Efficacy and Mechanisms of Computer Based Training for Cognitive Behavioral Therapy (CBT4CBT) for Alcohol Use Disorders
Phase: NA
Conditions: Alcohol Use Disorder
Sponsor: Yale University

Alcohol Study HIC# 511016759: Protocol and StatAnalysis Plan 
Clinical Trials# : NCT02742246
Note: Statistical Analysis Plan is on Page 35 of this document
Date: 2/15/2021

APPROVED BY THE YALE UNIVERSITY IRB 2/15/2021
HIC# 1511016759
Version 9; February 10, 2021
1
YALE UNIVERSITY
 HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research
100 FR1 (2011-6)
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: : 
 Efficacy and Mechanisms of CBT4CBT for Alcohol Use Disorders
Principal Investigator:
Brian Kiluk, PhD
Yale Academic Appointment:
Assistant Professor
Campus Address: 
40 Temple Street, Suite 6C; New Haven, CT  06511
Campus Phone: 
203-737-3314
Fax: 
203-737-1371
Pager: 
E-mail:
brian.kiluk@yale.edu
Protocol Correspondent Name & Address (if different than PI):
 Joanne Corvino; 40 Temple Street, Suite 6C; New Haven, CT  06511
Campus Phone: 
203-785-2012
Fax:
203-737-1371
E-mail:
joanne.corvino@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
   N/A
Campus Phone: 
Fax: 
E-mail:
Investigator Interests:
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:
Please refer to the HIC website for application 
instructions and information required to complete 
this application.  The Instructions are available at 
http://www.yale.edu/hrpp/forms-
templates/biomedical.html 
Submit the original application and two (2) copies 
of all materials including relevant sections of the 
grant which funds this project (if applicable) to 
the HIC.  
HIC OFFICE USE ONLY
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D oes t he pri nci pal i n vesti gat or, c o-i n vesti gat or, or a n y ot her res p o nsi ble researc h tea m  me m ber, or a n y of 
t heir fa mil y me m bers (s p o use, c hil d, d o mestic part ner) ha ve a n i nce nti ve or i nterest, fi na ncial or ot her wise, 
t hat ma y be vie we d as affecti n g t he pr otecti o n of t he h u ma n s u bjects i n v ol ve d i n t his pr oject, t he scie ntific 
o bjecti vit y of t he researc h or its i nte grit y? See Discl os ures a n d Ma na ge me nt of Pers o nal I nterests i n H u ma n 
Researc h htt p:// w w w. yale.e d u/ hr p p/ p olicies/i n de x. ht ml # C OI  
   Yes 
 √ N o
If yes, list na mes of t he i n vesti gat or or res p o nsi ble pers o n:
T he Y ale U niversity Pri nci p al I nvesti g at or a n d all Y ale U niversity a n d Y ale  Ne w H ave n H os pit al 
i n divi d u als w h o are liste d as c o-i nvesti g at ors o n a pr ot oc ol wit h a Y ale U niversity Pri nci p al 
I nvesti g at or m ust h ave a c urre nt fi n a nci al discl os ure f or m o n file wit h t he U niversity’s C o nflict 
of I nterest Office. If t his has n ot bee n d o ne, t he i n di vi d ual(s) s h o ul d f oll o w t his li n k t o t he C OI 
Office We bsite t o c o m plete t he f or m:  htt p:// w w w. yale.e d u/c oi/   
N O T E: T he re q uire me nt f or mai ntai ni n g a c urre nt discl os ure f or m o n file wit h t he U ni versit y’s 
C o nflict of I nterest Office e xte n ds pri maril y  t o Yale U ni versit y a n d Yale- Ne w Ha ve n H os pital 
pers o n nel.  W het her or n ot t he y are re q uire d t o m ai nt ai n a discl os ure f or m wit h t he 
U ni versit y’s C o nflict  of I nterest Office, all i n vesti g at ors a n d i n di vi d u als dee me d ot her wise 
res p o nsi ble b y t he PI w h o are  liste d o n t he pr ot oc ol are re q uire d t o discl ose t o t he PI a n y 
i nterests t h at are s pecific t o t his pr ot oc ol.
S E C TI O N II: G E N E R A L  IN F O R M A TI O N
1.
Perf or mi n g Or g a niz ati o ns:  I de ntif y t he h os pital, i n- patie nt or o ut patie nt facilit y, sc h o ol or 
ot her a ge nc y t hat will ser ve as t he l ocati o n of t he researc h.  C h o ose all t hat a p pl y:
 
a. I nter n al L oc ati o n[s] of t he St u d y:
 Ma g netic Res o na nce Researc h Ce nter 
 Yale U ni versit y P E T Ce nter
     ( M R- T A C)   
 Y C CI/ C h urc h Street Researc h U nit ( C S R U)
 Yale Ca ncer Ce nter/ Cli nical Trials Office ( C T O)      
 Y C CI/ H os pital Researc h U nit ( H R U)
 Yale Ca ncer Ce nter/ S mil o w
 Y C CI/ Kec k La b orat ories
 Yale- Ne w Ha ve n H os pital
 Ca ncer Data Re p osit or y/ T u m or Re gistr y
 S pecif y Ot her Yale L ocati o n:
b. E xter n al L oc ati o n[s]:
 A P T F o u n dati o n, I nc.
 Has ki ns La b orat ories
 C o n nectic ut Me ntal Healt h Ce nter
 J o h n B. Pierce La b orat or y, I nc.
 Cli nical Ne ur oscie nce Researc h U nit ( C N R U)  
Vetera ns Affairs H os pital, West Ha ve n
 Ot her L ocati o ns, S pecif y:                                   
 I nter nati o nal Researc h Site 
M C C A                       ( S pecif y l ocati o n(s))
Bri d ge p ort, C T a n d Ne w Ha ve n, C T
A N D
S A T U 
1 L o n g W harf Dri ve; Ne w Ha ve n, C T
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c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date: 
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 
April 2016-July 2021
3. Research Type/Phase: (Check all that apply)
a. Study Type
   
 Single Center Study
   
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
  
 Coordinating Center/Data Management
  
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c:
 Clinical Research: Patient-Oriented
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral 
                Health Services
 Translational Research #1 (“Bench-to-Bedside”)    
 Interdisciplinary Research
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
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NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx  or 
 contact YCCI at 203.785.3482)
6. Will this study have a billable service as defined by the Billable Service Definition?
Yes 
 No
If you answered "yes", this study will need to be set up in Patient Protocol Manager (PPM)
http://medicine.yale.edu/ymg/systems/ppm/index.aspx 
7. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No  X  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
 
c. Will a novel approach using existing equipment be applied?
 
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
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funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
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:     N/A
Name:
Company:
Address:
2.  Research Team:  List all members of the research team. Indicate under the affiliation column 
whether the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty 
or staff from a collaborating institution, or are not formally affiliated with any institution. ALL 
members of the research team MUST complete Human Subject Protection Training (HSPT) and 
Health Insurance Portability and Accountability Act (HIPAA) Training before they may be 
listed on the protocol.  See NOTE below.
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Brian Kiluk, 
PhD
Efficacy and 
Mechanisms of 
CBT4CBT for 
Alcohol Use 
Disorders
NIAAA
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M# 
R01AA024122-01A1           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
Name
Affiliation: Yale/Other 
Institution (Identify)
NetID
Principal Investigator 
Brian Kiluk, PhD
Yale
BK84
Role:  Co-Investigator
Elise DeVito, PhD
Yale
EED32
Role:  Co-Investigator
Stephanie O’Malley, PhD
Yale
SS02
Role: Data Manager
Tami Frankforter, MS
Yale
TLF7
Role: Research Assistant
Lawanda Frederick
Yale
LF384
Role: Administrator
Joanne Corvino
Yale
JKC9
Role: Research Assistant
Elizabeth Doohan
Yale
ED266
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NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
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.
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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
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For HIC Use Only
Date Approved
Human Investigation Committee Signature
This protocol is valid through ______________________________________________
SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
Well-controlled randomized clinical trials of computer-assisted therapies are  very rare, and 
there are few that would meet current methodological standards established for traditional 
evidence-based treatments.  We propose to conduct a randomized clinical trial of our web-based 
version of Computer Based Training in Cognitive Behavioral Therapy (CBT4CBT) to evaluate 
its effectiveness relative to therapist-delivered cognitive behavioral therapy or standard 
outpatient counseling with participants with alcohol use disorder.   Specific aims are as follows:
Aim 1 – Evaluate the efficacy of CBT4CBT and clinician-delivered CBT relative to standard 
treatment for reducing alcohol use through an 8-week randomized trial with 6-month follow-
up.  Our primary hypothesis is that either form of CBT will be more effective than standard 
treatment at increasing the percentage of days abstinent (PDA)2, 3 during treatment (8 weeks) and 
through the follow-up (6 months), assessed via Timeline FollowBack interviews4, 5.  Secondary 
outcomes will include percentage of heavy drinking days (PHDD)6, 7, urine ethyl glucoronide 
analysis (EtG)8-10, drinking-related consequences11, 12, quality of life13, and cost effectiveness14.  
Aim 2 – Evaluate the extent to which CBT’s putative mechanisms act as mediator of treatment 
effect on reducing alcohol use in both forms of CBT relative to standard treatment.  
Hypothesized mechanisms include enhanced behavioral, cognitive, and affective control, 
measured within treatment by indices reflecting acquisition and implementation of targeted skills 
(behavioral role-play assessment15, coping strategies inventory16, 17, and measures of homework 
completion and knowledge of CBT).  Latent growth curve modeling will test for mediation using 
the product of coefficients method18, 19.  We hypothesize:  
  (a) greater increases in skills acquisition for those assigned to either form of CBT compared to 
TAU; 
  (b) increased acquisition of skills during treatment will be associated with greater PDA during 
follow-up; 
  (c) CBT’s effect (in either delivery format) on PDA will be mediated by skills acquisition.  
Exploratory Aim -- To determine if genetic risk moderates the response to treatment. We 
hypothesize that genetic risk related to substance use disorders, co-occurring mental health 
disorders and cognitive dysfunction will negatively affect treatment response. 
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The primary outcome measures will be reduction in alcohol use (percent days abstinent - 
PDA) assessed via timeline follow back interviews.  Secondary outcomes will include the 
percentage of heavy drinking days (PHDDs), urine ethyl glucorinide analysis (EtG), drinking-
related consequences, quality of life, and cost-effectiveness.  Analyses will also determine 
whether web-based CBT4CBT retains key characteristics of traditional clinician-delivered CBT 
(e.g., acquisition of coping skills, use of change strategies) and to explore these as potential 
mediators of outcome (mechanisms of action).  Measures of cognitive function (e.g., sustained 
attention, working memory, response inhibition, planning, cognitive flexibility, decision-making) 
will be collected to explore the moderating effect on treatment outcomes.
     
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.
A  SIGNIFICANCE
Cognitive behavioral therapy (CBT) for alcohol use disorders has considerable empirical support 
for its efficacy21-25, and has shown to be highly compatible with pharmacotherapies for alcohol 
dependence26-33.  This is consistent with evidence supporting CBT’s efficacy across a number of 
psychiatric disorders, including depression, anxiety disorders, and eating disorders24, 34-36.  
Moreover, CBT stands out as a comparatively durable approach among empirically validated 
treatments for alcohol use disorders37, 38.  
A1.  Obstacles to broad dissemination and effectiveness of CBT 
Despite CBT’s strong support from efficacy trials, it has proven challenging to disseminate to the 
clinical community39-43.   Although clinicians and program directors report that they frequently 
utilize a range of empirically validated treatments in standard practice40, there is little evidence 
that they are actually doing so, particularly in a manner likely to improve patient outcomes44, 45.  
Despite clinicians frequently reporting use of CBT in clinical practice46-48, objective evidence 
suggests this is not the case.  For example, independent ratings of over 300 audiotapes of 
clinicians conducting standard individual counseling as practiced in 11 clinics across the US 
indicated that CBT interventions were virtually undetectable; any type or level of coping skill 
training was observed in only 3% of sessions and any mention of cognitions in only 8% of 
sessions49.  Furthermore, data from randomized clinician training studies50-52 highlight the 
multiple challenges in transferring empirically validated treatments to clinical practice.  For 
example, similar to Motivational Interviewing training trials52, we found in-person training plus 
ongoing supervision is the only training method that results in clinician competence at levels that 
would be commensurate with those in CBT efficacy trials50.  This level of training, however 
effective, is too costly and time-intensive to be feasible to train large numbers of clinicians in 
complex approaches like CBT45, particularly given the limited resources of most alcohol/drug 
use treatment settings40, 53, 54.  
A2.  Limited understanding of CBT mechanisms; methodological challenges
In addition to the challenges of dissemination and implementation of CBT in clinical practice, 
the lack of understanding regarding CBT’s mechanisms also limits the extent of effectiveness for 
the broad population of individuals with alcohol use disorders.  In order to translate CBT’s 
effects from research to practice, we need better understanding of mechanism, including optimal 
conditions for delivery and what components must not be diluted to achieve change55, 56.  
Although there is strong evidence that CBT works to reduce alcohol use, answers to the 
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questions of how, and for whom it works are not resolved57, 58.  CBT is based on the premise 
that individuals with alcohol problems develop impaired affective, behavioral and cognitive 
control over stressful states and opportunities to drink and hence lower self-efficacy59-62.  Thus, 
one promising explanation for CBT’s effectiveness and durability is its focus on conveying 
generalizable skills to exert cognitive/behavioral control over over-learned behavior and 
patterns, reduce impulsive responding to seek immediate reward in response to alcohol cues via 
control of craving strategies, improve decision-making and problem-solving skills, and 
recognize, challenge, and exert control over cognitions associated with alcohol use63.
Strategies for evaluating an intervention’s mechanisms of behavior change are comparatively 
well established55, 64-67.  Morgenstern and Longabaugh’s68 causal chain to demonstrate skill 
acquisition as a mechanism of CBT proposed four criteria, which included evidence that 
inclusion of coping behaviors as a covariate reduced the effect of CBT on drinking outcome 
(statistical mediation69).  However, much of the evidence regarding skills acquisition from 
CBT trials for alcohol use fails to meet all four of these criteria16, 68, 70, 71.   Several 
methodological features likely contribute to the mixed evidence regarding CBT’s mechanisms:  
First, most trials evaluating clinician-delivered interventions face issues of variability in 
treatment delivery that may confound the evaluation of mechanisms.  This includes variability in 
fidelity to the intervention72-74, dose and quality of delivery75, as well as ‘therapist effects’ that 
may directly affect the active treatment ingredients hypothesized to be responsible for 
contributing to behavior change.  Clinicians delivering standardized treatment in clinical trials 
regularly show substantial differences in the outcomes of clients they treat76-78, and in some 
trials, ‘therapist effects’ account for more variability in outcome than treatment factors79-81.  
Furthermore, distinguishing non-specific factors from specific active ingredients has proven 
difficult in trials examining mediators across clinician-delivered treatments58, 82, 83.  Specific 
effects are inseparable from ‘relational’ effects (e.g., therapeutic alliance) when treatments 
are delivered in the context of an interpersonal relationship76.  Second, there are relatively 
few reliable measures of skills acquisition and implementation16, 59, 68, as many self-reported 
assessments may not be adequately sensitive to the specific skills taught nor measured at the 
appropriate intervals to demonstrate change prior to the outcome55, 65.  Third, given the 
complexity of behavior change, trials have been limited by inclusion of only one level of analysis 
of the mechanism, rather than considering the contributions of multiple processes to form a more 
complete understanding of how, and for whom, CBT works.  For instance, there is considerable 
evidence that chronic, heavy alcohol use affects cognitive abilities associated with controlled and 
effortful processing of novel information, including executive functions and fluid cognitive 
abilities84-89, which have been shown to affect treatment processes90-93, and may affect the 
delivery of a cognitively-demanding therapy such as CBT (e.g., moderation of a mediator).  
Lastly, traditional methods for demonstrating statistical mediation (e.g., causal steps approach) 
have been limited by testing single mechanisms with inadequate power for detecting mediated 
effects94, 95.  More advanced statistical approaches have indicated the improvement in coping 
skills may mediate the effect of CBT on reductions in primary drug use96, marijuana97, 
gambling98, and chronic pain99.
A3.  Potential of computer-delivered interventions to address obstacles
The emergence of computer-delivered interventions offers tremendous promise with respect to 
making evidence-based treatments more broadly accessible to those who may benefit from 
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them100, 101.  This is crucial given that the vast majority of those with alcohol use disorders do not 
receive treatment102-104.  Computer-delivered interventions have the potential to reach rural 
populations and other groups whose access to treatment is limited, as well as those who do not 
seek treatment because of discrimination or stigma105, 106.  Furthermore, they also offer 
significant advantages of standardization and consistent quality, reduction of cost and clinician 
time, and potential 24/7 availability14, 107-111.  In addition, computer-delivered interventions 
may also facilitate evaluation of mechanisms via delivery of active treatment ingredients in 
a more focused and concentrated form than is possible with clinician-delivered treatments.  
One of the key benefits of computerized delivery of interventions is standardization101, 112, 113 
relative to traditional clinician-delivered treatments with respect to variability in treatment 
fidelity, quality, and delivery of active and common elements114.  These characteristics make 
computer-delivered interventions a promising solution to the dissemination and implementation 
challenges, as well as the challenges in identifying mechanisms, that have limited CBT’s broad 
use in clinical practice.       
However, in order for this potential to be realized, computer-delivered interventions need to be 
evaluated in well-controlled high-quality randomized trials, with appropriate control and 
comparison conditions.  Computer-delivered interventions should be subject to the same 
rigorous testing and methods that are required for establishing efficacy of behavioral and 
pharmacologic interventions prior to their dissemination115, 116.  Ideally such trials would include 
clinician- and computer-delivered versions of the same intervention, as adoption of computerized 
versions of empirically supported treatments is predicated upon their retaining the efficacy and 
putative active ingredients of the original clinician-delivered approach.  Further, such a design 
would also allow for investigation of client characteristics that influence how mechanisms 
operate in each form of treatment delivery, which would have high clinical utility.  
The current state of research on computer-delivered interventions includes very few trials with 
such a design.  Our recent methodological review of the existing randomized clinical trials 
evaluating all computer-delivered interventions for adult Axis I disorders117 found that only 3 of 
the 75 trials evaluated met minimal methodology standards for evaluating intervention efficacy, 
with most utilizing weak wait-list control conditions, non-validated self-reports of outcome, and 
having poor rates of follow-up.  Regarding computer-delivered interventions specifically for 
alcohol use, a 2011 meta-analyses of 25 randomized trials concluded “At present, it is not 
possible to interpret the evidence with any degree of certainty. The current literature is limited 
by small sample sizes, short-term follow-up, few studies in non-student adult populations 
and few comparisons with active comparator groups”118.  Thus, evaluation of a computer-
delivered version of CBT within a well-controlled trial that includes a clinician-delivered version 
would fill an important gap and potentially lead to a valuable new and easily disseminated 
treatment resource.   
A4.  Development and evaluation of computer-delivered CBT
In response to the (1) limited availability of CBT in clinical settings, (2) complexity of training 
in CBT and the increasing time constraints on clinicians, and (3) need to develop a version of 
CBT that can be implemented more consistently, with a high level of quality and at lower cost, 
we developed a computer-based training version of CBT for substance use disorders, called 
CBT4CBT119.  The original CBT4CBT program consists of seven modules targeting drug use 
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disorders, the content of which is based closely on the NIDA CBT manual120.  In developing 
CBT4CBT, we sought to construct a highly engaging version of CBT that could take advantage 
of the capacity of computer-based learning to convey key CBT skills via a range of media (e.g., 
video, graphics, audio instruction, interactive exercises).  In particular, we capitalized on the use 
of video-based examples to emphasize learning of targeted behavioral, cognitive, and affective 
strategies, with emphasis on modeling from examples of individuals utilizing skills in a range of 
realistic situations.  We conceived of CBT4CBT as a ‘skills training machine’; one that seeks to 
teach a core set of generalizable CBT strategies (functional analysis, coping with craving and 
strong affect, problem solving, decision making, challenging thoughts, and assertive drug 
refusal). Interactive exercises are included to reinforce patients’ understanding of targeted skills, 
as well as practice assignments (i.e., homework) to encourage implementation and practice of 
skills, and thus enhance durability of treatment effects. Given our previous work linking out-of-
session practice of homework with skill acquisition and outcome in CBT121, the CBT4CBT 
program places extensive emphasis on practice of skills through interactive homework exercises 
and close monitoring of homework completion. 
      
We have completed two randomized trials of CBT4CBT within independent samples of drug 
users119, 122, 123 (PRELIMINARY DATA – C.1.a.).  These have indicated: (1) statistically 
significant effects over standard treatment on biological outcomes (% drug-negative urine 
specimens)119, 122, (2) enhanced durability through a 6-month follow-up122, 123, (3) significant 
differences with respect to standard treatment in acquisition of coping skills96, and (4) changes 
in acquisition of coping skills via CBT-mediated reduction in drug use through follow-up96, 
124.  Dr. Kiluk’s 2010 report was one of the first successful demonstrations of skills acquisition as 
a mediator of CBT’s effect on drug use (PRELIMINARY DATA – C.1.b.), meeting the criteria 
described by Morgenstern and Longabaugh68, as well as most of those outlined by Kazdin and 
Nock64.  Several aspects of these trials may have enhanced our ability to detect mediation effects:  
First, we included a situational role-play assessment15 for measuring skill acquisition, which may 
have provided a more valid assessment than self-report questionnaires. Second, we focused on 
the quality rather than quantity of skills, which may have provided a more meaningful 
indicator of skill acquisition.  Third, standardized delivery of CBT via computer may have 
facilitated detection of changes in acquired skills and mediating effects by reducing variability in 
treatment delivery.  
Dr. Kiluk led the team that developed the adaptation of CBT4CBT specifically targeting alcohol 
use, which was completed in 2011.  The program follows the format used in the original drug-
based version, with content, situations, and videos adapted for individuals with alcohol use 
disorders and based closely on the NIAAA CBT manual125.  We have completed an R21 trial 
establishing its feasibility, safety, and preliminary efficacy at reducing alcohol use within a 
sample of outpatient treatment seekers (PRELIMINARY DATA – C.1.e.).  The next logical step 
in this program of research is a larger randomized controlled trial, which would include 
traditional clinician-delivered CBT and treatment as usual (TAU) in order to evaluate 
whether the computerized version retains key characteristics of clinician-delivered CBT.  
Although a direct comparison of CBT4CBT to clinician-delivered CBT (e.g., a non-inferiority 
study)126-128 would be premature at this stage (and not sufficiently powered in the proposed 
project), such a design could compare the cost-effectiveness of the two formats, as well as 
generate effect size and power estimates for a future non-inferiority trial.  Additionally, this 
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design is an ideal platform to evaluate mechanisms of CBT, for several reasons65, 129.  First, 
inclusion of a treatment condition consisting of CBT4CBT delivered with minimal clinical 
contact (focused on monitoring clients’ safety and assessing signs/symptoms of clinical 
deterioration) would offer the evaluation of an isolated form of CBT’s main active ingredient - 
coping skills training, without the presence of therapist factors and common factors associated 
with clinician-delivered CBT.  Second, although both delivery formats of CBT may facilitate 
change through similar mechanisms (e.g., enhanced affective, behavioral, and cognitive control), 
the processes by which they affect these mechanisms may differ in several ways.  For instance, 
there is likely to be a larger ‘dose’ of CBT skills training in the computer-delivered version.  It is 
also possible that the interpersonal and tailored discussion of completed homework activities 
may facilitate out-of-session practice in clinician-delivered CBT, whereas viewing the video-
based modeling of skills implementation may be most salient in CBT4CBT.  Third, retaining a 
TAU condition is essential for both evaluating the efficacy of CBT4CBT for alcohol use 
disorders, as well as permitting evaluation of the specificity of CBT’s mechanisms.  
A5,  BIOMARKER DEVELOPMENT TO FACILITATE CBT: Alcohol use disorder is a 
highly polygenic trait, which means that there are many common single nucleotide 
polymorphisms (SNPs) that affect risk within the population, perhaps thousands, with most 
having very small effects (e.g. OR < 1.1) {Gelernter, 2015 #648}. Information on individual 
differences in genetic risk can be used as a biomarker to develop more effective treatments as 
outlined by the NIH’s Precision Medicine Initiative {Collins, 2015 #679}. Techniques exist to 
study the aggregate effect of risk SNPs in an individual’s genome. For a given trait, the sum of 
risk SNPs in an individual’s genome is their genetic risk score, or polygenic risk score (PRS) 
{Purcell, 2009 #566}. The PRS for individuals in a population can be estimated using the 
summary statistics from independent genomewide association studies (GWAS). An individual’s 
PRS is the sum of non-correlated SNPs in their genome weighted by the SNP effects size (e.g. 
odds ratio) in the GWAS. SNPs with large effect in the GWAS will contribute more to an 
individual’s PRS compared to SNPs with small effect. For a given disorder, the amount of 
genetic risk carried by an individual might influence their response to certain treatments. For 
example, it has been suggested that treatment resistant schizophrenics have more schizophrenia 
genetic risk compared treatment responsive schizophrenics {Frank, 2015 #567}. Characterizing 
genetic effects on cocaine use disorder treatment response is important because it could help to 
explain heterogeneity in treatment outcomes and establish a foundation to develop more effect 
treatments. 
A6.  SUMMARY 

CBT has strong empirical support for the treatment of alcohol use disorders, yet 
implementation into clinical practice has been challenging.  CBT’s mechanisms are not yet 
fully understood, which may limit the potency of the intervention and the effectiveness for a 
broad population of those with alcohol use disorders.

CBT4CBT has demonstrated effectiveness at reducing illicit drug use and improving the 
acquisition of skills as compared to standard treatment, with benefits maintained through 
follow-up periods in two independent randomized clinical trials119, 122, 123.  We have used this 
form of CBT to demonstrate that skill acquisition mediates its effect on treatment 
outcomes96.  Preliminary data from the completed R21 supports the feasibility, safety and 
preliminary efficacy of CBT4CBT for reducing alcohol use. 
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
Computer-delivered interventions may reduce the variability in treatment delivery that may 
have limited trials of clinician-delivered interventions to demonstrate mechanisms of 
behavior change101, 112, 130, 131.  

A randomized trial investigating the short- and long-term efficacy of CBT4CBT for alcohol 
use disorders would be particularly valuable at this stage of research, as it would not only 
facilitate evaluation of CBT4CBT’s efficacy for alcohol use disorders with respect to 
standard treatment (TAU), but also permit some exploratory comparison with clinician-
delivered CBT.  Further, this strategy may prove a particularly informative means of 
evaluating mechanisms via CBT delivery in different formats.
B.  INNOVATION

The proposed project would be the first adequately powered RCT to evaluate the efficacy of 
a web-based version of CBT for alcohol use disorders.  The evaluation of CBT4CBT 
(delivered with minimal clinician contact) will provide evidence of CBT4CBT’s effect as a 
virtual ‘stand alone’ intervention for alcohol use, which could have broad implications for 
making this cost-effective form of CBT more broadly accessible. 

Evidence of an effective, empirically-supported web-based CBT intervention for alcohol use 
disorders could lead to a number of applications and potential research directions106, 132, 
including dissemination to rural and other hard-to-reach populations, evaluation in 
combination with alcohol pharmacotherapies, or implemented as a standard psychosocial 
platform for medication trials133, 134.  

Inclusion of a computer-delivered and clinician-delivered CBT in the same trial will allow 
some exploratory comparisons of these interventions in terms of their cost-effectiveness, 
specificity, and participant satisfaction.  The proposed project will generate data that could 
inform design and power calculations for a future non-inferiority study.  

Inclusion of two distinct forms of delivery of CBT in the same trial will allow for 
examination of one of CBT’s hypothesized primary mechanisms of change, acquisition of 
targeted skills.  The provision of targeted skills can be examined with and without 
‘relational’ factors that contribute to outcomes (e.g., therapist empathy, warmth, and 
therapeutic alliance).  
      
C.  APPROACH
      C1.  PRELIMINARY DATA
Our research group at Yale has completed a series of clinical trials evaluating clinician-delivered 
CBT in a range of populations, including alcohol3, 135-137, cocaine122, 138-141, and marijuana142, 143 
users.  Of particular relevance to our ability to meet the specific aims of the proposed project, our 
trials have focused on evaluation of treatment integrity and active ingredients75, 144-147, and on 
identifying mediators of outcome as potential mechanisms of behavior change15, 96, 121, 148.  
Moreover, we have achieved consistently high rates of completed follow-up interviews for our 
intention-to-treat samples (80-100%)149, 150.
C.1.a.  Validation of CBT4CBT in drug users 
Two independent 8-week trials of CBT4CBT14, 119, 122, 123 for drug use disorders have evaluated 
the efficacy of the program as an adjunct to standard outpatient treatment.  The initial trial 
included 78 individuals (46% female, 58% ethnic minority, 77% unemployed) entering 
outpatient treatment randomized to either standard outpatient treatment (weekly individual 
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Figure 1. Coping skills by treatment and time
3
   3.5
4
   4.5
5
     5.5
6
Pre-treatment
Post-treatment
6 month FU
CBT4CBT
TAU
Quality of skills
sessions and groups, TAU) or standard TAU with access to CBT4CBT weekly.  Nearly 80% of 
participants were users of both alcohol and drugs in this trial.  In terms of outcome, those 
assigned to the CBT4CBT condition submitted a significantly lower proportion of urines that 
were positive for any drugs compared to TAU (34% vs. 53%, respectively; F=3.9, p<.05, 
d=.46).  This difference represents a moderate effect size.   The second trial replicated these 
findings in a sample of 101 cocaine-dependent methadone-maintained individuals (60% female, 
40% ethnic minority, 89% unemployed).  Results indicated those assigned to CBT4CBT plus 
TAU, compared to TAU alone, were more likely to attain 3 or more weeks of continuous 
abstinence from cocaine (36% vs. 14%, p<.01), which is a meaningful outcome measure 
associated with greater rates of long-term abstinence and fewer problems in psychosocial 
functioning149, 150.  In terms of durability of effects, both trials retained >80% of the intention-to-
treat (ITT) sample at the 6-month follow up interview.  Random effect regression analyses of 
drug use across time indicated a significant enduring benefit of CBT4CBT in both trials, such 
that those assigned to CBT4CBT plus TAU tended to decrease their substance use over the 
follow-up period compared to TAU alone122, 123.  Thus, the ‘sleeper effect’ of CBT appears to be 
retained in its translation to computer-assisted format.
C.1.b.  Coping skills acquisition as a mediator of treatment outcome in CBT4CBT
Evidence for the promise of using a computer-based CBT for evaluating mechanisms comes 
from Dr. Kiluk’s  analysis of differential acquisition of coping 
skills in the initial CBT4CBT trial96.   We used a role-playing 
exercise we have validated in previous research (Drug Risk 
Response Test, DRRT)15 and adapted to assess the specific coping 
skills taught in the CBT4CBT modules.  Based on independent 
ratings (i.e., raters blind to treatment condition and time point) of 
pre/post-treatment/follow-up comparisons from 52 participants, 
there were significant group by time interactions, indicating 
those assigned to CBT4CBT had a significantly greater 
increase in the quality of their coping responses across the entire study period (F=9.3, 
p=.004; Figure 1).  Data from this trial also suggest that acquisition of skills during treatment 
may be a mediator of substance use outcomes (Fig 2, below).  A series of regression equations 
demonstrated: (1) an effect of treatment condition on the 
quality of coping responses (‘a’= .26, se=.11, p<.05) 
favoring CBT4CBT (TAU = 3.89, CBT4CBT = 4.40; 
F=4.6, (df 1,40), p <.05), and (2) a significant effect of the 
mediator (quality of coping responses) on outcome, 
controlling for treatment condition (‘b’ = 9.19, se=3.24, 
p<.01).  Using the product of coefficients method18, 19 to 
determine if the mediated effect is significantly different 
from zero, calculated as [(a x b)/(sea x seb)], resulted in 
Z=6.64, p<.05.  Also, confidence limits for the mediated effect using the program PRODCLIN151 
resulted in upper and lower confidence intervals of 5.39 and 0.31, consistent with a statistically 
significant mediated effect.  This suggests improvement in the quality of skills acquired during 
treatment was a mediator of post-treatment drug use.  This comparatively strong evidence 
supporting skills acquisition as a potential mediator of outcome in CBT4CBT is striking, 
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Week 0
Week 8
3
3.5
4
4.5
5
Above 
Median IQ
Below 
Median IQ
Figure 3.  Coping Skills Over Time by IQ
Quality of Skills
given that empirical support for mediation in CBT in the addictions has been elusive59, 68, 
124.  
C.1.c.  Cognitive factors associated with effectiveness of CBT4CBT
The potential role of cognitive functioning as a moderator of outcome in CBT was also 
suggested by Dr. Kiluk’s analysis of skills acquisition and cognitive factors152, 153.   Although 
examination of general intelligence measures (as estimated by Shipley Institute of Living 
Scale154) within the initial CBT4CBT trial did not indicate a direct effect on treatment 
retention152, we did find an indirect effect on substance use outcomes, through the acquisition of 
coping skills153.  First, results of repeated measures ANOVAs indicated significant group by time 
effects for the mean quality of coping response according to a median split of IQ (Group x Time,  
F(1,49) = 4.31, p<.05).  In other words, those who scored above the median IQ improved the 
quality of their coping skills more than those with lower IQ, during the course of the 8 week 
treatment (Figure 3).  Furthermore, the product of coefficients method indicated the acquisition 
of coping skills mediated the effect of IQ on the duration of continuous abstinence (Z= 8.55, 
p<.05), with confidence intervals indicative of a significant indirect effect153.  Preliminary 
evidence from our most recent completed trial of CBT4CBT122 indicated several domains of 
cognitive function at pre-treatment moderated treatment engagement and the acquisition of skills 
during treatment.  For instance, greater rates of inattention on a task of sustained attention155 at 
pre-treatment were associated with fewer sessions attended in TAU compared to CBT4CBT 
(F(1,72)=4.69, p<.05) and slower cognitive processing speed at pre-treatment was associated 
with lower quality of skills acquired in TAU but not CBT4CBT (F(1,64)=5.82,p<.05).  These 
results are consistent with others that have indicated treatment processes and/or mechanisms of 
behavior change may be different depending on level of cognitive impairment85, 91, 156, 157.  Thus, 
we have preliminary evidence that various measures of cognitive function may have moderating 
(and potentially indirect) effects on treatment outcome in CBT4CBT compared to standard 
treatment.  
C.1.d.  Therapeutic alliance in CBT4CBT
To explore the potential for individuals to develop some form of a therapeutic alliance with a 
computer-based intervention, and how it may differ from traditional features of a therapeutic 
alliance, we adapted a widely-used and well-validated measure of the alliance, the Working 
Alliance Inventory (WAI)158, for inclusion in our most recent trial of CBT4CBT for cocaine use 
disorders122.  This adapted version, the Working Alliance Inventory for Technology-based 
Interventions (WAI-Tech)159, included items that measured individuals’ level of relationship 
with the CBT4CBT program, and not their counselor or members of the research team.  Overall, 
the WAI-Tech appeared to have similar psychometric characteristics as the standard WAI in 
terms of internal consistency, mean scores, and stability over time, although not surprisingly, the 
‘bond’ subscale of the WAI-Tech was consistently lower than the other subscales and decreased 
over time [F(1,52) = 5.78, p<.05].  Results indicated 
individuals’ alliance with the CBT4CBT program did 
not negatively affect the alliance with their counselor 
(as this trial included CBT4CBT in addition to TAU).  
However, scores on the WAI-Tech were not 
associated with cocaine use outcomes, whereas total 
scores on the standard WAI for those assigned to TAU 
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were associated with the percentage of days abstinent from cocaine (r = .43, p<.05)159.  These 
findings suggest some concepts of the working (i.e., ‘therapeutic’) alliance may apply to 
computer-delivered CBT, yet the function of the alliance may be different than in face-to-face 
psychotherapies.  Differences in the role of the alliance on outcomes from a ‘stand alone’ 
CBT4CBT versus a clinician-delivered CBT remains an empirical question. 
C.1.e.  Feasibility and preliminary support for CBT4CBT for alcohol use disorders
As mentioned above, CBT4CBT for alcohol use disorders was evaluated in an R21 pilot trial 
wherein 68 participants with a current alcohol use disorder were randomized to one of the 
following 8-week treatment conditions: (1) 
standard treatment as usual (TAU), (2) 
TAU plus CBT4CBT, or (3) CBT4CBT 
plus minimal clinical monitoring (i.e., 
‘CBT4CBT only’).  The R21 data 
demonstrate this version of CBT4CBT was 
safe, feasible, and effective at reducing 
alcohol use when provided within a general 
community outpatient facility.  Of the 7 
modules contained in the CBT4CBT 
program, participants completed an 
average of 5 (sd=2.2), which is comparable 
to our prior trials of CBT4CBT119, 122.  
Participants reported high levels of 
satisfaction with CBT4CBT compared to TAU (72 vs. 67% “very satisfied”, respectively).  
Participants assigned to either CBT4CBT condition were significantly more likely to complete 
the 8-week course of treatment than those assigned to TAU (% completing treatment: TAU = 
23%; TAU+CBT4CBT = 59%; CBT4CBT only = 63%; Χ2 = 8.72, p<.01).  In terms of alcohol 
use outcomes, there was a significant treatment condition x time effect indicating a greater 
increase in the percentage of days abstinent for those assigned to either CBT4CBT condition 
compared to TAU over the course of the 8-week trial (F=5.81, p<.01).  Also, the percentage of 
subjects with no heavy drinking days (PSNHDD)160 in the final month of treatment was 
significantly higher for the CBT4CBT conditions compared to TAU (Figure 4 - TAU = 9%; 
TAU+CBT4CBT = 40%; CBT4CBT only = 33.3%; Χ2 = 5.79, p<.05).  Furthermore, there is 
promising evidence those assigned to a CBT4CBT condition increased their use of change 
strategies16 over time (pretreatment: M=31.9, sd=13.2; post: M=46.1, sd=15.2), increased 
abstinence self-efficacy161 (pre: M=33.9, sd=13.6; post: M=35.4, sd=12.0), decreased distress 
intolerance162 (pre: M=8.8, sd=8.3; post: M=7.6, sd=7.4), and increased their knowledge of 
CBT concepts as indicated by percent correct responses on a CBT quiz (pre: M=74.4, sd=11.8; 
post: M=82.4, sd=11.1).  Finally, no serious adverse events (SAEs) were related to any 
CBT4CBT condition, indicating the relative safety of CBT4CBT provided with minimal clinician 
contact.       
C.1.f.  Summary of preliminary studies and preparation for this project

CBT4CBT has established efficacy at reducing rates of drug use in two independent 
randomized trials, including the first known statistical evidence supporting skills acquisition 
as a mediator of CBT’s effect.
TAU only
TAU + 
CBT4CBT
CBT4CBT 
only
0
5
10
15
20
25
30
35
40
Figure 4.  PSNHDD in final month of treatment
% Subjects No Heavy Drinking
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
Data from our recently completed R21 evaluating the alcohol version of CBT4CBT 
(including CBT4CBT delivered with brief clinical monitoring) indicates that this approach is 
feasible, safe and well-accepted by individuals with alcohol use disorders.  Preliminary data 
further indicate CBT4CBT is effective at increasing the percentage of days abstinent and the 
percentage of subjects with no heavy drinking days compared to standard treatment only.  

Our published and preliminary data highlight the relevant experience and developing 
expertise of New Investigator Dr. Kiluk (PI), with respect to evaluation of mechanisms of 
behavior change in computerized CBT96, 122, 131, 153, 159, 163.  
C.2.  RESEARCH PLAN
C.2.a.  Overview
One hundred eighty individuals seeking treatment for alcohol use at the MCCA program in 
Bridgeport or New Haven, CT or SATU in New Haven will be randomized to (1) standard 
treatment as usual (TAU) at MCCA or SATU, (2) clinician-delivered CBT, or (3) CBT4CBT for 
alcohol use disorders (with brief clinical monitoring).  Treatments will be delivered over an 8-
week period with a six-month follow-up after termination of the study treatments, consistent with 
prior trials of CBT4CBT119, 122.  The primary outcome measure will be the percentage of days 
abstinent from alcohol (measured via Timeline FollowBack4), with secondary measures to 
include percentage of heavy drinking days, percentage of positive urine ethyl glucuronide (EtG), 
drinking-related consequences, quality of life, and cost effectiveness.  
The primary mediator of CBT’s effects will be measured by indices reflecting the acquisition and 
implementation of targeted skills, with additional mediators to include self-efficacy, and 
‘relational’ mediators such as therapeutic alliance collected during the treatment period.  
Cognitive moderators will include experiential measures of sustained attention, working 
memory, response inhibition, planning, cognitive flexibility, and decision making.  Participant 
characteristics explored as potential moderators of outcome include motivation, severity of 
alcohol use, and general intellectual function.  The clinician-delivered CBT condition will be 
implemented by carefully selected MCCA or SATU master’s level clinicians, highly trained and 
closely supervised throughout the trial.  Treatment fidelity and therapist skill in all conditions 
will be evaluated by independent process raters, using methods we have worked out in previous 
trials136-139, 164, 165.  Treatment utilization and costs will be measured by the Program and Client 
Costs for Substance Abuse Treatment14, 166 in all conditions from 12 months prior to baseline 
through follow up for cost-effectiveness evaluation.
C.2.b.  Participants
Participants will be 180 individuals seeking treatment at MCCA, an outpatient treatment 
facility, one of the largest providers of addiction treatment services within the 
Bridgeport-New Haven area or at SATU located in New Haven.  
1. Inclusion and exclusion criteria.  
Individuals will be included who:

Are 18 years of age or older.

Are applying for outpatient alcohol treatment and meet current DSM-5 criteria for 
alcohol use disorder, consuming at least 14/7 drinks (men/women) per week with at least 
4 heavy drinking days reported in the past 28 days,  
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
Are sufficiently stable for 8 weeks of outpatient treatment and can commit to a 6-month 
follow-up 

Are willing to provide locator information for follow-up, and 

Are fluent in English and have a 6th grade or higher reading level.   
        
Individuals will be excluded who: 

Have an untreated bipolar or schizophrenic disorder, 

Have a current legal case pending such that incarceration during the 8-week protocol is 
likely, 

Have been prescribed an alcohol pharmacotherapy (e.g., disulfiram, naltrexone) within 
the past two weeks, or 

Are physically dependent on alcohol, opioids or benzodiazepenes such that immediate 
medical detoxification is necessary for safety purposes (individuals demonstrating 
significant withdrawal symptoms would be eligible for re-screening following brief 
medical detoxification, which is arranged by MCCA or SATU staff at triage).
2. Rationale for sample choice.   We are proposing relatively few exclusions that 
parallel our  
completed trials of CBT4CBT119, 123 in recruiting a broad range of individuals whose primary 
substance use problem is alcohol (those with low levels of drug use will be eligible providing 
they do not meet current disorder criteria).  The inclusion criterion regarding level of drinking is 
consistent with NIAAA definitions of risky/heavy drinking167, 168 and comparable to prior 
randomized trials for establishing efficacy of cognitive behavioral treatments 3, 28, 169.  We will 
exclude those initiating an alcohol pharmacotherapy to limit potential confounds, as well as 
exclude individuals experiencing significant alcohol withdrawal symptoms in need of medical 
detoxification for safety reasons.
 
C.2.c.  Procedures
1.  Initial screening by Research Coordinator:  All new MCCA or SATU patients will 
be invited to participate in the protocol at the time of their initial clinic appointment.  See below 
for detailed description.     
2.  Urn randomization:  To increase the likelihood that treatment groups are balanced
 with respect to demographic variables (gender, race, education) as well as likely prognostic 
variables (severity of alcohol dependence, level of familiarity with and access to computers) 
participants will be assigned to treatment conditions through urn randomization173, 174, using a 
Microsoft Access program we have implemented successfully in multiple trials 138, 142, 171, 175, 176. 
3.  Treatment phase:   Study treatments will last 8 weeks.  During the treatment phase, 
all participants will meet weekly virtually either via Zoom and/or phone with research staff for 
completion of self-report and interview assessments.  In all conditions, we will closely monitor 
participant treatment response and safety via BAC, urine screens which are taken by the clinic on 
the clinic’s usual schedule and assessment of psychiatric status. Although in our experience this 
is a very rare event in behavioral trials177, including those of computer-delivered interventions110, 
119, 122,  participants who show significant deterioration (e.g., significant increases in alcohol use 
or psychiatric symptoms that cannot be managed within the protocol) will be regarded as 
symptomatic failures, withdrawn from the treatment arm of the study, and referred for 
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appropriate treatment (typically a more intensive level of care).  See Protection of Human 
Subjects, below.   
4. Termination, post-treatment assessment, and follow-up:  At the end of the 8-week 
treatment period, all participants will be re-interviewed (see Assessments) virtually either via 
Zoom and/or phone .  Access to the CBT4CBT program will be terminated, and participants in 
all three conditions will be offered the opportunity to continue in treatment as usual at MCCA or 
SATU if desired/needed.   Follow-up interviews (using the full post-treatment battery that 
includes treatment utilization) will be conducted 1, 3, and 6 months after termination  virtually 
either via Zoom and/or phone.  We will attempt to follow all participants in our intention-to-treat 
sample, using strategies that have been successful in our multiple previous studies178, where our 
current rate of follow-up approaches 90-95% across studies149, 179, 180.
5.  Rationale for 8-week treatment with 6-month follow-up:  We are proposing an 8-
week treatment period to be consistent with prior and ongoing trials of CBT4CBT119, 122.  The 
CBT4CBT program contains 7 modules; individuals are recommended to complete one module 
per-week (essentially mimicking a traditional once-per-week clinician-delivered CBT treatment 
course).  Although a 12-week (or longer) treatment period may be more typical for clinician-
delivered CBT protocols, a shorter 8-week trial was chosen as the optimal time period for 
establishing the efficacy of CBT4CBT.  Also, the NIAAA CBT manual describes only 8 core 
sessions, which includes a termination session (with 14 elective sessions)125.  Thus, an 8-week 
course of therapist-delivered CBT would not be unreasonable, as it would cover core topics.  A 
6-month follow-up period was chosen to evaluate the durability and or delayed emergence of 
treatment effects; CBT often shows greater effects in the period following treatment completion, 
as individuals continue to gain mastery of skills for avoiding alcohol and drug use (i.e., ‘sleeper 
effect’)140.  Moreover, there is prior evidence that individuals who attain alcohol abstinence or 
are low-risk drinkers (i.e., non-heavy drinkers) at 6-months post-treatment are more likely to be 
abstinent or low-risk drinkers at 12-months181, 182, thereby reducing the need to include a longer 
follow-up period and thus further reducing costs.            
6. DNA analysis 
This optional part of the study will continue to be paused. Saliva samples will be collected into 
Oragene DNA collection kits made by DNA Genotek (Ottawa, ON, Canada). DNA will be 
extracted with kits made by DNA Genotek. Subjects DNA will be genotyped using the 
HumanOmniExpress-24 array (Illumina, San Diego, CA) or a similar high-density SNP array 
that has genomewide SNP content. The DNA extraction and analysis procedures will take place 
at the Genetics Laboratory or a Yale Core facility.  Samples will be stored at the Genetics 
Laboratory
C.2.d.  Treatments
1.  Standard treatment as usual (TAU):  Participants randomized to this condition will 
receive treatment-as-usual at MCCA or SATU.  This typically consists of group counseling 
delivered by masters-level and certified counselors trained and employed by MCCA or SATU 
and supervised by MCCA Clinic Director, Victor Pittman, or the SATU Clinical Director, Donna 
La Paglia.  Patients in this and all conditions are offered standard ancillary services, delivery of 
which is monitored closely throughout the trial (see Assessments).
2.  Individual clinician-delivered CBT:  Participants assigned to this condition will 
receive 8 weekly individual sessions of manual guided CBT120, 125, which provides detailed 
instructions to clinicians regarding the same topic areas covered in CBT4CBT.  Clinicians will 
be trained and supervised using procedures we have developed in multiple previous CBT trials50, 
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136, 138 to protect internal validity and treatment integrity.  Extensive procedures for clinician 
selection, training, and supervision should minimize variability in outcome due to ‘therapist 
effects’183, however as noted earlier, some level of clinician variability is expected.  The CBT 
clinicians will be at least masters-level clinicians drawn from MCCA or SATU staff and selected 
on the basis of audio-taped samples of their work.  Following an initial 2-day didactic training, 
they will each complete at least 3 closely supervised training cases on which they will receive 
detailed feedback on their fidelity and skill based on ratings of their audio-recorded sessions 
using our validated therapy process assessment system, the Yale Adherence and Competence 
Scale (YACS)75.  Once certified to begin the trial, the CBT clinicians will meet weekly with a 
CBT supervisor (Dr. Bold), which will involve updating of case material, review of audio 
recordings of each clinicians’ work, and comparison of self-monitoring of CBT implementation 
with supervisors’ ratings145 (see Assessments).  This technique, used in our previous 
psychotherapy studies143, 145, 184, is included to assure fidelity to manual guidelines and a 
consistent high level of adherence and skill throughout the trial.   Clinicians will review and 
make copies of completed homework assignments and will report, after each session, which CBT 
modules were covered.
3.  CBT4CBT plus brief clinical monitoring:  Participants assigned to this condition 
will be given a username and password to access the CBT4CBT website at the clinic.  Access to 
the CBT4CBT program will be restricted outside the clinic to ensure greater control over the 
delivery of CBT4CBT, eliminate the potential confounds of outside internet access/speed, and to 
reduce risks to privacy/confidentiality.  The Research Coordinator will instruct each participant 
concerning the first session to assure they know how to use the program and answer any 
questions they might have.  Participants will be asked to spend at least one hour per week 
working with the program at the clinic in a private room.  Participants will be asked to complete 
all 7 modules over the course of the 8-week study treatment period.  The program tracks, for 
each participant, time logged onto the program, modules accessed, progress through the program 
from session to session, completion of homework assignments, and learning of CBT principles 
through multiple choice tests.  Because participants will be composed of treatment-seeking 
individuals, participants will also meet weekly with an MCCA or SATU clinician according to 
clinic policy, trained and supervised to provide brief clinical monitoring (10 minutes maximum) 
using our modified ‘Clinical Management’ manual185, following guidelines for low-intensity 
interventions used in previous placebo-controlled trials186-188 and trials of internet-delivered 
treatment 189 (See Protection of Human Subjects).  These brief monitoring sessions are for the 
purposes of ensuring client safety and will focus on assessment of clinical symptoms and level of 
risk to harm self and/or others.     
Treatment Integrity:  20 audio-recorded sessions from each condition will be randomly 
selected and rated by trained coders blind to treatment condition, in order to evaluate therapist 
fidelity to manual guidelines as well as skill across conditions and therapists using the YACS75, 
which includes validated scales for standard counseling, CBT, and clinical monitoring.  This is 
included to assess treatment integrity across conditions using procedures we have worked out in 
multiple trials136, 144, 147, 184, 190.
4. Rationale for study design:  The primary aim of this trial is to provide a rigorous 
evaluation of 
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the efficacy of CBT4CBT for alcohol use disorders.  Although a 2-group design (CBT4CBT vs. 
TAU) may be efficient for establishing the efficacy and evaluating the mechanisms of CBT4CBT, 
a 3-group design including a clinician-delivered CBT provides greater scientific yield.  The 
standard treatment control condition allows for evaluation of relative efficacy of CBT4CBT to 
active outpatient alcohol treatment, however, it would not control for expectations of 
improvement from CBT.  The standard treatment control condition also would not permit 
exploration of the effects of computer- versus clinician-delivered CBT on acquisition of coping 
skills, duration of effects, cost effectiveness, etc. and hence we believe the inclusion of the 
clinician-delivered CBT condition is both novel and appropriate at this stage of evaluation of 
CBT4CBT.  We recognize that this study is not powered for a direct comparison of 
CBT4CBT to clinician-delivered CBT (e.g., a non-inferiority analysis).  We believe such a 
study would be premature, as there have been no direct comparisons of computer- versus 
clinician-delivered CBT for alcohol use upon which to base power calculations, and such a study 
would require a comparatively large sample size and would be extremely costly.  Moreover, 
power calculations for non-inferiority analyses require estimations of confidence intervals 
around predetermined ranges of equivalence126, 128, 191.  If CBT4CBT shows adequate promise in 
the proposed study, it could generate those estimates and sample size estimation of a possible 
future non-inferiority analysis.  We do, however, expect a significant difference in cost 
effectiveness favoring CBT4CBT over clinician-delivered CBT, and can explore differences in 
indirect effects across conditions. 
C.2.e.  Assessments   
To facilitate cross-study analyses as well as comply with NIH recommendations for PhenX 
(Consensus Measures for Phenotypes and eXposures; https://www.phenxtoolkit.org/)192, 193, we 
propose a battery of assessments similar to those used in multiple previous trials through Yale’s 
Psychotherapy Development Center, which include instruments with strong psychometric 
properties.  Instruments used for assessing primary drinking outcomes and mediators/moderators 
of treatment effects are briefly described below (See Schedule of Assessments for full battery):

Drinking outcome:  The Timeline Follow-Back (TLFB)4, 5 will be used for measuring the 
primary outcome (PDA) and secondary outcome percentage of heavy drinking days (PHDD), 
as well as measurement of frequency of tobacco product use194 (which will include 
verification through measurement of exhaled CO levels195).  A heavy drinking day is defined 
as any day of consumption of 5 or more standard drinks for men, and four or more standard 
drinks for women.  These outcomes were chosen based on CBT’s focus on promoting alcohol 
abstinence, as well as reduction of overall alcohol consumption as a treatment goal125, and 
based on the evidence of PHDD as a meaningful non-abstinence based clinical indicator of 
treatment response6, 7, 196, 197. The TLFB method for collection of drinking data will allow for 
the computation of a variety of drinking measures4, 7, 198.  Urine toxicology screens for drugs 
of abuse will include Ethyl glucuronide (EtG), which will be used as a biological indicator of 
recent heavy drinking (cutoff 500 ng/ml)10, 199-202, with the percentage of positive EtG urine 
results included as a secondary outcome.  

Acquisition of targeted skills:  The acquisition and implementation of targeted skills will be 
assessed by: (1) the Alcohol  Risk Response Test (ARRT) - a version of the Drug Risk 
Response Test (DRRT)15 adapted from the Situational Competency Test203, with excellent 
psychometric qualities, including high inter-rater reliability, concurrent and predictive 
validity15, and treatment-specific acquisition of skills96; (2) Coping Strategies Inventory 
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(CSI)16 - self-reported frequency of strategies for avoiding alcohol use, which has 
demonstrated treatment-specific coping strategies in CBT4CBT17; (3) the number and quality 
of homework assignments completed during treatment; and (4) a CBT knowledge 
assessment50 - a multiple choice test that evaluates the extent to which participants 
understand CBT concepts, with each item drawn from the NIAAA CBT manual125 and the 
content of CBT4CBT.  

Therapeutic Alliance:  The Working Alliance Inventory (WAI)158 will be used for 
measuring level of therapeutic alliance at multiple time points during the treatment period.  It 
is a widely-used instrument designed to measure alliance between client and clinician across 
three dimensions (Task, Bond, Goal), and has strong psychometric properties, including 
association with alcohol treatment outcome204, 205.  Both the client (WAI-C) and therapist 
(WAI-T) versions will be administered to all participants/clinicians across all treatment 
conditions.  Participants assigned to the CBT4CBT condition will also complete an adapted 
version designed to assess their level of alliance with the computer program (WAI-Tech), 
which has been described in a recent report by Dr. Kiluk159.   

Cognitive Function: Shipley Institute of Living Scale
 Shipley Institute of Living Scale Shipley Institute of Living Scale Schedule of Assessments
Instrument name
Domain assessed
Scree
n/ Pre 
Tx
Week
ly
Mont
hly
Post 
Tx
(8 
wks)
FU 
1, 3, 
6 
mo
Informed Consent Quiz216, 217
Informed consent
X
Screening & Demographics
Description
X
DSM-5 diagnosis SCID 218
Description, 
diagnosis
X
X
X
Brief Symptom Inventory (BSI) 219
Moderator, 
monitoring
X
X
X
X
Obsessive Compulsive Drinking Scale (OCDS)220
Severity, 
monitoring
X
X
X
X
Timeline follow-back 4, 5 w/ BAC
Primary Outcome
X
X
X
X
Urine toxicology screen including ETG199-201, 221 
taken on clinic schedule
Outcome
X
X
X
X
Optional Genetics
Exploratory
X
World Health Organization Quality of Life– Brief222
Quality of life, 
Outcome
X
X
X
Short Inventory of Problems (SIP)12
Consequences, 
Outcome
X
X
X
Alcohol Use Dis. Ident. Test (AUDIT) 223-227
Description, 
moderator
X
Shipley Institute of Living Scale 228, 229
Cog moderator
X
Stages of Change Questionnaire (SOC)230
Motivation, 
Moderator
X
X
X
Alcohol Risk Response Test (ARRT)15
Coping skills, 
Mediator
X
X
X
X
Change Strategies Inventory (CSI)16, 98, 231
Coping skills, 
Mediator
X
X
X
X
CBT Knowledge Quiz50
Knowledge, 
Mediator
X
X
X
X
Situational Confidence Questionnaire (SCQ)232
Self-efficacy, 
Mediator
X
X
X
X
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Program and Client Costs (PACC-SAT)14, 166, 233
Tx utilization & 
cost 
X
X
X
X
Yale Adherence & Competence Scale 75
Process, Tx 
integrity
3 sessions/participant
Working Alliance Inventory (WAI)234-237 
Process, Tx 
integrity
Sessions 2, 6
Endpoint rating form, satisfaction 238
Evaluation
X
 
C.2.f.  Data Management and Analyses
The system of data management will include a combination of scannable forms (Teleforms), 
direct entry interface (Access), and a relational database (SQL Server) within a closed, secure 
network, allowing data to flow in a continuous cycle of collection, processing, error checking, 
and correction on a real-time basis while the study is ongoing. Outlined below is the general 
strategy for data analyses which will address each of our specific aims.  Preparatory analyses will 
include evaluation of baseline equivalence of groups on demographic and prognostic variables, 
comparability of rates of data availability and treatment exposure across conditions239, 240, as well 
as consideration for the potential contribution of assessment reactivity241, 242.  Data analyses will 
be conducted on the intention to treat sample, and we will attempt to follow all participants 
regardless of their retention in the treatment arm of the trial179, 180. 
Aim 1 -  Evaluation of treatment effects:  
The principal strategy for assessing the efficacy of the study treatments on outcome will be 
random effects regression models for continuously measured primary (e.g., percentage of days 
abstinent - PDA) and secondary (e.g., percentage of heavy drinking days, quality of life, etc.) 
outcomes. Our research group has used these methods to evaluate main and interaction effects, 
with appropriate covariates (e.g., retention, compliance with treatment) in multiple previous 
trials121, 138, 142, 171, 172.  We will include treatment utilization data during the follow-up period as a 
covariate in analyses evaluating treatment effects through follow-up.
Analysis of treatment effects at post-treatment and follow-up will include the following 
contrasts:

H1a:  Main effect for CBT on PDA by month during treatment:  Clinician-CBT and 
CBT4CBT>TAU.

H1b:  Main effect for CBT on PDA by month through follow-up:  Clinician-CBT and 
CBT4CBT>TAU.
Adequacy of sample size:  H1a – Using conventional effect size estimates, we determined that 
our proposed sample size of 60 per condition would be sufficient for detecting a small-medium 
effect (d=.35) of treatment on PDA using a random effects regression model (2 groups, PDA by 
month, 3 data points, ICC=.6, alpha=.05, beta=.80).  H1b – The proposed sample is sufficient to 
detect a medium effect (d=.50) through the follow-up period with a random effect regression 
model (2 groups, PDA by month, 7 data points, ICC=.6, alpha=.05, beta=.80). These effect sizes 
are conservative, based on estimates from completed studies of CBT4CBT119, 122.  
Cost-effectiveness analyses:  Dr. Brian Yates of American University, an expert in cost 
analyses, particularly of behavioral therapies with substance using populations243-250, is a 
member of the Scientific Advisory Board as well as a consultant to Dr. Carroll’s NIDA-
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supported Psychotherapy Development Center.  In this capacity, he directs cost-effectiveness 
evaluations of Center projects, including all those related to CBT4CBT as well as the proposed 
study.  He was involved in the design of the Program and Client Costs for Substance Abuse 
Treatment (PACC-SAT)14, 166, the instrument that will be used to assess participants use of a 
wide variety of physical and mental health services, substance use and legal services utilization.  
The PACC-SAT covers the 12 months prior to randomization, the full-8 week treatment period, 
and the entire follow-up period (See Schedule of Assessments). The general approach used to 
evaluate cost-effectiveness of the protocol interventions will be to evaluate the relationship 
between value of resources used in intervention implementation (e.g., costs associated with the 
facility, staff, and transportation) and nonmonetary outcomes produced by the intervention (e.g., 
reduction in drinking behavior and drinking consequences, improvement in quality of life).  This 
will include calculating the total cost for each treatment condition, cost per participant in each 
condition, as well as outcomes of ‘alcohol-free days’, and comparing the average cost per 
‘alcohol-free day’ gained per month across treatment conditions, using strategies outlined in Dr. 
Yates’s previous work243, 246, 247, 249, 250.    
Aim 2 – Evaluation of skills acquisition as mediator of CBT effects:  
Latent growth curve modeling will be the principal strategy for evaluating mediation using 
Mplus version 7251.  The product of coefficients method18, 19 will be 
used to determine the mediating effects of skills acquisition during the 
treatment period on PDA during follow-up.  In this model (Figure 4), 
M1 through M3 are repeated measures (weeks 0, 4, 8) of the mediator 
‘acquisition of skills’ (as measured by ARRT15, CSI16, homework 
completion and quality, and knowledge assessment50).  Both the 
intercept (IM) and slope (SM) act as joint mediators of the effect of X 
(treatment condition) on Y (PDA during 6 month follow-up), allowing 
the examination of the average level (i.e., intercept) and average change 
over time (i.e., slope) of the mediator.  We will be using the 6-month 
period following treatment as our alcohol use outcome in this model to 
support the temporal relation criterion64, as well as to evaluate the delayed emergence of CBT’s 
effect on alcohol use139. This model will test:

H2a:  Effect of CBT on acquisition of skills (a2 path: XM):  Clinician-CBT>TAU; 
CBT4CBT>TAU

H2b:  Effect of change in acquisition of skills on PDA by month during follow-up (b2 path: 
MY)

H2c:  Indirect effect of CBT on PDA via change in acquisition of skills (a2*b2 / sea2*seb2)
Adequacy of sample size:  Parameter estimates from our initial trial of CBT4CBT that 
supported coping skills acquisition as a mediator of treatment effects on substance use96 were 
used to estimate effect sizes of treatment condition on PDA via skills acquisition (a=.26; b=.59).  
Based on these effect sizes and power estimates for testing mediation derived from a simulation 
study94, we will have adequate power (.80) to detect significant mediating effects with the 
proposed sample size of 60 per condition.   
Exploratory Aims:
X
M2
Y
a1
a2
b2
b1
c’
Figure 4.  Latent Growth Curve Mediation Model
IM
SM
M1
M3
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(a) Pre-treatment cognitive function as indicated by measures from CANTAB tasks (sustained 
attention, 
working memory, response inhibition, cognitive flexibility, planning, decision-making) will be 
evaluated as moderators of CBT’s effect on PDA (clinician-delivered CBT and CBT4CBT vs. 
TAU), using linear moderation regression models, such that a significant 
interaction between pre-treatment cognitive function measures and 
treatment condition would indicate a moderated effect (i.e., the effect of 
CBT on PDA is dependent on levels of pre-treatment cognitive function);     
(b) Using a conditional process analysis252, CANTAB measures at 
pre-treatment will be explored as a moderator of the effect of CBT on the 
acquisition of skills (i.e., moderated-mediation; Figure 5).  In this model, 
baseline measures of cognitive function (W) moderate both the direct (c’3) 
and indirect effects (a3*b1) of CBT (X) on PDA (Y);   
(c) (i) Using latent growth curve modeling outlined in Aim 2 we will 
explore differences in mediation across the two forms of CBT (clinician-delivered CBT vs. 
CBT4CBT) to evaluate the role of skills acquisition across formats; (ii) Additional potential 
mediators such as therapeutic alliance and self-efficacy253 will be explored across CBT delivery 
formats using serial multiple mediation models254; (iii) Pre-treatment cognitive function 
(CANTAB) will be evaluated as a moderator of the treatment effect on alcohol use outcomes 
across CBT delivery formats, as well as on the mediated effect of skills acquisition (moderated-
mediation across CBT formats).  Additional potential moderator variables will be explored 
across CBT formats, such as client motivation (Stages of Change Questionnaire), alcohol use 
severity (AUDIT) and general intelligence (Shipley) using linear moderation regression models.
3. Genetic Testing   N/A 
      
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
     No immortalized cells will be utilized or established. Genomewide association 
studies will be conducted.
ii. the plan for the collection of material or the conditions under which material will 
be received
     Saliva samples will be collected from study participants by study staff.
iii. the types of information about the donor/individual contributors that will be 
entered into a database
     Demographic information, diagnostic information and assessment and 
outcome responses will be entered into a database. 
iv. the methods to uphold confidentiality
     There will be no personal identifiable information associated with the 
biological materials (saliva sample and DNA). The biological material from 
subjects will be identified by code rather than by personal identifiable information
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
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     Some de-identified genotype and phenotype data will be made available to qualified 
investigators in the research community, including distribution via an NIH-sponsored 
data repository
C. Is widespread sharing of materials planned?
     Yes, via an NIH-sponsored data repository.
D. When and under what conditions will materials be stripped of all identifiers?
     At the time of collection, biological materials (saliva sample and DNA) from subjects 
will be identified by a code number rather than by name or other personal identifier.
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
    Donor-subjects can withdraw the identifiers that connect them to their 
biological materials at anytime. If a subject chooses to withdraw their identifiers, 
all identifiers and links to identifiers for the participant will be deleted and 
destroyed
 
F. Describe the provisions for protection of participant privacy
     Any records with identifiable patient information will be kept either in locked cabinets 
(hard copies), on encrypted removable computer media (electronic files) or on a 
password-protected, firewalled network server, and no such records will leave any 
clinical site.
G. Describe the methods for the security of storage and sharing of materials 
     Extracted DNA samples will be stored in the Genetics Laboratory. 
4. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
Participants will be 180 individuals (aged 18 and older) seeking treatment for a primary alcohol 
use disorder at MCCA, which is an outpatient treatment facility, one of the largest providers of 
addiction treatment services in the Bridgeport-New Haven area or from SATU located in New 
Haven. In 2014, MCCA served 934 individuals with a substance use disorder (53%; n=491 with 
primary alcohol use disorder).  The clinic population data indicate that 25% are female, and 60% 
represent ethnic minority groups (34% African American, 23% Hispanic, 3% other - primarily 
Asian or Native American).  Thus, it is reasonable to anticipate we will recruit a sample with 
roughly these proportions of women and ethnic minorities, as we have in our previous trials.  
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
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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?
Individuals will be included who:

Are 18 years of age or older.

Are applying for outpatient alcohol treatment and meet current DSM-5 criteria for 
alcohol use disorder, consuming at least 14/7 drinks (men/women) per week with at least 
4 heavy drinking days reported in the past 28 days,  

Are sufficiently stable for 8 weeks of outpatient treatment and can commit to a 6-month 
follow-up 

Are willing to provide locator information for follow-up, and 

Are fluent in English and have a 6th grade or higher reading level.   
        
Individuals will be excluded who: 

Have an untreated bipolar or schizophrenic disorder, 

Have a current legal case pending such that incarceration during the 8-week protocol is 
likely, 

Have been prescribed an alcohol pharmacotherapy (e.g., disulfiram, naltrexone) within 
the past two weeks, or 

Are physically dependent on alcohol, opioids or benzodiazepenes such that immediate 
medical detoxification is necessary for safety purposes (individuals demonstrating 
significant withdrawal symptoms would be eligible for re-screening following brief 
medical detoxification, which is arranged by MCCA or SATU staff at triage).
7. How will eligibility be determined, and by whom? 
All new MCCA or SATU patients will be invited to participate in the protocol at the time of 
their initial intake appointment.  They will be identified by their clinicians, interest sheets, 
and clinics postings.  Those interested will be given a research packet containing the flyer, 
consent form, consent quiz and a self-addressed, stamped envelope for mailing the consent 
form and quiz back to the research team.  Individuals who indicate they are interested in 
hearing more about the study will be offered a virtual meeting with the Research Coordinator 
by calling the study staff from the flyer.   If potential participants prefer, with verbal consent 
to their clinicians, the clinician can give contact information to the research staff.  At the first 
virtual interview, the Research Coordinator will provide a brief overview of the protocol and 
obtain written informed consent via Zoom using established guidelines of Yale University in 
which a photo is taken of the signature page of the consent form that the participant has 
received from the clinic in the research packet. The photo is taken by the research staff on the 
research cell phone.   After determination of eligibility, the pretreatment assessments will be 
completed virtually.  
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8. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
1   Standard outpatient treatment: Treatment As Usual (TAU) and clinician-
delivered CBT 
The behavioral treatments used here, standard group counseling and clinician-delivered, 
NIAAA manual-guided Cognitive Behavioral Coping Skills Therapy (CBT)125 at the MCCA 
and SATU clinics have been used safely in multiple previous studies at our centers and by 
investigators in other centers in the past.  CBT will be delivered by highly trained clinicians 
who receive ongoing supervision and regular feedback/monitoring based on ratings of 
fidelity and skill by licensed study staff.  Psychological risks are minimal and not different 
from those of equivalent non-study psychotherapeutic interventions255.  
For all treatment conditions, frequent monitoring (at least weekly) of the participant’s clinical 
status by clinicians and research staff will insure identification and withdrawal from the 
study of participants who show significant psychological or symptomatic deterioration (and 
thus may require a higher level of care).  
2.  Computer-assisted training program:  CBT4CBT
The ‘CBT4CBT’ program will be delivered in addition to brief (<10 minute) weekly clinical 
monitoring of safety.    The clinical monitoring will be provided by a trained and supervised 
MCCA or SATU clinician using our modified ‘Clinical Management’ manual185, following 
guidelines for low-intensity interventions used in previous placebo-controlled trials186-188 and 
trials of internet-delivered treatment 189.  These brief monitoring sessions are for the 
purposes of ensuring client safety and will focus on assessment of clinical symptoms and 
level of risk for harm (e.g., suicide/homicide risk).  The session will include an assessment of 
alcohol use frequency (for determination of significant increases in alcohol use), current 
severity of any psychiatric symptoms including suicidal/homicidal ideation, and 
determination of any immediate case management needs (with appropriate referral for case 
management services as needed – e.g., housing support, applications for financial 
assistance).
      
The CBT4CBT program is modeled closely on the NIAAA and NIDA CBT treatment 
manuals120, 125 that have been evaluated in several randomized clinical trials and widely 
accepted as an empirically validated treatment for alcohol use disorders.   We have 
completed two randomized clinical trials of the program for drug use disorders and one trial 
of the program for alcohol use disorders and have found it safe and effective for a broad 
range of substance users119, 122, 123, with no adverse events attributable to the program.    
The web-based intervention is highly secure, and does not collect any PHI identifiers nor 
specific information regarding illegal activities, and has passed stringent Yale Information 
Technology Security Design Review.  It is accessible only through a username/password 
system monitored by Yale staff.  Moreover, the design of the CBT4CBT program has closely 
followed recommended ethical and safety guidelines for use of computer assisted behavioral 
therapies developed by Sampson and Pyle256, including (1) assurance of confidentiality, (2) 
determination of appropriateness of the specific form of training, in this case, CBT, which 
has been shown to be effective for a wide number of substance use disorders and populations, 
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(3) adequate introduction to the computer program by staff to reduce possible anxiety about 
use of the system, (4) provision of follow-up consultation with a clinician if needed, and (5) 
supervision of the treatment process by a clinician256, 257.
Computer-based interventions have been used safely in multiple investigations with a range 
of populations117, 258-260 , and we are unaware of any reported risks associated with these 
interventions.  A recent Agency for Healthcare Research and Quality (AHRQ) 
comprehensive review of computer-assisted interventions for a wide range of health and 
mental health issues found no reports of adverse events associated with these programs110.   
Similarly, the CBT4CBT program was not associated with any adverse events in our 
previous trials with a comparatively severe drug using population nor in our completed R21 
pilot study with an alcohol using sample119, 122, 123.  
Thus, while we believe adverse events are likely to be rare, because the proposed trial 
includes an evaluation of the CBT4CBT version delivered as an approximation of a ‘stand-
alone’ intervention, special efforts will be made to monitor patient safety and response 
closely.  In addition to weekly assessments that include breath and urine monitoring taken on 
the schedule of the clinic and self-reports of substance use, the ‘CBT4CBT’ virtual 
standalone condition will be implemented with one 10-minute or less, manual-guided, 
clinician monitoring session per week delivered by a trained and supervised master’s level 
MCCA or SATU clinician supervisor. This will enable us to monitor each participant’s 
clinical status closely and thus address potential Human Subjects concerns associated with 
evaluation of a ‘stand-alone’ computer-based intervention for treatment seekers.   
Participants assigned to this condition who show significant psychological or symptomatic 
deterioration will be withdrawn from this condition and referred immediately to the 
appropriate level of treatment (consistent with criteria for withdrawal from the other 
treatment conditions).   
These procedures are also consistent with recommended guidelines for monitoring adverse 
events in behavioral trials177.  The Research Coordinator will supervise the participants’ use 
and understanding of the program closely, and Dr. Kiluk, will be available to monitor 
patients’ reactions to the program and answer any clinical issues.  In addition, participants 
will be notified at both login and logoff that any feelings or thoughts that concern them 
should be discussed immediately with their clinician, the Research Coordinator, and/or Dr. 
Kiluk.  Dr. Kiluk can be reached via cell phone to discuss any issues or concerns related to 
the computer-based intervention.
3.  Urine, breath and saliva specimen collection
Urine and breath specimens are collected primarily as safeguards to participants. Saliva 
samples, collected for DNA analysis and should add no risks other than those normally 
associated with these procedures.
4.  Rating scales and questionnaires
These are all non-invasive, should add no risk, and have been used without difficulty or any 
adverse events in our previous studies with this population.  The major disadvantage is the 
time taken to complete them.  Our past experience with these measures indicates that they are 
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acceptable to patients.  Careful efforts aimed at maintaining confidentiality have been 
effective in previous research, and only participants’ study code numbers will be recorded on 
the forms themselves to protect confidentiality.
9. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
As noted above, for the standard treatment and clinician-delivered CBT condition, psychological 
risks are minimal and not different from those of equivalent non-study psychotherapeutic 
interventions.  Careful training and supervision of staff, including annual training in Human 
Subjects Protection and Good Clinical Practice will further minimize these risks.
In all conditions, we will closely monitor participant treatment response and safety through 
virtual weekly assessment sessions; these will include assessment of psychiatric status. Although 
in our experience this is a very rare event in behavioral trials, including those of computer-
assisted therapy 156, participants who show significant deterioration (e.g., increased alcohol use 
or psychiatric symptoms that cannot be managed within the protocol, including significant 
suicidal or homicidal ideation) will be regarded as symptomatic failures, withdrawn from the 
treatment arm of the study, and referred for appropriate treatment (typically a more intensive 
level of care).  The independent evaluator (Dr. O’Malley) will make the final determination as to 
whether a participant should be withdrawn from the treatment arm of the study.  At the time of 
withdrawal, endpoint ratings will be made which include the full termination assessment battery.  
Participants withdrawn from the treatment arm of the trial for these reasons or because they wish 
to withdraw from the study will be offered treatment as usual at the MCCA or SATU clinic or be 
referred to a higher level of care when appropriate.  Private referral and/or hospitalization may 
also be offered according to the participants’ needs and wishes.
For the CBT4CBT condition, no adverse consequences have been noted in our previous studies, 
nor in the general literature on computer-based and web-based interventions.  For the CBT4CBT 
condition, the chief difference from the other conditions is in the level of interaction with a 
clinician.  We have built in the following safeguards: 

Understanding of and use of the CBT4CBT program.  The Research Coordinator will 
work with each participant to assure they are comfortable using the program and answer 
any concerns they may have.  The ‘checkout’ page of each module reminds participants 
they can contact Dr. Kiluk at any time.  For this efficacy trial, participants will be asked 
to access the program at the clinic once per week at the time of the weekly assessment.  
The program tracks, for each participant, time logged onto the program, modules 
accessed, progress through the program from session to session, completion of homework 
assignments, and learning of CBT principles through multiple choice tests after each 
module.   

Provision of monitoring and limited clinician support.  Participants assigned to the 
CBT4CBT condition will also meet weekly with a trained MCCA or SATU clinician for 
a ‘monitoring/support’ visit per clinic policy.  These brief (10 minutes maximum) 
monitoring/support manual-guided visits will take place at the time of the weekly 
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assessment sessions and follow guidelines for low-intensity interventions used in 
previous placebo-controlled trials 159,210 and are intended to provide a means of closely 
monitoring each participants’ status, inquire as to whether the participant has any 
questions or concerns, and assess availability and use of supports.  We have modified our 
‘Clinical Management’ manual 163, modeled on that used in Project Combine 160, and 
which has been used as a low-intensity monitoring/support condition in multiple previous 
trials, for this use.  These sessions will be taped and monitored for fidelity.  

Participants in all conditions are also able to call the MCCA or SATU on-call clinician at 
any time should questions or concerns arise; emergency services are available through 
MCCA or SATU. 
We have used similar procedures to monitor participant response and safety in several previous 
studies evaluating a range of types and intensities of behavioral therapies, as well as in our 
recently completed R21 pilot trial evaluating CBT4CBT for alcohol use disorders.  As in the 
proposed study, participants in the R21 pilot trial (and all conditions) were monitored weekly by 
research staff; participants whose frequency or intensity of alcohol or drug use worsened or did 
not improve were evaluated by the Project Director for possible withdrawal from the treatment 
arm of the study with referral to inpatient or intensive day treatment (i.e., higher level of care).  
Of 24 participants assigned to the CBT4CBT condition with brief clinical monitoring in that 
study, only one was withdrawn from the treatment arm of the study and referred to intensive day 
treatment.   No other adverse or serious adverse events were seen in that condition.
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?   Minimal Risk
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? 
c.
Copy, paste, and then tailor an appropriate Data and Safety Monitoring Plan 
from  http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal/moderate risk
iii. High risk
A Data and Safety Monitoring Board (DSMB) will monitor this project.  This board, is already in 
place for the Yale Psychotherapy Development Center, monitors all of Dr. Kiluk’s clinical trials.  
The DSMB is composed of Yale investigators (Drs. Feillin, McKee, Barry) who are independent 
of the proposed trial and experienced in various aspects of the conduct of clinical trials for the 
treatment of addictive disorders.   We have developed a standard DSMB report form that is used 
in all Center and Center-related trials that summarizes, on a quarterly basis:
1. Recruitment, retention, and follow-up rates for the study and compares them to target 
rates.
2. Rates of data completeness and availability of primary outcome data
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3. Occurrence of AEs and SAEs
4. Report of study progress since the last report.  
5. Rates of recruitment of women, minorities, and children with respect to targets.
These reports are generated by the Data Manager each quarter, reviewed and signed by Dr. Kiluk 
prior to their submission to the DSMB.  DSMB comments are documented and forwarded to the 
Yale IRB at the time of the annual review and re-approval.
Because the projected effect sizes may not be large enough for detection during interim analyses, 
we are not proposing a preliminary analysis of accumulating efficacy and feasibility data by 
treatment assignment. Instead, we propose to submit a quarterly report of aggregate data to the 
DSMB members that contains screening data, baseline demographics, retention data, serious 
adverse events data, as well as accrual status including projections, times to milestones, and any 
other data that will help in the assessment of the clinical trial. Based on this report, each DSMB 
member will complete a form making one of two recommendations: 1) continue recruitment as 
planned; or 2) schedule formal DSMB meeting immediately. If any DSMB member recommends 
a meeting, this will be scheduled within one week, minutes will be kept, the report will be 
reviewed with Dr. Kiluk, and the committee will vote on whether the study should: 1) continue 
recruitment unchanged; 2) continue with a protocol amendment; 3) stop recruiting pending 
further investigation. If, after this meeting, any DSMB member votes to stop recruitment or 
requests a protocol modification, the Yale IRB will be informed.
Participants who experience a significant psychiatric or medical problem requiring an overnight 
hospitalization at an acute care facility will be considered to have experienced an SAE.  In 
general, most SAEs will result in inpatient care and thus in transfer from MCCA or SATU. All 
SAEs will result in the completion of an SAE Form and a verbal report within one hour to the 
Principal Investigator (Dr. Kiluk) and the MCCA Clinic Director, Victor Pittman, or the SATU 
Clinical Director, Donna LaPaglia.  Within 24 hours, the following additional individuals will be 
informed: 1) all co-investigators; 2) the DSMB.  All of these individuals will receive a copy of 
the SAE Form within one week at which point a decision will be made whether to convene a 
meeting of the DSMB.  Adverse events that are serious and unanticipated and probably, possibly, 
or definitely related or adverse events occurring with greater frequency than anticipated will be 
reported to Yale Human Investigation Committee within 48 hours of discovery.
The procedures for SAE reporting include written documentation using the clinical notes related 
to the adverse event and specific forms detailing the event with a sign-off by all appropriate 
supervisory personnel. Communication of recommendations and decisions from all parties 
(DSMB, Yale Human Investigations Committee, and MCCA or SATU Administration) are made 
back to the investigator in a timely manner. We will report all protocol amendments or changes 
in the informed consent form to NIAAA as well as any temporary or permanent suspension of 
patient accrual.  
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?
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iii. What will the multi-site process be for protocol modifications?
11. Statistical Considerations: Describe the statistical analyses that support the study design. 
Aim 1 -  Evaluation of treatment effects:  
The principal strategy for assessing the efficacy of the study treatments on outcome will be 
random effects regression models for continuously measured primary (e.g., percentage of days 
abstinent - PDA) and secondary (e.g., percentage of heavy drinking days, quality of life, etc.) 
outcomes. Our research group has used these methods to evaluate main and interaction effects, 
with appropriate covariates (e.g., retention, compliance with treatment) in multiple previous 
trials121, 138, 142, 171, 172.  We will include treatment utilization data during the follow-up period as a 
covariate in analyses evaluating treatment effects through follow-up.
Analysis of treatment effects at post-treatment and follow-up will include the following 
contrasts:

H1a:  Main effect for CBT on PDA by month during treatment:  Clinician-CBT and 
CBT4CBT>TAU.

H1b:  Main effect for CBT on PDA by month through follow-up:  Clinician-CBT and 
CBT4CBT>TAU.
Adequacy of sample size:  H1a – Using conventional effect size estimates, we determined that 
our proposed sample size of 60 per condition would be sufficient for detecting a small-medium 
effect (d=.35) of treatment on PDA using a random effects regression model (2 groups, PDA by 
month, 3 data points, ICC=.6, alpha=.05, beta=.80).  H1b – The proposed sample is sufficient to 
detect a medium effect (d=.50) through the follow-up period with a random effect regression 
model (2 groups, PDA by month, 7 data points, ICC=.6, alpha=.05, beta=.80). These effect sizes 
are conservative, based on estimates from completed studies of CBT4CBT119, 122.  
Power calculations
Power
Estimated 
effect size
# of 
datapoints
Sample size 
per cell
H1a:   (Clinician CBT + CBT4CBT stand-alone) v 
TAU, main effect for active treatment
.80
.35
3
60
H1b :  (Clinician CBT + CBT4CBT stand-alone) v 
TAU, main effect for follow up
.80
.50
7
60
Aim 2 – Evaluation of skills acquisition as mediator of CBT effects:  
Latent growth curve modeling will be the principal strategy for evaluating mediation using 
Mplus version 7251.  The product of coefficients method18, 19 will be used to determine the 
mediating effects of skills acquisition during the treatment period on PDA during follow-up.  We 
will be using the 6-month period following treatment as our alcohol use outcome in this model to 
support the temporal relation criterion64, as well as to evaluate the delayed emergence of CBT’s 
effect on alcohol use139. This model will test:

H2a:  Effect of CBT on acquisition of skills (a2 path: XM):  Clinician-CBT>TAU; 
CBT4CBT>TAU

H2b:  Effect of change in acquisition of skills on PDA by month during follow-up (b2 path: 
MY)
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
H2c:  Indirect effect of CBT on PDA via change in acquisition of skills (a2*b2 / sea2*seb2)
Adequacy of sample size:  Parameter estimates from our initial trial of CBT4CBT that 
supported coping skills acquisition as a mediator of treatment effects on substance use96 were 
used to estimate effect sizes of treatment condition on PDA via skills acquisition (a=.26; b=.59).  
Based on these effect sizes and power estimates for testing mediation derived from a simulation 
study94, we will have adequate power (.80) to detect significant mediating effects with the 
proposed sample size of 60 per condition.   
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   N/A
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
  targeted for enrollment at Yale for this protocol    180
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): Direct referral from MCCA or SATU triage clinicians, billboards, bus ads
3. Recruitment Procedures: 
a.
Describe how potential subjects will be identified.
b.
Describe how potential subjects are contacted. 
c.
Who is recruiting potential subjects? 
All new MCCA or SATU patients will be invited to participate in the protocol at the time 
of their initial triage appointment.  They will be identified by their clinicians, interest sheets, 
and clinics postings.  Individuals who indicate they are interested in hearing more about the 
study will be offered a virtual meeting with the Research Coordinator.   Clinicaltrials.Gov 
will not be used as a recruitment tool because everyone the study is presented to must be 
applying for treatment at MCCA or SATU .  Therefore, if a potential participant were to call 
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the study directly from ClinicalTrials.Gov they would be instructed to apply for treatment at 
MCCA or SATU in the usual manner and then be offered the study as indicated above.  At 
the first virtual interview, the Research Coordinator will provide a brief overview of the 
protocol and obtain written informed consent via Zoom using established guidelines of Yale 
University in which a photo is taken of the signature page of the consent form.   After 
determination of eligibility, the pretreatment assessments will be completed virtually.  
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 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
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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.)
N/A
Choose one: For entire study: ______ For recruitment purposes only: ______
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
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. 
Brian Kiluk, PhD
Lawanda Frederick, BA
Elizabeth Doohan, BA
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. 
Individuals identified by MCCA or SATU clinicians will be offered the opportunity to meet 
with the Research Coordinator virtually at the time of triage or be given the research study 
telephone number to contact. At the virtual research and consent interview, the Research 
Coordinator will describe the requirements of the study and explain informed consent 
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procedures.  Following provision of informed consent, Dr. Kiluk or the Research Coordinator 
will review inclusion and exclusion criteria and determine eligibility.  
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. 
We routinely use an informed consent quiz to assure all prospective participants understand 
all aspects of the protocol and its requirements.   This will be done virtually along with the 
other assessments. We also routinely collect urine and breath samples from all participants; if 
potential participants are determined to be under the influence of drugs or alcohol at the 
consent session, the informed consent session is rescheduled and the results from urine and 
breath screen are not formally recorded.
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. 
      
HIC approved Compound Consent and Authorization Form and consent quiz
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use. 
        As per inclusion criteria, reading and comprehension in English at a 6th grade level is 
required.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
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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
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c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?  
b.    How will the research data be collected, recorded and stored? 
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?
Do all portable devices contain encryption software? 
 Yes   
 No
         If no, see http://hipaa.yale.edu/guidance/policy.html 
e.
What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and Safety 
Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-identified 
data) 
g.   If appropriate, has a Certificate of Confidentiality been obtained?  
       Yes; CC-AA-16-044 expires 12/31/2022.
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 

Our study forms have been designed to avoid collecting identifiable information.  We 
previously collected only birthdates and session dates.  As of September 2007 this 
practice has been changed to collecting age.  Session dates are changed to ‘number of 
sessions completed’ if data sets are released to other Yale investigators.

Research data are collected on CRFs, and sent to data managers in our research offices on 
a closed secure network.  All computers used by research staff are password protected.  
No identifying information is on CRFs.

The screening of patients using the inclusion and exclusion criteria, and the 
comprehensive evaluations will minimize the risk of including subjects with insignificant 
substance use (or who are otherwise inappropriate for the study).  

Confidentiality in regards to collected materials will be maintained via a numbered 
reference system maintained by the Research Coordinator.  Participants’ names will 
appear only on the consent form, HIPPA authorization form, and “key” form kept by the 
Research Coordinator.  
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
Limits to confidentiality include only disclosure of acute suicidality, homicidality, or 
abuse of a minor, as is standard in clinical practice.

Data are stored at our secure data management center; data sets do not include identifying 
information.  At the conclusion of the study, all locator data are destroyed.

The funding agency, NIAAA, may access the data for routine audits.

We have received a Certificate of Confidentiality.

All research staff and clinicians receive annual Good Clinical Practice training through 
the Core.  
Our data collection and management procedures are fully compliant with HIPAA
Information about participants and their health, which might identify them, may be given to 
the following for audit and oversight reasons

Regional Network of Programs

MCCA

The Substance Abuse Treatment Center (SATU)

Yale University School of Medicine

National Institute of Health (NIH). The research sponsor

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Members of the Human Investigations Committee or ethics Committee(s)

Key Investigators

Key Study Personnel

Data and Safety Monitoring Board and others authorized to monitor the conduct of the 
study
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.) 
Benefits to participants include significant psychotherapeutic exploration through the 
provision of study therapies. Psychiatric examinations are also potential benefits.  The major 
potential benefit in this study is in reduction of alcohol use via the study treatments, which may, 
in turn, foster improvement in participants’ legal, medical, interpersonal, psychological and 
occupational functioning.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
Regular clinical care at MCCA or SATU
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. 
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 All subjects will be offered a material inducement for participation in study evaluations 
in the form of either gift card or cash including $25 for screening, $50 for pretreatment, $10 for 
each weekly assessment completed in the treatment phase of the study ($10 per week), $50 for 
week 4 assessments, $50 at the end of the study (week 8) with a bonus of $25 for completing on 
time, and $75, $100, and $125 for each completed follow-up interview (1-, 3-, and 6-months, 
respectively)with a $25 bonus at each timepoint for completing assessments on time.  
Completion of follow-up interviews will be paid in gift card form if the participant is still 
enrolled in treatment at MCCA or SATU at the time of the interview.  The maximum 
compensation available for the study is $655 if all assessments are completed.  If participants do 
not complete all assessments they will be paid on a prorated basis for those they complete.
Participants who choose to participate in the optional genetics sub study will receive $15.
Subject Compensation Schedule
Activity
Compensation Available
Form of Payment
Screening
$25
Gift Card
Pretreatment
$50
Gift Card
Active Sessions (1x/wk for 
8 weeks)
$80 Total (@ $10 a session)
Gift Card
Week 4 Assesments
$50
Gift Card
Post (end of study, week 8)
$75 ($50+ $25 bonus if 
completed on time)
Gift Card
Follow up 1 Month
$100  ($75+ $25 bonus if 
completed on time)
Gift card 
Follow up 3 Months
$125  ($100+ $25 bonus if 
completed on time)
Gift card 
Follow up 6 Months
$150  ($125+ $25 bonus if 
completed on time)
Gift card 
Total Available
$655
The major potential benefit in this study is in reduction of alcohol use via the study 
treatments, which may, in turn, foster improvement in subjects legal, medical, interpersonal, 
psychological and occupational functioning.
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.     
Subjects will not be charged for study treatments (CBT4CBT program) or research 
evaluations they receive at the clinic.  Subjects may be charged for treatment as usual at the 
clinic; but most patients receive treatment with no-out of pocket expenses or on a sliding scale.  
There will be no monetary cost to participants associated with this research protocol.
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? 
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b.     Where and from whom may treatment be obtained? 
c.     Are there any limits to the treatment being provided? 
d.     Who will pay for this treatment? 
e.     How will the medical treatment be accessed by subjects? 
Because we are evaluating standard behavioral approaches with strong empirical support and no 
known adverse consequences, study related injuries are expected to be extremely rare.  There 
will be no compensation and/or medical treatment available if injury occurs. Participants or their 
insurance carrier will be expected to cover costs of any medical treatment
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