.02.  
Participants will be given dinner and will stay in the hospital overnight in order to ensure that 1) 
they do not continue to drink following exposure to alcohol in ADP, 2) they are safe and are not 
discharged while intoxicated and, 3) they are motivated to drink during the ADP since they will 
not have access to more alcohol later that same day.  The next morning participants will 
complete assessments, blood draws (50cc), be given breakfast and then discharged.  
Follow up interview
Subjects will participate in a 1-week follow-up appt. during which drinking over the past week 
and remaining adverse events will be monitored and a blood sample to for safety laboratory 
tests will be obtained (50cc). A brief motivational intervention will be provided by a licensed 
clinical psychologist or licensed social worker to encourage subjects to address their alcohol 
problem and an immediate referral to treatment will be made if they are interested.  Even 
though participants are not seeking treatment for their drinking, we feel that their presence in 
the hospital provides a “teaching moment” to address their drinking behavior (Sinha et al., 
1997).  Subjects will also participate in a 1-month follow up during which information about 
their drinking since their prior appointment will be assessed. 
Motivational intervention:  A brief motivational intervention will be provided at the one-week 
follow-up to encourage the subject to address their alcohol problem.  For Study 1, this session 
will be audiotaped if the subject agrees to sign consent for audiotaping. Tapes will only be 
used for training purposes and will be identified by code numbers and erased within 7 years of 
study completion. Even though the subjects participating in this study are not seeking 
treatment for their drinking, we feel that participation in this study is an opportunity to address 
their heavy drinking behavior.  This brief motivational interview is based on the principles of 
Miller’s Motivational Enhancement Therapy (MET) [133].  We will provide subjects with 
personalized feedback regarding their physical exam and laboratory findings, and on the 
influence of drinking on their health. We will also review with them the potential benefits of 
quitting drinking. We have found that similar brief advice resulted in decreases in alcohol 
drinking behavior and increased motivation to quit drinking [132].  If interested, an immediate 
referral to treatment will be made. Also, subjects will also be given the option of participating in 
one of our alcohol treatment studies. 
Functional Magnetic Resonance Imaging
Described learning and/or memory paradigms will be used involving functional neuroimaging. If the 
participant agrees to complete this portion of the study, he/she will be carefully screened for 
contraindications to participation in an fMRI study. The screening process involves a phone 
interview with the participant coordinator who goes through a set of screening questions. At the 
scanner, before entering the scanner environment, the participants fill out a number of forms, 
including a MRI screening form and are questioned verbally by the experimenter giving informed 
consent. Following this screening, acceptable participants will lie on their back in the MRI machine 
for 2 – 3 hours. 
During the fMRI session participants will be asked to perform a series of tasks involving learning, 
attention and memory similar to the ones they may complete during the behavioral assessment. 
Participants will be given detailed instructions by the experimenter explaining the task instructions. 
During some of the cognitive tasks participants may see various distracting images some of which 
will be photographs. The photographs that participants will see may cover a broad range of 
contents, including slides of flowers, children, families, people’s faces, insects, animals, sports, 
and graphic slides similar to those that might be seen in a documentary of war footage (including 
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mutilated individuals and dead bodies). Some people experience some degree of distress when 
viewing the most graphic pictures. If participants will be shown these graphic images they will have 
an opportunity to view some sample pictures to make certain that they understand the types of 
slides you will see during our study. Subjects will be able to elect which level of pictures they are 
willing to view and they will be informed that they can stop viewing the emotional pictures at any 
time.
Assessments
•
Socio-demographic/General Information: At intake, 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, educational and occupational levels, 
and significant medical history.  
•
SCID5: The Structured Clinical Interview for DSM5 (SCID5) (First et al., 2015) will be used to 
determine psychiatric diagnoses. This interview assesses DSM-V current and lifetime 
psychiatric diagnoses for anxiety, mood, psychotic, alcohol and substance use, somatoform, 
and eating disorders.
•
Psychiatric Family History by Interview, the FHAM: As a source of pedigree information, the 
psychiatric status (including substance abuse/dependence, mood disorder, ASPD, etc.) of all 
first- and second-degree biological relatives will be obtained from each subject (including 
parents) using the family history method (FHAM-Family History Assessment Module) 
developed by COGA. DSM-IV criteria will be used to diagnose all biological family members. 
The FHAM is a reliable method for obtaining family history information and the specificity and 
sensitivity of the FHAM for the diagnosis of substance dependence is quite good (Rice et al., 
1995). We will administer the FHAM in three steps. First, the structure of the family pedigree 
is drawn and reviewed with the informant. Next, psychiatric screening questions are asked 
about all relatives in the pedigree. Then, based on the responses to the screening questions, 
symptom checklists are completed for each first-degree relative, spouse, or other relative well 
known to the informant.
•
Time-Line Follow-Back Assessment Method (TLFB: Sobell and Sobell, 1992): We will obtain 
quantity /frequency alcohol consumption for each day during 30-days prior to the study, the 
7day outpatient medication and follow-up periods. The TLFB has good test-retest reliability and 
validity for verifiable events. 
•
Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar): A 10-item scale that 
assesses alcohol withdrawal signs (nausea/vomiting, tremor, headache, anxiety, agitation, 
orientation, sweating, and auditory, visual/tactile disturbances). It is used for the clinical 
management of alcohol withdrawal (Sullivan et al., 1989; Saitz and O'Malley, 1997) and in 
research (Sellers et al., 1991; Saitz et al.,1994).
•
SAFTEE (Levine and Schooler, 1986). A tool for systematic assessment of adverse effects in 
clinical trials which includes 1) open-ended questions about any changes in physical or health 
problems, appearance, or activity level, and 2) yes/no responses to a specific list of symptoms 
(which correspond to anticipated adverse events associated with Saracatinib). For each 
symptom reported, the date of onset, severity (minimal, mild, moderate, severe), whether it was 
drug-related, and action taken, is recorded. The SAFTEE will be administered daily during the 
outpatient period, on the ADP day and at follow ups, to monitor and document rates of adverse 
events.
•
Yale Craving Scale (YCS; Rojewski et al., under review; Krishnan-Sarin et al., in press):  The 
YCS is a five-item measure that employs a generalized Labeled Magnitude Scale (gLMS) to 
assess the intensity of craving for alcohol relative to the intensity of the strongest imaginable 
sensation. A psychometric evaluation of the YCS suggests that it evidenced: 1) good internal 
consistency, 2) scalar measurement invariance which makes it well suited for between group 
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comparisons, and 3) concurrent relationships with drinking outcomes. The training exercise 
and the full 5-item YCS will be administered at baseline. During the ADP, the first item (“desire 
to drink right now”) will be used at each time point. To confirm that use of the single item scale 
was psychometrically justifiable, we conducted a series of bivariate correlations (using data 
from 111 participants in earlier CTNA trials) between the YCS item assessing current alcohol 
craving, the total YCS score, and the Alcohol Urge Questionnaire (Bohn et al., 1995). The YCS 
single item on current craving correlated strongly with the YCS total score (r=0.78, p<0.001) 
and the AUQ (r=0.59, p<0.001).  The YCS had superior psychometric properties relative to the 
AUQ in measuring craving in dependent and non-dependent drinkers. 
•
Biphasic Alcohol Effects Scale (BAES; Martin et al., 1993): This scale is used to measure the 
stimulant and sedative effects of alcohol and has been found to be sensitive to memantine and 
naltrexone's effects (Krishnan-Sarin et al., in press; Kranzler et al., 2000; Swift et al., 1994). We 
and others have validated the use of a shorter 6-item BAES (Rueger and King, 2013; Krishnan-
Sarin et al., in press), which will be used. 
•
Alcohol Urge Questionnaire (AUQ) (Bohn et al., 1995): The AUQ is an 8 item questionnaire, 
derived from a larger 49 item "Questionnaire of Alcohol Urges," that assesses desire for a 
drink, expectation of positive effect from drinking, and inability to avoid drinking if alcohol was 
available. The AUQ is a reliable and valid scale for the measurement of self-reported alcohol 
urges, and scores have been shown to be strongly related to alcohol dependence severity (as 
measured by ADS scores) and to cognitive preoccupation with alcohol. Its brevity and time 
frame for ratings (i.e., right now) makes it suitable for administration during the alcohol drinking 
period.
•
Padua Inventory (Sanavio, 1988): consists of 60 items describing common obsessional and 
compulsive behavior and allows investigation of the topography of such problems in normal 
and clinical symptoms.
•
The Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) (Carver and White, 
1994; Gray, 1981) will assess behavioral activation and inhibition, which have been proposed 
as biological systems underlying behavior and affect. This measure has been shown to have 
good convergent, discriminant, and predictive validity in which it measures sensitivity rather 
than the person’s typical experience. The BIS will be used to tap the component of impulsivity 
related to decreased sensitivity to the negative consequences of behavior.
•
Barratt Impulsiveness Scale (BIS)(version 11) (Patton et al.,1995): This 30 item self- report 
instrument provides a trait measure of impulsiveness and yields four scores: a total score, 
nonplanning activity, cognitive impulsivity, and motor impulsivity. Cronbach alpha coefficients 
range from .79-.83.
•
Short Inventory of Problems (SIP) [153a]: A brief version of the Drinker Inventory of 
Consequences (DrInC), this is a 15-item test that measures physical, social, intrapersonal, 
impulsive, and interpersonal consequences of alcohol consumption. Subjects indicate whether 
each item occurred in the previous 12 months.
•
Self-Rating of Effects of Alcohol (SRE) [153b]: This 5-item self-report contains questions 
related to the number of drinks required for up to four different effects early in the drinking 
career.
•
Alcohol Expectancy Questionnaire (AEQ) [153d]: This 68-item questionnaire is an empirically 
derived self-report form designed to measure the degree to which individuals expect alcohol to 
produce a variety of general and specific positive effects.
•
Negative Alcohol Expectancy (NAEQ) [153e]: This 60-item self-report provides assesses the 
current level of motivation to restrain/stop drinking and the constituent components of the 
current level of motivation. The NAEQ also identifies negative expectancies that may serve as 
a deterrent and represent motivation to stop or restrain drinking.
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•
Sensation Seeking Scale (SSS) [153f]: 40-item self-report measures individual differences in 
optimal levels of stimulation and arrival.
•
Depression Anxiety Stress Scale (DASS) [153g]: This 42-item self-report which measures the 
negative emotional states of depression, anxiety and stress.
•
Childhood Trauma Questionnaire (Bernstein, et al. 1994): This 28-item self-report inventory 
that provides brief, reliable, and valid screening for histories of abuse and neglect. It inquires 
about five types of maltreatment - emotional, physical, and sexual abuse, and emotional and 
physical neglect. Also included is a 3 item Minimization/Denial scale for detecting falsenegative 
trauma reports.
•
Drinking Motives Questionnaire (DMQ)(Cooper et al. 1992): contains 15 reasons why people 
might be motivated to drink alcoholic beverages. Participants rate on a 4-point scale how 
frequently each of the 15 listed reasons motivate them to drink alcoholic beverages. The 
measure yields three scale scores reflecting different motives for drinking alcohol.
•
Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ)(Torrubia et al., 
2001): consists of 48 yes-no items that included questions about habitual behaviours in 
response to cues of punishment, frustrative non-reward and novel stimuli as well as stimuli 
related to reward and approach-related tendencies.
•
The Self-Report Habit Index (SRHI) (Verplanken & Orbell, 2003).: a 12-item index of habit 
strength developed on the basis of features of habit; that is, a history of repetition, automaticity 
(lack of control and awareness, efficiency), and expressing identity.
•
UPPS Impulsive Behavior Scale (Whiteside & Lynam, 2003): a 45-item self-report 
questionnaire which distinguishes four facets of impulsivity: urgency, lack of premeditation, lack 
of perseverance, and sensation-seeking. It is scored on a 4-point scale from Strongly Agree to 
Strongly Disagree.
•
Alcohol approach-avoidance task (AAT) (Wiers et al., 2009): We chose to use the AAT to 
assess automatic alcohol-affect associations since it has been used to show that heavy 
drinkers with a G allele of the OPRM1 gene have stronger automatic approach tendencies for 
alcohol. The AAT is an alcohol variety of the Approach Avoidance task developed by Rinck and 
Becker (2007) and measures approach bias for alcohol related stimuli. The subject pushes or 
pulls computer presented stimuli according to a content irrelevant feature, the tilt of the 
stimulus. Pushing the joystick gradually decreases stimulus size, while pulling gradually 
increases stimulus size.  The zooming feature also generates a sense of approach or 
avoidance (Neumann, 2000). Reinout Wiers will provide consultation to our group on the AAT.
•
The Implicit Association Test (IAT) (Greenwald et al., 2003): This task measures implicit 
affective asssociations with the alcohol. Using a computerized sorting task, individuals 
simultaneously classify two target conditions, ‘alcohol’ (ie., wine, beer, pint, vodka, whiskey, 
wine cooler) versus ‘soft drink’ (coca cola, juice, orange soda, root beer, sparkling water, 7- up) 
, and two affective categories relevant to drinking, ‘pleasant’ (ie. talkative, excited, cheerful, 
happy, funny, lively), versus ‘unpleasant’ (i.e., nauseous, listless, awful, miserable, sad, 
annoying). IAT effects will be calculated with the D600 scoring algorithm. Internal consistency 
for biploar alcohol-related affective IAT was .79 in (Houben, in press); the bipolar IAT predicted 
drinking above explicit measures and outperformed five other variants of the IAT(e.g., unipolar 
positive, uniplor negative IAT).
•
Ratings of Drinking Behavior during the Alcohol Self-Administration Period: Subjects will be 
videotaped during the self-administration portion of the study. These videotapes will be rated 
by two independent raters who will indicate the onset and offset of each sip of alcohol. Using 
this data, dependent measures will be constructed including time until the first sip and average 
time to consume each drink. 
•
Psychophysiological Measures will include heart rate and blood pressure monitored using a 
Critikon Dinamap while skin temperature will be measured using Yellow Springs Instruments 
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4600 precision thermometer. The cuff of the Dinamap will be on subject's dominant arm while 
the probe of will be attached to the middle finger of the subject's non-dominant arm.   These 
data will be further used to examine the safety of combining Saracatinib with alcohol during the 
ADP.Blood Alcohol Levels: Blood samples will be stored at -4°C and will be analyzed using gas 
chromatographic techniques at the HRU laboratory.
•
Patient-Reported Outcomes Measurement Information System (PROMIS Alcohol Use – Short 
Form): The PROMIS adult Alcohol Use item bank assesses drinking patterns (e.g. quantity and 
frequency of consumption, time spent drinking, episodes of heavy drinking), cue-based drinking 
(internal states and external contexts), cravings to drink (e.g. urgency, compulsivity), and 
efforts to control drinking (e.g. difficulty in limiting drinking) that indicate problematic drinking, 
particularly at the high end of the severity continuum. This bank, however, also provides good 
precision at moderate and low severity drinking levels (unlike many traditional measures of 
alcohol use and abuse). Although negative consequences are often associated with problem 
drinking, these consequences are assessed by a separate bank.
•
Ethylglucuronide (EtG):  The ethanol metabolite, ethylglucuronide (EtG) will be assayed in 
urine samples collected at the initial screening visit. EtG is a biomarker of recent alcohol 
consumption that provides an objective measure of abstinence (Jatlow et al-2014). We will use 
this to validate any self-report of heavy drinking within 80 hours of the appointment.
•
Baseline Predictors of Drinking Behavior and Saracatinib response: We will focus on important 
predictors identified in earlier CTNA (impulsivity) and new predictors based on hypotheses 
regarding habitual behavior. 
•
Habit: One of the goals of our alcohol center which funds this proposal is to understand the 
relationship between goal-directed and habitual drinking and in earlier work we observed 
correlations between drinking and measures of habit. Thus, we will assess propensity for habit 
using The Self-Report Habit Index (SRHI; Verplanken and Orbell, 2003) is a 12-item index of 
the degree to which a behavior, in this case, alcohol drinking, is habitual based on features of 
habit (a history of repetition, automaticity, lack of control and awareness, efficiency), and 
expressing identity. In an earlier project we observed that this scale predicts alcohol problems, 
coping motives and medication response 
•
Learning in response to rewards and punishments: Alcohol dependence may be related to 
differential learning in response to positive and negative reward outcomes which may reflect 
differential dopamine sensitivity (i.e. those with higher D1 sensitivity may be more likely to learn 
from positive prediction errors, and those with higher D2 sensitivity may learn from the lack of 
expected reward). We will use the Probabilistic Selection Task (PST; Frank et al., 2004) to 
probe the tendency to learn from positive outcomes or reward (direct pathway) versus negative 
outcomes or punishment (indirect pathway. During training, participants are presented with 
pairs of symbols (AB, CD, EF) and asked to select one of the two stimuli. Feedback then 
indicates if the choice was correct or incorrect. Participants then learn to perform accurately 
(that is, learn to select A, C and E) by learning, which stimulus is associated with positive 
feedback (Go learning), and which one is associated with negative feedback (NoGo learning) 
or both. Participants are then presented with novel pairs of stimuli consisting of either an A or a 
B paired with each of the other stimuli (C through F, which on average had a 50% probability of 
positive feedback during training). If participants perform better on the pairs that include A then 
they learn better from positive feedback (Go learning). If they perform better on the pairs that 
include B, they learn better from negative feedback (NoGo learning).
3. Genetic Testing   N/A 
A. Describe
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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 
We plan to use the samples to conduct pharmacogenomics studies related to the 
targeted neurochemical systems.  For example, since we are exploring the use of 
Fyn kinase inhibitor, we will explore if medication response on drinking is related to 
the various FYN SNP’s.  The samples may also be stored for future research to 
examine genes related to alcohol drinking.  For this we may look through genetic 
markers throughout the participant’s genomes to identify one or more markers near, 
or within genes, influencing risk of alcohol drinking. We will decode all or part of the 
sequence of their DNA.  We may also study genes that influence other behaviors 
and characteristics that may be related to alcohol drinking, such as smoking or 
impulsivity.  We may also study other substances in the blood to help us learn more 
about genetic variation, gene effects, characteristics, and different population 
groups. The DNA will also be used to study differences in genes and sequences 
between individuals.  Results from these genetic studies will be shared with public 
databases (per our data sharing agreement with NIH) but no personal identifying 
information will be shared.
ii. the plan for the collection of material or the conditions under which material will be 
received
The genetics samples will be collected at the time of physical exam from those who 
have consented to providing these samples.  The samples will be stored in a -70 
freezer prior to being de-identified and transported to Dr. Gelernter’s lab.
iii. the types of information about the donor/individual contributors that will be entered 
into a database
The PI will retain identifiable information about each sample that is collected.  The 
samples identified by code and stripped of any identifiers prior to being transported 
to Dr. Gelernter’s lab.
iv. What are the methods to uphold confidentiality
The identifiers will be stored in a locked file cabinet at the PI’s Office.
B. What are the conditions or procedures for sharing of materials and/or distributing for future 
research projects?  Genetic testing will only be conducted for research purposes and the 
results will be available to investigators on this study. Eventually, DNA extracted may be 
available to any qualified researcher; so will some of the genetic information from the DNA.  
C. Is widespread sharing of materials planned? Yes
D. When and under what conditions will materials be stripped of all identifiers?  The PI will 
retain identifiable information about each sample that is collected.  The samples identified 
by code and stripped of any identifiers prior to being transported to Dr. Gelernter’s lab. All 
samples are made anonymous prior to distribution.  Some of the investigators may have 
commercial interests.
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E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers that 
connect them to their materials? Donors will be told during the consenting process that they 
can choose to withdraw their materials at any time.
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? Donors will be told to 
contact the PI directly to request withdrawal of participation
F. Describe the provisions for protection of participant privacy.  The PI will retain identifiable 
information about each sample that is collected.  The samples identified by code and 
stripped of any identifiers prior to being transported to Dr. Gelernter’s lab.
G. Describe the methods for the security of storage and sharing of materials.  The identifiers 
will be stored in a locked file cabinet at the PI’s office.
4. Subject Population: Provide a detailed description of the types of human subjects who will be 
recruited into this study.
Approximately 90 male and female non-treatment seeking alcohol dependent volunteers will be 
recruited and evaluated for eligibility.  We anticipate that 60 will complete the baseline ADP 
and be randomized to one of two medication groups. Based on our current experience, we 
anticipate a final completer sample of 50 heavy drinkers will complete the baseline ADP, the 
drug administration period and the second ADP.  
5. 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)
6. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion? Inclusion criteria:
1) Ages 21-50 
2) Able to read English at 6th grade level or higher and to complete study evaluations 
3) Meet DSM-5 criteria for alcohol use disorder assessed using the SCID and the 
psychological evaluation.
4) Average weekly alcohol consumption of 30-70 standard drinks for men and 20-65 drinks for 
women, thus, an average of 4.3 standard drinks/day for men and 2.87 standard drinks/day 
for women, which defines a high-risk drinker based on World Health Organization (WHO, 
2000) Risk Levels
Exclusion Criteria:
1) Individuals who are seeking alcohol treatment or have been in alcohol treatment within the 
past 6 months 
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2) Current DSM-V criteria for substance use disorder, except for tobacco use disorder or mild 
cannabis use disorder. 
3) Positive test results at more than one baseline appointment on urine drug screens 
conducted for opiates, cocaine, benzodiazepines and barbiturates. 
4) Psychotic or otherwise severely psychiatrically disabled; as determined by psychological 
evaluation. 
5) Medical conditions that would contraindicate the consumption of alcohol including hepatic 
dysfunction.
6) Clinically significant abnormalities in screening laboratories, including Aspartate 
aminotransferase (AST) >3 times ULN; Alanine aminotransferase (ALT) > 3 times ULN; 
Total bilirubin >1.5 times ULN; Serum creatinine >2.0 times ULN, and in TFT’s (Using 
values in the “mild- (Grade 1)” range listed on page 6 of the 2007 FDA Guidance for 
Industry brochure).
7) Any neurological trauma or disease, delirium, or hallucinations, hepatic, cardiovascular, 
metabolic, endocrine or gastrointestinal disease. Clinically significant or unstable medical 
conditions, including uncontrolled hypertension or diabetes, or significant cardiac, 
pulmonary, renal, hepatic, endocrine, or other systemic diseases which in the opinion of the 
study physician and PI, may put the patient at risk because of participation in the study.
8) Anemia or Neutropenia (defined as absolute neutrophils count of <1500/microliter) or 
Thrombocytopenia (defined as platelet count <150,000/microliter). 9) Self-reporting of GI 
bleeding
10) Current blood clotting or bleeding disorder, or significantly abnormal PT or PTT at 
screening.
11) History of interstitial lung disease 
12) Current use of any strong CYP3A4 inhibitors (because Saracatinib is CYP3A4 inhibitor) 
including: atazanavir, indinavir, ritonavir, saquinavir, nelfinavir, ketoconazole, itraconazole, 
clarithromycin, telithromycin, and nefazodone, rifampicin, phenytoin, phenobarbital, and 
carbamazepine; certain CYP3A4 substrates including colchicine, cyclosporine, 
disopyramide, fluticasone, quinidine, vinblastine, vincristine or phosphodiesterase inhibitors 
like sildenafil, tadalafil, and vardenafil. 
13) Regular use of psychoactive drugs including anxiolytics and antidepressants and other 
medications (for e.g. typical neuroleptics, narcotic analgesics, antiparkinsonian 
medications, systemic corticosteroids, medications with significant central anticholinergic 
activity, or drugs with psychotropic activity or drugs which cause excessive sedation). 
14) Current use of warfarin
15) Subjects with CIWA-r scores of 8 or greater, or a history of significant repeated alcohol 
withdrawals, to reduce the likelihood of withdrawal symptomatology if subjects reduce their 
drinking.
16) Women who are pregnant or nursing
17) Participants (males and females) who refuse to use a reliable method of birth control. 
18) Subjects who report disliking spirits will be excluded because hard liquor will be provided 
during the alcohol administration components of the study.
19) Subjects who have taken any investigational drug within 4 weeks of medication treatment 
and/or participated in another study, which involves additive blood sampling, and/or 
interventional measures that would be considered excessive in combination with the 
current protocol within 4 weeks immediately preceding admission to the treatment period. 
Investigational amyloid lowering therapies are prohibited two months prior to screening and 
for the duration of the trial.  Other investigational agents are prohibited one month prior to 
screening and for the duration of the trial.
20) Subjects who have donated blood within the past six weeks. 
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21) Report any heavy drinking of alcohol within three days on TLFB prior to initial screening 
and have a negative result on EtG urine test
22) Subjects going through chemotherapy or on any chemotherapy drugs like anastrozole.
7. How will eligibility be determined, and by whom? 
All potential participants will be screened over the phone and if they appear to be eligible, will be 
brought in to be consented by Suchitra Krishnan-Sarin, Ph.D., Dana Cavallo, Ph.D., Tricia Dahl, 
Thomas Liss, Nicholas Franco, Heather LaVallee, Asti Jackson, or Alissa Goldberg.  If no 
exclusion criteria are determined, a physical exam will be scheduled and reviewed by our Study 
Physician. 
8. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, 
or inconveniences associated with subjects participating in the research. 
Risks Associated with Study Drug, AZD0530 
Previous animal studies that have tested the effects of AZD0530 at doses that were higher 
than those used in the current project, or for longer periods of time, have shown that the drug 
can cause problems with the heart, liver, blood cells, and digestive system (including the 
stomach and intestines). These harmful effects have included irritation of the digestive system 
(which can lead to symptoms of vomiting and diarrhea).  Other side effects include lower blood 
pressure, higher heart rate, lower white blood cell counts (infection-fighting cells), and higher 
liver enzymes (which can be a sign of damage to the liver). It is not known for sure if AZD0530 
would produce the same harmful effects in humans that it has with long-term doses in animals.  
In addition, animal studies suggest that taking AZD0530 during pregnancy could result in eye 
defects in the fetus.
AZD0530 has been extensively studied in human subjects, including published studies with 
healthy individuals 25,26, and patients with solid tumors 27,28. AstraZeneca has extensive safety 
data of this drug in human subjects, described in detail in the Investigator Brochure (IB), and 
described in detail below. Notably, in a multiple ascending dose study, AZD0530 doses of 60 
mg to 185 mg were well tolerated, and although adverse events were noticeably more frequent 
and severe at the 250 mg dose, no major safety issues were identified from adverse events at 
any of the doses studied.
To date, 187 healthy volunteers and 421 patients with advanced cancer have received single 
or multiple once-daily oral doses of AZD0530. In a single ascending dose study, the maximally 
tolerated dose (MTD) was considered 1000mg. In a multiple ascending dose study, the MTD 
was considered 250mg, although a toxicity- limiting dose was not pursued. In patients with 
advanced cancer, the MTD was 175mg. What follows is a detailed review of the effects of 
AZD0350 in both healthy volunteers and patients with advanced cancer on various organ 
systems and systemic function.
Existing preclinical toxicology in two species demonstrates safety through 6 months, supporting 
chronic administration for this duration in humans. In clinical oncology, the duration of 
AZD0530 treatment has been 2-4 weeks in most trials.
The dose proposed in this study, 125 mg, has generally been well tolerated in both healthy 
volunteers, and in patients with advanced solid tumors. The most common adverse events at 
this dose have included rash, headache, and diarrhea. Less common adverse events have 
included nausea, vomiting, anorexia, palpitations, fatigue, influenza-like symptoms, and 
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abnormal liver function tests. Other adverse effects at higher doses have included upper 
respiratory infection, myalgia, abdominal pain and tenderness, and epididymitis.
Importantly, with AZD0530 monotherapy, febrile neutropenia or other serious hematologic 
adverse events have not been documented in doses equal to or lower than 175 mg. In a total 
of 7 phase 1 trials, including 187 healthy volunteers, no major safety issues were identified 
from adverse events in any of the doses studied, up to 250 mg daily (AZ Investigator’s 
Brochure). There is a potential for a mild decrease in values for both white cell count and 
platelets with doses of 125 mg and above, but these abnormalities never fell below reference 
levels, and levels normalized while patients remained on (AZ Investigator’s Brochure). The 
timing for hematologic effects of AZD0530 is within 14 days of drug initiation, providing the 
rationale for the 30-day monitoring period in the phase 1 study (AZ Investigator’s Brochure). It 
should be noted that 2/3 of the safety data have been generated from patients with solid 
tumors, and some of these patients were included in the study despite mild baseline 
pancytopenia.
In studies where AZD0530 was used to treat patients with cancer the following side effects 
were noted: GI disorders: nausea, vomiting, diarrhea, decrease appetite, General disorders: 
flu-like syndromes, asthenia, Hematologic disorders: neutropenia, lymphopenia, 
thrombocytopenia, leukopenia, anemia, bleeding, bruising, Investigations: increases in serum, 
creatinine, positive findings on urine dipstick testing for protein and/or blood, elevations in 
serum transaminases, Respiratory Disorders: pneumonitis, Skin and Sub-cutaneous tissue: 
rash (general popular). 
Healthy Volunteers
•
Vital signs, ECG parameters, and physical findings: No clinically relevant changes seen with 
AZD0530.
•
Systemic: Flu-like symptoms have been reported in healthy volunteers exposed to a single 
dose of AZD0530, and at doses of 125mg and higher.
•
CNS: Headache and myalgia were reported in volunteers exposed to a single dose of 
AZD0530 of 1000mg.
•
Pulmonary: Upper respiratory tract infection has been reported in healthy volunteers exposed 
to a single dose of AZD0530. No clinically relevant changes in pulmonary function seen in 
doses up to 500mg.
•
Renal: While a rise in plasma and serum creatinine due to reduction in tubular secretion of 
creatinine was reported, multiple dosing of AZD0530 has no effect on renal function as shown 
in a dedicated study26.
•
Hematologic:
•
Bleeding: Events consistent with bleeding occurred in 33/187 volunteers after receiving 
AZD0530, and in 6/57 receiving placebo. The majority of events involved epistaxis or 
venipuncture site bleeding. All events related to AZD0530 were grade 1 (CTCAE).
•
Neutropenia: One volunteers experienced neutropenia considered a grade 2 adverse event. 
The dose was 200 mg daily. In doses of 125 mg and 200 mg a decrease in neutrophil count 
was noted in some patients but did not fall below the normal reference range.
•
Thrombocytopenia: In doses of 125mg and 200mg a decrease in platelet count was noted in 
some patients but did not fall below the normal reference range.
•
Anemia: Hemoglobin and hematocrit are not changed with AZD0530. While a reduction in 
these values was seen in healthy volunteers, it was also observed in subjects receiving 
placebo.
•
Death: No deaths occurred in studies in healthy volunteers.
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•
Genitourinary: One healthy volunteer experienced epididymitis while on 200 mg AZD0530 
daily.
•
Liver function: Isolated increases in AST, ALT, and GGT have been seen in a multiple 
ascending dose study of AZD0530. Two healthy volunteers discontinued intervention – one 
received 60mg of AZD0530, the other placebo.
•
Endocrine: There is a trend for lowering estradiol levels in AZD0530 doses of 125, 185, and 
250mg. However, none of these changes are statistically significant compared to placebo. At 
the 185mg dose there may be a small reduction in testosterone levels, but this is not thought to 
be clinically relevant.
•
Dermatologic: Rash has been reported in healthy volunteers exposed to a single dose of 
AZD0530.
Patients with advanced cancer:
AZD0530 was developed for the treatment of solid tumors, and a significant amount of safety 
data exist in patients with advanced cancer. The rate of adverse events, as expected, is higher 
in this group than in healthy volunteers.
•
Vital signs, ECG parameters, and physical findings: No clinically relevant changes seen.
•
Systemic: Nausea (37%), Anorexia (36%), Vomiting (27%), Diarrhea (26%). Drug 
discontinuation was rare, and typically in doses of 200mg and higher. Other reported 
symptoms include abdominal pain, constipation (up to 16%), dry mouth, melena, fatigue (up to 
15%), and peripheral edema.
•
CNS: Dizziness, headache, somnolence, up to 10%.
•
Pulmonary: Rare cases of pneumonitis-type events, including fatal events. These were cases 
involving advanced cancer; however, AZD0530 could not be excluded as the causative agent.
•
Renal: No clinically relevant renal dysfunction related to AZD0530.
•
Hematologic:
•
Bleeding: Up to 27% of subjects. Hematuria, GI bleeding, epistaxis, and hemoptysis reported, 
but majority mild (grade 1). Not clear that bleeding events were directly related to AZ0530.
•
Neutropenia: Occurred in up to 17% of patients with doses of 175-200. There are reported 
cases of febrile neutropenia in patients with renal cancer and liver metastases. Rarely caused 
the need for dose change or drug discontinuation.
•
Thrombocytopenia: Reduction in platelets seen across doses except 50mg, up to 20% of 
subjects. No patient required a dose interruption or supportive therapy.
•
Anemia: Up to 30% of patients, but majority continued study without need for dose interruption 
or reduction. Seen in doses of 175mg and higher.
•
Death: No deaths directly caused by AZD0350.
•
Genitourinary: no events noted
•
Liver function: Isolated increases in AST, ALT, GGT reported. None requiring drug 
discontinuation.
•
Endocrine: No significant dysfunction reported.
•
Dermatologic: Erythema reported (rare)
In a recent 4-week multiple ascending dose, randomized, double-blind, placebo-controlled 
trial of AZD0530 in 24 patients with Alzheimer ’s disease, AZD0530 was found to be safe. 
Patients received doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks with primary 
endpoints of safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. 
AZD0530 was generally safe and well tolerated across doses. 29
Overall, the safety profile of the dose of AZD0530 proposed in this project is very good.
 
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Alcohol:
A number of medical conditions could potentially be worsened by acute alcohol administration 
(e.g., liver disease, cardiac abnormality, pancreatitis, diabetes, neurological problems, 
diabetes, and gastrointestinal disorders). As a result, subjects with medical problems as 
revealed by physical exam and laboratory findings will be excluded from the study.
Alcohol may also cause nausea in high doses; however, nausea is not expected at the dose 
being used in this sample of heavy drinkers. Subjects will not be drinking to levels more than 
they typically consume in their own drinking context, and, with the exception of the priming 
dose, they determine the amount of alcohol consumed.
Another area of potential risk to subjects under the influence of alcohol involves their safety 
during the experimental procedures. Although impairment of gross motor coordination in heavy 
drinkers is rare at the alcohol dose used in this study, all subjects will be under the supervision 
of the experimenters to prevent possible accidents such as falls. Subjects will not leave the 
laboratory during the self-administration procedure. By staying in the HRU overnight, the 
possibility that the subject might leave the session and continue to drink alcohol, thereby 
placing themselves at risk for accidents, is prevented.
Alcohol is a reinforcing agent, which may cause changes in behavior including repetitive or 
excessive alcohol consumption. Because of this, the administration of alcohol to alcoholics in 
treatment could potentially impede the progress of their recovery. In addition, the 
administration of alcohol to sober alcoholics living in the community presents a possible risk of 
relapse. As a result, we will be recruiting non-abstinent non-treatment-seeking alcoholics in 
keeping with the National Advisory Council on Alcohol Abuse and Alcoholism's recommended 
guidelines (1989) on ethyl alcohol administration. At completion of the study, we will make a 
serious and concerted effort to link the subject with treatment for their alcohol problems. This 
will be done by giving the subject objective feedback about the fact that their drinking exceeds 
standards for avoiding hazardous drinking, providing a brief one-session motivational 
intervention for their drinking, and by arranging for alcohol treatment services if they are 
interested. In our previous and ongoing work, several participants quit drinking and many 
others reduced their drinking in the three months following this intervention.
Interactions of Saracatinib and Alcohol:
There are no known interactions of co-administering Saracatinib and alcohol.  We are 
completing a pilot study (HIC 0602001068) examining the effect of administering up to 80 
mg/dl of alcohol which is close to the maximum BAC that participants in our ADP paradigms 
achieve and 125 mg/day of AZD (administered for eight days; similar to what is being proposed 
in the current study).  We have had two subjects participate in this protocol to date and have 
not observed only minimal and anticipated adverse events.   
Intravenous Access:
Insertion of an intravenous catheter involves risk for hematoma at the site of the venous 
puncture. Very rarely, venous puncture can also result in a blood clot or infection.
Blood and Urine Collections:
Screening blood and urine collections are performed primarily as safeguards to subjects and 
should add no risks other than those normally associated with these procedures. Subjects will 
have approximately 50 cc of blood drawn at the intake, second self-administration, and at one 
week follow up appointments to determine liver and kidney functioning. In addition, a total of 10 
cc of blood will be drawn at the lab sessions to determine alcohol levels. Therefore, the total 
amount of blood drawn during the study (160 ml) is well within the HIC guidelines of 450 cc 
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within eight research weeks, and the blood loss poses minimal risk in healthy subjects. We will 
advise subjects against donating blood for six weeks following study participation.
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 will be made.
Functional Neuroimaging (fMRI): 
Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-rays, to 
take pictures and measure chemicals of various parts of the body. The United States Food and 
Drug Administration (FDA) has set guidelines for magnet strength and exposure to radio 
waves, and we carefully observe those guidelines. Those who participate will be watched 
closely throughout the MR study. Some people may feel uncomfortable or anxious. If this 
happens to the patient, he/she may ask to stop the study at any time and we will take you out 
of the MR scanner. On rare occasions, some people might feel dizzy, get an upset stomach, 
have a metallic taste or feel tingling sensations or muscle twitches. These sensations usually 
go away quickly but we will instruct the patient to please tell the research staff if this occurs. 
There are some risks with an MR study for certain people. If a person has a pacemaker or 
some metal objects inside your body, he/she may not be in this study because the strong 
magnets in the MR scanner might harm them. Another risk is the possibility of metal objects 
being pulled into the magnet and hitting a participant. To reduce this risk, we require that all 
people involved with the study remove all metal from their clothing and all metal objects from 
their pockets. We also ask all people involved with the study to walk through a detector 
designed to detect metal objects. It is important to know that no metal can be brought into the 
magnet room at any time. Also, once a participant is in the magnet, the door to the room will be 
closed so that no one from outside accidentally goes near the magnet. We will make sure the 
participants read and answer very carefully the questions on the MR Safety Questionnaire 
related to their personal safety. We will ask each participant to take a moment and be sure that 
they have read the MR Safety Questionnaire and be sure to tell us any information they think 
might be important.
This MR study is for research purposes only and is not in any way a clinical examination. The 
scans performed in this study are not designed to find abnormalities. The primary investigator, 
the lab, the MR technologist, and the Magnetic Resonance Research Center are not qualified 
to interpret the MR scans and are not responsible for providing a diagnostic evaluation of the 
images. However, hi-resolution de-identified structural images may be shared with referring 
clinicians if requested for select patients to rule out gross anatomical markers or findings. 
Moreover, if a worrisome finding is seen on a scan, a radiologist or another physician will be 
asked to review the relevant images. Based on his or her recommendation (if any), the primary 
investigator or consulting physician will contact the participant, inform them of the finding, and 
recommend that they seek medical advice as a precautionary measure. The decision for 
additional examination or treatment would lie solely with the participant and their physician. 
The investigators, the consulting physician, the Magnetic Resonance Research Center, and 
Yale University are not responsible for any examination or treatment that they receive based 
on these findings.
Genetic Samples: 
Donation of 30 ml of blood for genetics studies will be part of every Informed Consent 
document. Subjects will be informed of possible risks and benefits of participation in genetics 
research will be informed of the potential genomewide scope of the genotyping effort, and will 
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be informed that their DNA samples will be retained indefinitely (banked). A Certificate of 
Confidentiality from NIAAA has been obtained to further protect the confidentiality of this 
information.
9. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
Saracatinib:
Effective screening will exclude all subjects who would be at greater risk for complications 
because of medical, neurological or psychiatric illnesses or who have any of the other 
exclusion criteria (described above). Individuals currently dependent on other drugs will be 
screened out.  Subjects maintained on study medication will be issued "keyed" cards which 
allow health professionals to break the double blind by calling the Yale-New Haven pharmacy 
switchboard, which answers 24 hours a day. Subjects will also be monitored daily for 
frequency and severity of adverse events using the SAFTEE.  These adverse events will be 
reviewed daily by the study physician, Dr. Julia Shi or the APRN, Denise Romano.  We will 
also repeat blood draws for routine CBC tests and hepatic, kidney and thyroid function tests at 
the end of the treatment period and at one week follow up (51cc). 
The Investigator’s Brochure states that Saracatinib should not be administered to pregnant or 
breast-feeding women and it is recommended that non-childbearing status should be 
confirmed by a negative pregnancy test before administration of Saracatinib in women of 
childbearing potential. Conception must be avoided during maternal or paternal exposure to 
Saracatinib. 
Therefore, the following precautions will be taken for women: 1) Urine pregnancy tests will be 
performed at intake, prior to starting the medication, and on the day of the alcohol self 
administration sessions. Pregnant or nursing women will be excluded from participation and 
encouraged to seek advice about the risk of heavy drinking, encouraged to seek alcohol 
treatment, and, if interested, referred to other cessation programs. 2) Women and men must 
agree to use a reliable method of birth control while they are in the study. Each female subject 
will be asked to alert the principal investigator if she departs from her birth control plans or if, in 
spite of adherence to these plans, she thinks she might be pregnant. Each male subject will be 
asked to alert the principal investigator if he departs from his birth control plans or if, in spite of 
adherence to these plans, he thinks his partner might be pregnant.  
Confidentiality Safeguards
Right to privacy for participation in this research will be protected through anonymous coding of 
data and proper storage of research records. A list of numbers and the corresponding names 
will be maintained by the Project Director. Access will be limited to the PI and her designates 
involved in the study. Data from CTNA projects will be maintained by the Data Management 
and Biostatistics Component (DMBC) and/or Investigator. Data will be available on request 
after the completion of analyses by the Investigators and after publication of results. Requests 
should be submitted to the Investigator with details about the type of information needed and 
plans for use. After review between the Requestor and Investigator, and approval by the 
Executive Committee, the agreed-upon list of files will be submitted to the DMBC for 
preparation and delivery to the Requestor.
A certificate of confidentiality has been obtained from the NIAAA, which will protect the 
confidentiality of all research records generated by this study. Other safeguards include 
screening by experienced professionals in order to ensure that the inclusion and exclusion 
criteria are met before patients are entered in the study, including physical exam and 
laboratory tests. 
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Subjects will be informed about possible risks from participating in genetics research. They will 
be informed that DNA will be stored indefinitely. They will be informed that genotyping 
(possibly extending to genomewide extent) will take place on their donated DNA.  They will 
also be told that under some circumstances, it can be a risk for genetic information about to be 
known but that we will keep the results of the genetic testing confidential.  We will not make 
any of our results available to them or add it to their medical records. If they want to know their 
risk of a genetic disease, we will refer them to a genetic counselor.  Finally, they will also be 
informed that this genetic data may be subject to sharing with other investigators, and that if 
data are shared, it will be in anonymous form, that is, with no personal identifiers.
Alcohol challenges
The alcohol challenges will be conducted by personnel experienced in alcohol challenge 
research. We provide a number of safeguards to reduce the risk of physical injury by 
supervising all sessions and having subjects stay in a safe environment overnight. We also 
exclude subjects for whom physical or psychological problems contraindicate alcohol 
consumption. By selecting non-treatment-seeking subjects who are currently drinking heavily 
on a regular basis, we are not exposing subjects to alcohol consumption levels that differ from 
their normal drinking context. Although we have never had a subject chose to leave a session 
early, should a subject insist on leaving the research setting prematurely, we will provide 
transportation back to their residence. This contingency is explicitly addressed in the consent 
form. Clearly, subjects are free to discontinue the experiment at any time, although we would 
strongly encourage them to remain in the research setting until their blood alcohol level is 
below .02. Because subjects are not in treatment, participation in an alcohol challenge study 
will not interfere with efforts to achieve abstinence. At the end of the study, however, a 
potential benefit is that subjects will be provided with a professional evaluation and a 
motivational intervention to encourage them to seek treatment.
Functional Neuroimaging (fMRI) 
Participants will be appropriately screened for metals as will all personnel who enter the room 
that contains the MRI scanner. This screening will involve a self-report questionnaire, an 
interview with a trained radiographer and assessment with a ferromagnetic metal detector. 
Subjects will also be monitored physiologically throughout the scanning session using pulse 
oximetry. Their heart rate and blood pressure will be monitored at all times while they are in the 
MRI scanner.
10. 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.
a.
What is the investigator’s assessment of the overall risk level for subjects participating 
in this study? This protocol is a greater than minimal risk protocol and therefore requires 
a data safety and monitoring plan.  
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.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are   
available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk ii.
Greater than 
minimal
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1) Plan for Grading Adverse Events and Attribution of Adverse Events
Side effects/adverse experiences are collected on standardized forms, using the SAFTEE (Levine 
and Schooler, 1986). The SAFTEE includes 1) open-ended questions about any changes in 
physical or health problems, appearance, or activity level, and 2) yes/no questions on a specific list 
of symptoms (which correspond to anticipated adverse events associated with Saracatinib) for a 
specified time period. For each symptom reported on the SAFTEE a rater also records the date of 
onset, severity (minimal, mild, moderate, severe), whether it was drug-related, and action taken. 
The SAFTEE is administered at baseline, during the inpatient periods, and every other day during 
the outpatient treatment periods. We will monitor the number of patients experiencing symptoms 
and the severity of symptoms.
2) Plans for unanticipated and anticipated serious adverse events reporting to the IRB/HIC, 
funding agency, and regulatory agency
2.a. Definition of Serious Adverse Events: The FDA’s definition of serious adverse events (21 
CFR 312) will be used. SAEs include any untoward medical occurrence that at any dose results in 
death or the immediate risk of death, hospitalization or the prolonging of an existing hospitalization, 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect (NIH Guide- 
6/11/99)
2.b. Plans for reporting serious adverse events: Adverse events that meet the criteria for a 
Serious Adverse Event will be reported to the IRB, MAC, and NIAAA within 24 hours by phone and 
in writing within 1 week. 
3) Plans for reporting non-serious anticipated and unanticipated adverse events
The number of subjects (and percentage) reporting each anticipated adverse event would be 
reported on an annual basis to the IRB, MAC, and NIAAA as part of annual progress report 
(NIAAA) and annual reapproval (IRB). These will be reported for the overall sample and not by 
treatment condition in order to maintain the blind. However, if anticipated adverse events occur in 
greater magnitude or frequency than expected, then these will be reported to the IRB and NIAAA.
3.a. Anticipated Adverse Events: 
3.a.1.Saracatinib-induced side effects: Studies to date suggest relatively few adverse events of 
Saracatinib and that it is safe and well tolerated across doses. Diarrhea, headache, fatigue and 
nausea were the top adverse events observed at 100 and 125 mg dose of Saracatinib in 
Alzheimer’s patients, but the incidence rates were low and did not differ from the rates observed 
with placebo. The 50 mg dose was associated increased headache in one individual. 
3.b.1. Blood Drawing: Possible adverse events include feeling lightheaded, bruising at the 
withdrawal site, fainting, and pain.
4) Identification of who will perform the safety review and with what frequency
4.a. Establishment of a DSMB to perform the safety review
We will be accessing the Data and Safety Monitoring Board (DSMB) developed for the Center. The 
DSMB is multi-disciplinary and includes representatives with expertise in the primary components 
of the proposed trial. The following individuals will be on the DSMB as voting members:
Robert Swift, MD, PhD, Prof. Psych (Brown)/ VAMC Chmn., DSMB
Robert Stout, PhD, Director, Decision Sci. Int., Statistician, DSMB
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Howard Zonana, MD, Dir., Dept. Psychiatry Ethics Committee, IRB Rep., DSMB 
Lisa Newton, PhD, Prof. Applied Ethics, Fairfield Univ. Ethicist, DSMB
This DSMB will follow the operational guidelines outlined in the YCCI plan for DSMB. 
 
4.b. Frequency of Review of Safety Reports
Subjects are recruited at a maximum rate of 2 per month; thus, the DSMB will review safety reports 
two times a year. More frequent meetings will be scheduled if indicated by interim findings.
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A
i. How will adverse events and unanticipated problems involving risks to 
subjects or others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results? iii. What 
will the multi-site process be for protocol modifications?
11. Statistical Considerations: Describe the statistical analyses that support the study design. 
Power Calculations: We will to recruit up to 90 subjects and randomize 40 subjects to the 125 mg 
Saracatinib dose and 20 subjects to placebo. We will use the number of drinks consumed at the 
baseline session (5 or less, 6 or more) and gender as stratification variables in the randomization. 
6 drinks is half the total number of drinks they are allowed to drink in the self-administration period 
and will allow the participant to reach a BAC of 0.07 or higher which is the threshold for heavy 
drinking.  We anticipate that we will obtain complete data on 52 subjects in approximately 2:1 ratio 
on active vs. placebo. This would give us 80% power to detect large effects of drug (d=0.8 or 
greater) at two-sided alpha level of 0.05. Such an effect size is considered clinically meaningful 
and is consistent with our pilot data where we observed large effects of the 125 mg dose 
(administered over eight days) on alcohol-induced stimulation and feeling intoxicated and feeling 
good (all >0.8) following exposure to a fixed dose of alcohol (0.8 mg/kg) in heavy social drinkers. 
Randomizing more subjects on active drug will allow us to explore relationships between potential 
predictors (e.g. gender, smoking status) and outcome in the treatment group. Thus, we will be well 
powered with our proposed sample to detect clinically relevant effects of Saracatinib.
Statistical analyses: All data will be transcribed onto teleforms, checked for completeness and 
clarity, and sent to the data manager, Ms. LaVelle. All outcomes will be summarized descriptively 
and assessed for normality prior to analysis using normal probability plots and Kolmogorov test 
statistics.  Transformations or nonparametric analyses will be performed as necessary.  In the 
mixed models described below, the correlation between repeated measures on an individual will 
be modeled using random effects and/or structured variance-covariance matrices. The best fitting 
variance-covariance structure will be determined by information criterion.  The mixed effects 
approach is advantageous in that it is unaffected by randomly missing data and allows greater 
flexibility in modeling the correlation structure of repeated measures data (Gueorguieva & Krystal 
2004). All tests will be two-sided and considered statistically significant at alpha=.05.  Significance 
levels for secondary comparisons will be adjusted for multiple tests using the Bonferroni correction, 
basing the adjustment on the number of conceptually related statistical tests within each 
hypothesis.
Aim 1: Scores on the Yale Craving Scale will represent the dependent variable in a linear mixed 
model with treatment (0 or 125 mg Saracatinib) as a between-subjects factor and time (see time 
points, Table 1) and session (baseline, post-treatment) as within-subject factors. All multilevel 
interactions will be modeled and interpreted by plotting and comparing least squares means. We 
anticipate a significant treatment by time by session interaction explained by greater posttreatment 
reductions in craving with Saracatinib compared to placebo. We will also explore the influence of 
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treatment on alcohol craving in response to the alcohol cue exposure just prior to the start of the 
drinking session using a similar model. In the above models, treatment will be considered as a 
categorical predictor but linear and quadratic effects of dose will also be tested. Aim 2:  Total 
number of drinks consumed during the ADP will be compared among treatment conditions using 
linear mixed models as above with treatment (0 mg or 125 mg Saracatinib) as a between-subjects 
factor and session (baseline, post-treatment) as a within-subject explanatory factor. We anticipate 
a significant treatment by session interaction owing to reduced drinking following Saracatinib 
treatment, but not placebo. We will also consider change from baseline as the outcome measure 
and compare the treatment groups using ANOVA.
Secondary Aim 1: Alcohol-induced stimulation and sedation during ADP will be evaluated using 
the same linear mixed models outlined in Specific Aim 1, with BAES subscale scores as the 
dependent variables.
Secondary Aim 2: Adverse events will be recorded and summarized qualitatively by treatment 
group. Total and severe adverse event frequencies will be compared between groups using 
chisquare or Fisher's exact test. Similar to what our collaborators, Drs. Strittmatter and Nygaard 
observed among AD subjects (see preliminary data), we anticipate AE profiles of the two active 
Saracatinib groups will be similar to placebo.  Vital signs and blood alcohol levels and plasma 
Saracatinib levels assessed during the ADP will also be evaluated using linear models to examine 
alcohol-Saracatinib interactions. 
Exploratory Aims: All measures (e.g., PST, Habit, genetic markers, neural markers) will be 
evaluated using the same models outlined in Specific Aim 2.  
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
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). 
AZD0530, or Saracatinib, is a selective inhibitor of Src family kinases, with high specificity for Fyn 
kinase. The drug was developed for the treatment of solid tumors and has been found safe and well 
tolerated in both phase 1 and phase 2 clinical trials (AZ Investigator’s Brochure). AZD0530 has not been 
approved for clinical use by the FDA. 
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?
We have already received an IND (Holder: John Krystal; # 124428) for the use of AZD0530 for 
neuroimaging study (PI: Godfrey Pearlson) and for a safety study with alcohol administration (HIC 
protocol 0602001068; PI Krishnan-Sarin); this IND is attached.  We submitted the report from our 
safety study to the FDA on November 29, 2016 along with modifications to the same IND to allow 
us to conduct the current study in heavy drinkers. We heard back from the FDA on Dec 22, 2016 
requesting us to modify the IND to add information about the criteria and procedures for 
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discontinuing or delaying access to additional alcohol during the self-administration session.  We 
responded with a modification that included stopping language (as highlighted in the section titled 
“Alcohol Drinking Paradigm” earlier in this protocol) on February 7th, 2017.  As of March 8, 2017, 
no further queries were made by the FDA, clearing the IND for use on this study. 
b. Who holds the IND? John Krystal, a Co-I will hold 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 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
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 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. 
AZD0530, or Saracatinib, is a selective inhibitor of Src family kinases, with high specificity for Fyn 
kinase. The drug was developed for the treatment of solid tumors and has been found safe and well 
tolerated in both phase 1 and phase 2 clinical trials (AZ Investigator’s Brochure). AZD0530 has been 
extensively studied in human subjects, including published studies with healthy individuals78,94, and 
patients with solid tumors95,96.  AstraZeneca has extensive safety data of this drug in human subjects, 
described in detail in the Investigator Brochure (IB). Notably, in a multiple ascending dose study, 
AZD0530 doses of 60 mg to 185 mg were well tolerated, and although adverse events were 
noticeably more frequent and severe at the 250 mg dose, no major safety issues were identified 
from adverse events at any of the doses studied.  To date, 187 healthy volunteers and 421 patients 
with advanced cancer have received single or multiple once-daily oral doses of AZD0530. More 
recent evidence also suggests that AZD at 100 mg and 125 mg was safe and well tolerated when 
used for up to 4 weeks in patients with Alzheimers disease (Nygaard et al., 2015). 
Animal studies that have tested the effects of AZD0530 at higher doses than those used in the 
current project, or for longer periods of time, have shown that the drug can cause problems with the 
heart, liver, blood cells, and digestive system (including the stomach and intestines). These harmful 
effects have included irritation of the digestive system (which can lead to symptoms of vomiting and 
diarrhea).  Other side effects include lower blood pressure, higher heart rate, lower white blood cell 
counts (infection-fighting cells), and higher liver enzymes (which can be a sign of damage to the 
liver). It is not known for sure if AZD0530 would produce the same harmful effects in humans that it 
has with long-term doses in animals. Animal studies also suggest that taking AZD0530 during 
pregnancy could result in eye defects in the developing baby.
3. Source: a) Identify the source of the drug or biologic to be used. 
AZD0530 and matching placebo will be provided by Astra Zeneca; Astra Zeneca will not provide any 
other support for the current protocol. Study medication will be dispensed by the Investigational Drug 
Service. 
b) Is the drug provided free of charge to subjects?  Yes   No  If 
yes, by whom? 
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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.  This is not a treatment trial or a treatment seeking population of heavy 
drinkers. We need a placebo to confirm the effects of Saracatinib. 
b. State the maximum total length of time a participant may receive placebo while on the study. 8   
days
c.
Address the greatest potential harm that may come to a participant as a result of receiving    
  
   placebo. Not a treatment seeking population, thus no harm is anticipated
d. Describe the procedures that are in place to safeguard participants receiving placebo. Not a 
treatment seeking population.
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 Yale-
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No    If Yes, please be aware of the following requirements:
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a.       A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the Tools 
tab in the EPIC Banner, Click on Lawson, Click on “Add new” under the New Technology 
Request Summary and fill out the forms requested including the “Initial Request Form,” 
“Clinical Evidence Summary, “ and attach any other pertinent documents. Then select 
“save and submit” to submit your request; and
c.
Your request must be reviewed and approved in writing by the appropriate YNHH committee 
before patients/subjects may be scheduled to receive the investigational device or 
investigational procedure.
2.
What is the name of the device to be studied in this protocol?
Has this device been FDA approved? 
 Yes  
 No
If yes, state for what indication.
3.
Background Information: Provide a description of previous human use, known risks, and 
any other factors that might influence risks. If this is the first time this device is being used in 
humans, include relevant data on animal models. 
4.
Source: 
a) Identify the source of the device to be used. 
b) Is the device provided free of charge to subjects? 
 Yes   No
5.
What is the PI’s assessment of risk level (significant or non-significant) associated with the 
use of the device? 
 Significant Risk (SR) Device Study: A study of a device that presents a potential for serious risk 
to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, safety, 
or welfare of a participant.   
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA.
What is the IDE number assigned by the FDA? 
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B 
(nonexperimental/investigational)?
Who holds the IDE?
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the   
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is not 
required.
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6.
Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and there 
also are exemptions to the requirement for an IDE.  See the criteria in the HIC Application 
Instructions, Section VI.B.4 at 
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-
2511.pdf to determine if these pertain to this study.
  
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions are 
met, copy and paste the completed relevant section from the Instructions into this application.
7.
Investigational device accountability:
a.
State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows:
Maintains appropriate records, including receipt of shipment, inventory at the site, 
dispensation or use by each participant, and final disposition and/or the return of the 
investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch or 
serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements:
Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1.
Targeted Enrollment: Give the number of subjects:
a.
targeted for enrollment at Yale for this protocol 50 completers
b.
If this is a multi-site study, give the total number of subjects targeted across all sites 
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.
Participants will be recruited through advertisements in local newspapers, community 
locations (bars, coffee shops, grocery stores), listings on Craig's list and social 
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networking sites or through our Facebook page or our url “www.paidalcoholstudy.com” 
which links subjects to confidential surveys and provides preliminary information about 
the project.  
b.
Describe how potential subjects are contacted. 
Potential subjects will be contacted using the telephone number or other contact 
information that they provide. 
c.
Who is recruiting potential subjects? 
Potential participant’s eligibility will be assessed by an approved research staff member 
who will then set them up for the initial intake appointment.  We do not anticipate 
problems recruiting these subjects since their profile is similar to that of participants in 
earlier projects and we have been very successful in our earlier recruitment efforts.  
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 
  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 (medical diagnosis, medications, substance 
use)
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
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 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
☐ For inclusion of non-English speaking subject if short form is being used
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of 
this data; Subjects are screened over the phone and voluntarily complete the Qualtrix Survey 
i. 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;
It would be impractical to obtain the subject’s authorization (for recruitment purposes only) 
because potential participants will be calling in to be screened over the phone before any 
face-to-face meeting, therefore will not be able to sign the HIPAA authorization at that time. 
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.
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. *see IRES for list 
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. 
At the start of the intake session, all subjects will receive an explanation of the study including 
its risks, benefits, and procedures, and will be given an opportunity to withdraw from the study. 
Following the resolution of any questions, the subject will be asked to sign the consent form if 
he/she agrees to participate.
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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. 
Subjects with limited decision-making capacity will not be enrolled in this study. Since we are 
recruiting a population of heavy drinkers, we will evaluate breath alcohol levels at the start of 
the intake session and will not continue obtain consent if the individuals breath alcohol level is 
positive.  
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. Adult Compound Authorization Form
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use. Due to the 
intensity and complexity of the design of this study we will only enroll Englishspeaking subjects. 
12(a) As a limited alternative to the above requirement, will you use the short form* for consenting 
process if you unexpectedly encounter a non-English speaking individual interested in study 
participation and the translation of the long form is not possible prior to intended enrollment? 
YES ☐  NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time a 
subject speaking that language is to be enrolled.
Several translated short form templates are found on our website at: 
 http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short form is 
not available on our website, then the translated short form needs to be submitted to the IRB office 
for approval via amendment prior to enrolling the subject. Please review the guidance and 
presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above. 
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
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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
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? 
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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?   
Name, address, telephone number, email address SS #, and birth date, medical/psychological 
diagnosis and current medications will be collected from subjects
b.
How will the research data be collected, recorded and stored? 
As required by law, all reasonable efforts will be made to protect the confidentiality of subjects’ 
protected health information, which may be shared with others to support this research, to 
conduct public health reporting, and to comply with the law as required (according to a HIPAA 
compliant research authorization form signed by the subject). Yale Staff will collect required 
research data through study procedures as outlined in this protocol and record it in confidential 
research records and protected computer files. Each subject will have a paper “research chart” 
created for this information, which will be kept in a locked room and file cabinet. In all study 
records (except for the subject’s research chart which includes the subject’s name and other 
unique identifiers and all original records received by Yale with such identifiers), subjects will 
be referred to by a code number (with access to codes restricted to research staff).
Patient health information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the Compound Consent and Authorization form signed by the 
patient or unless permitted or required by law. Medical information may be given to a 
patient’s personal physician or other appropriate medical personnel responsible for the 
patient’s welfare for treatment purposes as permitted by an Authorization for Access/Release 
of Health Information form signed by the patient. Medical records that identify subjects and 
the consent form signed by subjects must be available for inspection upon request by 
representatives of the U.S. FDA and other regulatory agencies, national and local health 
authorities, the study investigators, the sponsor and the sponsor’s representatives and 
collaborators, and the local IRB. Only research personnel will have daily access to the 
research records.
Although considered unlikely to be encountered, limits to confidentiality such as mandatory 
reporting requirements for abuse of children or the elderly will be complied with. Subjects will 
be notified of this mandatory reporting in the consent form.    
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?
Data will be stored on an encrypted password protected laptop computer without any HIPAA 
identifiers. Strict confidentiality will be maintained in all records of the study by identifying 
subjects by code numbers. Information that is obtained in connection with this study and that 
can be identified with a subject will be kept confidential (subject’s charts are kept in a locked 
room and file cabinet. Files will be kept in locked cabinets in a security system protected 
office. 
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All information obtained from subjects is referred to by code number and kept in locked 
confidential files (subjects’ paper charts are kept in an area protected with a security system, 
in a locked room and file cabinet). Any published results are published as group data without 
the use of characteristics that would identify individual subjects. We quote information only by 
number in conference discussions, scientific reports or publications in order to maintain 
anonymity. 
Do all portable devices contain encryption software? 
 Yes   
 No          
If no, see http://hipaa.yale.edu/guidance/policy.html
 
a.
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.
Study data will be archived in a secure storage facility, data will not be destroyed until at least 7 
years after completion of the study, at which point it will be shredded in accordance to university 
policy.
b. Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, FDA, Data and Safety Monitoring Committee (DSMC), SSC, 
etc.)? (please distinguish between PHI and de-identified data) 
The PI and research staff will have access to all data. The DSMB, FDA, DHHS, Yale 
HRPP/HIC, Yale EMR, and NIAAA will only have access to de-identified data.  A CMHC record 
containing PHI will also be kept in a locked file at CMHC.
c.
If appropriate, has a Certificate of Confidentiality been obtained?
Because this study contains sensitive information and drug testing and is funded by the NIH, per 
the Notice of Changes to NIH Policy for Issuing Certificates of Confidentiality (NOT-OD-17-109), 
effective October 1, 2017, this study is assumed to now have a Certificate of Confidentiality, 
subjects are anticipated to be protected, and the consent form Privacy and Confidentiality section 
reflect this.  
d. 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. 
Any voluntary reports of child abuse, elder abuse and intent to harm self or others will be 
reported to the appropriate authorities and if appropriate treatment will be recommended. 
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.) 
This study will not directly benefit the participants but will help advance knowledge in the area of 
development of pharmacotherapies for alcohol drinking.  Subjects will be offered feedback about 
their drinking and active referral to treatment for their alcohol drinking behavior should they so 
desire. The proposed study may be a conduit for some to receive treatment and for others to 
reduce their drinking on their own.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
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1.
Alternatives: What other alternatives are available to the study subjects outside of the research?
N/A
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 will have the opportunity to receive up to $1277 for completing all phases of the study. 
Payment for the intake interview will be $50, and they will receive an additional $50 for the physical 
examination. Subjects will also receive $200 for participating in the first drinking paradigm, $160 for 
taking the study medication ($10/day of travel, and $300 for participating in the second alcohol 
drinking paradigm. Subjects will earn a $250 bonus for completing both drinking paradigms. 
Subjects will have the opportunity to earn up to $36 during the self-administration period at each 
overnight. Subjects will be paid $10/day for travel during the outpatient medication phase and $30 
for completing each of the two follow-up appointments (one week and one month). Subjects will be 
reimbursed $18 per overnight for parking.
Lastly, if the subject agrees to participate in the fMRI portion of the study, he/she will earn an 
additional $75. Transportation will be provided if necessary.
We have also included a referral bonus of $50 if a participant refers someone to our study that 
successfully completes their first overnight (randomized).
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.     
The subject has no costs associated with participation in this research since all research 
procedures are provided at no cost. 
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? It is unlikely that a 
participant will incur injury as a result of participation in this research.  However, should an 
injury occur, treatment will be provided.   However, the participant or their insurance company 
will have to cover the costs of treatment; this will be specified in the consent form. 
b.
Where and from whom may treatment be obtained? Participants may receive treatment 
wherever they wish.
c.
Are there any limits to the treatment being provided? No
d.
Who will pay for this treatment? The participant or their insurance carrier will be expected to 
pay for the cost of the treatment.
e.
How will the medical treatment be accessed by subjects? Subjects will have a 24-hour 
emergency phone number to contact in the event of an emergency.
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