Clinical trial NCT02896400
Conditions: Tobacco Use Disorder
Sponsor: Yale University
Start date: 2017-02-13; Completion date: 2019-08-14
Enrollment: 1056 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The investigators propose an innovative full-factorial design in a cohort of 1056 adult smokers in an urban emergency department (ED), to test the efficacy of four key intervention components: motivational interviewing, medication, quitline referral, and texting. At the trial's completion, a mixed-methods approach will be used to identify the components that were efficacious within the proposed cost constraint, along with feasibility and acceptability to providers and subjects. The investigators will then assemble an intervention that maximizes efficacy, given a cost-effectiveness constraint and findings from a qualitative analysis.

Detailed description:
The investigators propose to optimize the identification and treatment of adult smokers seen in a hospital ED. To do this the Multiple Optimization Strategy (MOST) will be employed to develop a multicomponent intervention that will consist of some combination of the following: (1) a Brief Negotiation Interview (BNI, a variant of a motivational interview), delivered by a trained research assistant; (2) provision of 6 weeks of nicotine patches and gum to the research participant, with application of the first patch in the ED (NRT); (3) active referral to the Connecticut Smokers' Quitline (QL); and (4) enrollment in the SmokefreeText a short-messaging service (SMS) texting program for mobile phones (Text). Using MOST principles, the first phase of the study will use a 2x2x2x2 full-factorial design to identify the components most likely to be efficacious in combination. Although the factorial design requires the allocation of participants to 16 different combinations of the 4 components (Table 1), evaluation of each individual component is performed comparing all of those receiving a component to all of those not receiving a component, making this an efficient design. For instance, evaluation of the BNI component will compare those randomized to arms 1 through 8 to those in arms 9 to 16.The second phase will consist of designing and proposing a 2-arm randomized clinical trial comparing the efficacy of the multicomponent intervention package to usual care; this will be conducted in a future application.

The specific aims of this proposed study are:

Aim 1. To conduct a fully powered factorial randomized trial of 1056 adult smokers to test the efficacy of 4 key components of ED-initiated tobacco treatment: Brief Negotiated Interview (BNI), nicotine replacement therapy (NRT), Quitline referral (QL), and SmokeFreeText (Text).

Aim 2. To identify the most efficacious components of our intervention, within fixed constraints of cost effectiveness and feasibility/acceptability to providers and subjects.

Aim 3. To lay the groundwork for a future randomized trial testing the previously identified components, delivered as a package, against a control arm in a new cohort of adult ED smokers.

Our associated hypotheses are:

1. At 3 months, at least 1 intervention component will yield a biochemically verified tobacco abstinence rate at least 5% greater than in the control condition. Carbon monoxide breath test will be used for biochemical verification.
2. At 3 months, at least 1 intervention will be cost-effective, using a societal perspective.
3. At 3 months, at least 1 intervention will be acceptable and feasible to providers and subjects.

Arms: arm 1: Brief Negotiated Interview (BNI) Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Referral to CT Smokers Quitline (QL) Registration in SmokefreeText (Text) arm 2: Brief Negotiated Interview (BNI) Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Referral to CT Smokers Quitline (QL) arm 3: Brief Negotiated Interview (BNI) Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Registration in SmokefreeText (Text) arm 4: Brief Negotiated Interview (BNI) Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply arm 5: Brief Negotiated Interview (BNI) Referral to CT Smokers Quitline (QL) Registration in SmokefreeText (Text) arm 6: Brief Negotiated Interview (BNI) Referral to CT Smokers Quitline (QL) arm 7: Brief Negotiated Interview (BNI) Registration in SmokefreeText (Text) arm 8: Brief Negotiated Interview (BNI) arm 9: Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Referral to CT Smokers Quitline (QL) Registration in SmokefreeText (Text) arm 10: Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Referral to CT Smokers Quitline (QL) arm 11: Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply Registration in SmokefreeText (Text) arm 12: Nicotine replacement therapy (NRT) patches and gum, 6 weeks supply arm 13: Referral to CT Smokers Quitline (QL) Registration in SmokefreeText (Text) arm 14: Referral to CT Smokers Quitline (QL) arm 15: Registration in SmokefreeText (Text) arm 16: Control arm, no intervention
Interventions: intervention 1: Brief Negotiated Interview (BNI) intervention 2: Nicotine replacement therapy (NRT) intervention 3: CT Smokers Quitline (QL) intervention 4: SmokefreeText (Text)
Intervention descriptions: intervention 1: Brief motivational interview on smoking behavior intervention 2: 6 weeks of nicotine replacement, patches and gum. First dose of each started in ED. Patches are 14mg or 21 mg. Gum is 2mg per piece. intervention 3: Faxed referral to the CT Smokers Quitline for the subject. QL will then call subject to offer phone based counseling. intervention 4: Enrollment in a version of NCI's SmokefreeTxt, tailored for the study.

Protocol documents:
Prot_SAP_000.pdf: 
 
Optimizing Tobacco Dependence Treatment in the Emergency Department 
IRB Protocol and Statistical Analysis Plan 
 
PI: Bernstein, Steven L. 
NCT #: NCT02896400 
Document Date: 02/28/2020 


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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: Optimizing Tobacco Dependence Treatment in the Emergency Department
Principal Investigator: Steven L. Bernstein, MD
Yale Academic Appointment: Professor of Emergency 
Medicine and Public Health
Department: Emergency Medicine
Campus Address: 464 Congress Avenue, Suite 260
Campus Phone: 7-3574
Fax: 5-4580
Pager: 
E-mail: 
steven.bernstein@yale.edu
Protocol Correspondent Name & Address (if different than PI): June-Marie Weiss, same address
 
Campus Phone: 7-3582
Fax: 5-4580
E-mail: Junemarie.weiss@yale.edu
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable): N/A
Campus Phone: 
Fax: 
E-mail: 
Business Manager:
Campus Phone :
Fax :
E-mail
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
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: 
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See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes
  X  No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes
 X  No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form:  http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)    
 YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael Campus
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location:
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories
 Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
 International Research Site 
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(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Yale University RSC (YU-RSC)
Approval Date:
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date:
 *Nursing Research Committee
Approval Date:
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 
7/1/16-6/30/20
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
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5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
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 
  NCT02896400
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
 contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects. 
Yes 
 No
 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
8.. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No __X_  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or  mid-level 
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practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Bernstein, SL.
Optimizing Tobacco 
Dependence 
Treatment in the 
Emergency 
Department
NIH – National Cancer 
Institute 
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M# 1R01 
CA201873-01A1           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name:
Company:
Address:
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
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Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below.
SEE IRES-IRB
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
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.)
X 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)
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.
_____
3/3/16
 
PI Name (PRINT) and Signature
Date
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X 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.
   Lori Post 
3/8/16
   Chair Name (PRINT) and Signature  
    
 Date
   Emergency Medicine__________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
The specific aims of this proposed study are:
Aim 1. To conduct a fully powered factorial randomized trial of 1056 adult smokers to test the 
efficacy of 4 key components of ED-initiated tobacco treatment: MI, NRT, QL referral, and SMS 
texting.
Aim 2. To identify the most efficacious components of our intervention, within fixed constraints 
of cost effectiveness and feasibility/acceptability to providers and subjects.
Aim 3. To lay the groundwork for a future randomized trial testing the previously identified 
components, delivered as a package, against a control arm in a new cohort of adult ED 
smokers.
Our associated hypotheses are:
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1.
At 3 months, at least 1 intervention component will yield a biochemically verified tobacco 
abstinence rate at least 5% greater than in the control condition.
2.
At 3 months, at least 1 intervention will be cost-effective, using a societal perspective.
3.
At 3 months, at least 1 intervention will be acceptable and feasible to providers and 
subjects.
In Year 4, we will propose a randomized clinical trial to test, as a package, the components 
identified as both clinically effective and cost-effective.
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.
Fifty years after the landmark 1964 Surgeon General’s report, smoking remains the 
leading cause of preventable death in the United States, with about 480,000 deaths per 
year.1 In 2012, $289 billion in direct and indirect costs were associated with tobacco use. In 
2012, 18.1% of Americans smoked,2 still far short of the Healthy People 2020 goal of 12% 
prevalence.3 Certainly, much progress has been made. However, after half a century of 
research, regulation, policy advances, drug development, public service campaigns, and 
litigation, it is apparent that smoking has increasingly become an addiction that 
disproportionately affects the medically disadvantaged: those with low income or low 
education, the mentally ill, and individuals with other substance use disorders. These are 
among the groups identified in a 2006 NIH State-of-the-Science conference as those most 
in need of advances in treatment and treatment engagement.4
These groups of smokers are commonly treated in hospital emergency departments 
(EDs). EDs are a frequent site of care for all Americans, with approximately 136 million visits 
across 4000 EDs in 2011.5 ED patients are disproportionately of low socioeconomic status, 
more likely to smoke compared with the general population, 6,7 and more likely to have 
limited or irregular access to primary care. ED smokers often present with illnesses caused 
or exacerbated by tobacco use, or have injuries (like lacerations and fractures) for which 
tobacco abstinence may aid wound healing.8-10 Hence the ED visit represents an opportune 
time to discuss patients’ tobacco use, its relevance to their current visit, and a moment to 
initiate treatment and aftercare.11 
Our group has recently shown the efficacy of a multicomponent intervention that 
includes behavioral and pharmacologic therapies in promoting tobacco abstinence among 
ED smokers.10 Our model adapts the treatment paradigm known as Screening, Brief 
Intervention, and Referral to Treatment (SBIRT).12 The components of our intervention were: 
an adaptation of motivational interviewing (MI), initiation of nicotine replacement therapy 
(NRT) in the ED, with provision of a 6-week supply, referral to the state smokers’ telephone 
quitline (QL), provision of a smoking cessation brochure, and a booster phone call 3 days 
after enrollment. Another recent pilot study of ours showed the feasibility and potential 
efficacy of ED-initiated short-message-service (SMS) texting for tobacco dependence 
treatment.
One limitation of our work is that we cannot disentangle the contribution to abstinence of 
the individual components of the intervention. We assume that each is important, but we 
cannot model their contributions, or whether important interactions exist. It is therefore 
important to identify the most clinically effective, and cost effective components, to create an 
intervention that can be delivered in real-world ED settings.
To that end, we propose to study the effect of our intervention components using a new, 
innovative methodology: the Multiple Optimization Strategy (MOST).13-17 The MOST 
approach, developed by Collins (a consultant on this proposal), is an iterative process that 
involves testing intervention components in a full- or reduced-factorial design, examining the 
effects of each, and assembling those components found to be effective within a fixed cost 
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constraint into a package, which is then tested in a traditional randomized clinical trial. 
MOST has been particularly useful in designing interventions to treat tobacco 
dependence.17,18
Hence, the goal of this proposal is to conduct a factorial trial, in the ED, of the 4 key 
components of our intervention package—motivational interviewing, nicotine replacement 
therapy (NRT), QL referral and texting. We will then identify the clinically effective 
components, subject to cost effectiveness and qualitative analyses, and assemble a 
multicomponent, generalizable package to be tested in a future clinical trial.
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
RESEARCH STRATEGY:
A. SIGNIFICANCE
1. Millions of Americans smoke. Smoking remains the leading cause of preventable death 
and illness in the United States, causing 480,000 deaths per year.1 In 2012, $289 billion in direct 
and indirect costs were associated with tobacco use. In 2009, US adults had approximately 14 
million major medical conditions attributable to smoking.19 In 2012, 18.1% of Americans 
smoked,2 still far short of the 12% prevalence projected by the Healthy People 2020 goals.3 
Certainly, much progress has been made. However, after half a century of research, regulation, 
policy advances, drug development, public service campaigns, and litigation, it is apparent that 
smoking has increasingly become an addiction that disproportionately affects the medically 
disadvantaged: those with low income or low education, the mentally ill, and individuals with 
other substance use disorders. These are among the groups identified in a 2006 NIH State-of-
the-Science conference as those most in need of advances in treatment and treatment 
engagement.4
2. Urgent need for interventions with better reach to low SES populations. Tobacco 
dependence is traditionally treated by primary care practitioners. However, office-based tobacco 
dependence treatment with medication or counseling is relatively infrequent.20 Fortunately, 
hospital EDs are ideal clinical venues in which to identify and treat the lower socioeconomic 
status (SES) groups mentioned previously. In 2011, nearly half of all US ED visits were made by 
patients with Medicaid, Children’s Health Insurance Plan (31.8%) or no insurance (16.0%).5 
There is an urgent need to improve the reach of tobacco dependence treatment offered to these 
smokers. The interventions need to be scalable and practical. Dissemination and 
implementation research in emergency care settings is a focus of our work.21
3. Smokers use emergency departments (EDs) frequently. Patients who use EDs exhibit 
more risky health behaviors than others.22 Smoking is no different. Numerous surveys from the 
1990s found that ED patients, or parents of children in the pediatric ED, had prevalence rates of 
smoking in excess of 40%.7,23,24 Even now, with reduced prevalence rates, ED patients continue 
to smoke more than the general population, often present with a tobacco-related problem, and 
are well-positioned for the “teachable moment.”11
4. Texting shows promise as a smoking cessation aid. A growing body of literature, 
including a Cochrane meta-analysis, attests to the efficacy of texting as primary or adjunctive 
treatment method for smoking cessation tobacco dependence.25-28 In 2011, the Guide to 
Community Preventive Services in the US added mobile programs for smoking cessation to its 
list of “recommended” treatments for smoking cessation.29 A pilot study conducted by our group, 
the first to use texting for smoking in an ED, found the texting intervention in tandem with 
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nicotine replacement and quitline referral was feasible, well-accepted by patients, and 
efficacious . In combination with nicotine replacement and quitline referral, texting showed 
evidence of efficacy, as measured by self-reported abstinence at 1 and 3 months. Results are 
given in Section C.2.
5. ED patients, including smokers, own cellphones. Because smokers are 
disproportionately of lower socioeconomic status (SES), it is important to note that they do, in 
fact, have widespread access to cellphones. A recent survey by our group of 5539 adult patients 
in 3 high volume, urban EDs found that 4758 (85.9%) owned cellphones.30 Of the cell owners, 
3469 (72.9%) had texting capability. A separate study by our group of low-income ED smokers 
found that, of 563 smokers insured by Medicaid or uninsured, 515 (91.5%) had cellphones 
(presented at 2014 meeting of the Society for Research on Nicotine and Tobacco). Two-thirds 
of the cell owners had monthly calling plans offering unlimited minutes. Hence, even though 
smokers who visit EDs are disproportionately low-income, most have cellphones offering 
texting, with unlimited minutes.
6. Advent of STIR: Screening, Treatment Initiation, and Referral. A large but 
heterogenous body of evidence supports the efficacy of Screening, Brief Intervention, and 
Referral to Treatment (SBIRT) to reduce unsafe levels of drinking.31 SBIRT adapts principles of 
motivational interviewing32 to evaluate and treat individuals with risky health behaviors, and refer 
them for aftercare.12 It has been endorsed by the Substance Abuse and Mental Health Services 
Administration and the American College of Surgeons to assess for alcohol use in injured 
patients.33,34 We have adapted SBIRT for use in the ED with smokers. An important modification 
is that we begin nicotine replacement medication during the index ED visit—in contrast to 
standard approaches, in which smokers set a “quit date” 2 or 3 weeks after treatment initiation.35 
We call this approach Screening, Treatment Initiation, and Referral (STIR). Our group at Yale 
has used STIR to reduce opioid use by the ED-based initiation of buprenorphine, as reported in 
JAMA.36 STIR jump-starts the process of behavioral change by incorporating FDA-approved 
pharmacologic treatment into standard behavioral approaches.
7. Integration of quitlines and texting services. Increasingly, state-run quitlines are 
offering texting services, in addition to traditional telephone-based counseling, print materials, 
starter doses of NRT, and web-based services.37 In 
2012, 13 state quitlines offered texting;38 now, 
Connecticut does too. Callers to quitlines who 
receive both services report higher levels of 
satisfaction with the service.37 With the growing 
integration of referrals to quitlines into electronic 
medical records,39  it will become increasingly easy 
for providers to refer patients to these evidence-
based, widely available forms of behavioral 
counseling for tobacco dependence.
8. Promising modality to reach low SES 
populations. Because of widespread ownership 
and use of cellphones among low socioeconomic 
status (SES) groups, quitlines and texting programs 
hold great promise as treatment modalities with 
wide reach. Cultural adaptation of quitline and 
texting content may provide a cost-effective, 
clinically effective way to reach smokers,26,40 who 
increasingly belong to low SES populations.
9. Use of innovative study design: Multiple 
Optimization Strategies (MOST). It is common to 
treat behavioral disorders and addictions with multi-
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component approaches. Given the complex behavioral, genetic, physiologic, and environmental 
factors that mediate disorders such as addiction, it is perhaps unsurprising that combinations of 
treatments often work better than monotherapy. Traditional approaches to assess efficacy 
typically involve a two- or more arm randomized trial that tests a package of interventions 
against control, or usual care. An important shortcoming of this approach is that it does not 
enable the investigator to disaggregate the effects of individual interventions, or examine 
whether important interactions exist between interventions.
A new approach to understand the effects of individual interventions, and then test them in a 
package, is the Multiple Optimization Strategy (MOST) (Fig. 1). The MOST design, developed 
by Collins (a consultant on this proposal), is an iterative process that often employs a factorial 
design (Optimization) followed by a traditional randomized trial (Evaluation), that allows 
investigators to efficiently identify efficacious components of an intervention, subject to a cost 
constraint, and combine them in a package to be tested in a follow-on trial. Our group’s work in 
ED-initiated tobacco dependence treatment done to date would constitute the Preparation 
phase. MOST has been used in a number of smoking cessation trials,18,41-43 but not in the ED. 
MOST borrows two principles from engineering: (1) the resource management principle, which 
says that research resources should be managed strategically to maximize information gain in a 
timely fashion, and (2) continuous optimization, which says that a new cycle of research should 
begin soon after conclusion of the previous cycle, employing the information gained from that 
cycle.43
Our study will use a full 24 (i.e. 16-arm) factorial design to evaluate the effects of 4 
intervention components at a fraction of the cost, using one-fourth of the subjects it would take 
to conduct 4 individual experiments to evaluate each component separately. 
B. INNOVATION
This proposal offers innovation in a number of fronts: (1) This is the first study to assess the 
efficacy of the individual components of ED-initiated tobacco dependence treatment; (2) This is 
the first ED-based study to use the MOST clinical trial methodology; (3) This is the first study in 
the ED of mobile health technology for tobacco dependence treatment; (4) Our treatment 
paradigm initiates nicotine replacement therapy at the time of enrollment, without the 
traditional 2-3 week period prior to a formal “quit date;” (5) To identify intervention components 
to be assessed in a future clinical trial, we will use a mixed-methods approach that 
incorporates measures of clinical efficacy, cost-effectiveness, and feasibility/acceptability of the 
interventions to providers and subjects.
APPROACH
C. PRELIMINARY STUDIES
1. SBIRT + NRT. The objective of this study was to examine the efficacy of an intervention 
incorporating motivational interviewing, nicotine replacement, and quitline referral for low-
income adult smokers in an ED. Methods: A two-arm randomized clinical trial conducted from 
October 2010-December 2012, at a 90,000 visit/year urban ED. Eligible subjects were age 18 
years or older who smoked and were self-pay or had Medicaid. Intervention subjects received a 
motivational interview by a trained research assistant, 6 weeks of nicotine patches and gum 
initiated in the ED, a faxed referral to the state smokers’ quitline, a booster call, and a brochure. 
Control subjects received the brochure, which provided quitline information. The primary 
outcome was biochemically confirmed tobacco abstinence at 3 months. Of 778 enrolled 
subjects, 774 (99.5%) were alive at 3 months. The prevalence of biochemically confirmed 
abstinence was 12.2% (47/386) in the intervention arm vs. 4.9% (19/388) in the control arm, for 
a difference in quit rates of 7.3% (95% CI 3.2%, 11.5%). The proportion of subjects using 
quitline services in the intervention and control arms was, respectively, 32.0% (124/386) and 
18.7% (73/388) (P<0.0001). Thus, an intensive intervention improved tobacco abstinence rates 
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in low-income ED smokers. Because approximately 20 million smokers, many of whom are low-
income, visit US EDs annually, these results suggest ED-initiated treatment may be an effective 
technique to treat this group of smokers.
Table 1 shows the uptake of the various components of our intervention in the two arms. 
For all components other than the brochure, intervention subjects used or received more 
components. We are not, however, able to disentangle the individual effects of these 
components, or their potential interactions. That is the goal and the rationale of this proposed 
study.
Relevance: Our group has demonstrated 
the efficacy of a multicomponent ED-
initiated intervention for tobacco control, 
one that targeted low-income smokers. We 
have the ability to conduct a large-scale 
randomized clinical trial in the ED and 
recruit adequate numbers of subjects in a 
timely fashion. This study is currently being 
examined by the Cochrane group for 
inclusion in a review of combined 
pharmacologic and behavioral approaches 
for smoking cessation.
2. Texting pilot. The objective of this 
study was to assess the feasibility of an ED-
initiated program of tobacco dependence 
treatment that employs a publicly available text messaging program. Smokers age 18 or older 
were randomized to intervention or control arms. Control subjects received a brochure 
describing the state smokers’ quitline. Intervention subjects received the brochure, 4 weeks of 
patches and gum, with the initial dose administered in the ED, a faxed referral to the quitline, 
and enrollment in SmokefreeTXT, a free SMS-messaging service developed by the National 
Cancer Institute. SmokefreeTXT delivered 28 days of messages, 2-5 messages/day. Message 
content adapts principles of cognitive behavioral therapy. Messages are interactive; some ask 
subjects to provide data on current smoking, mood or craving, using Ecological Momentary 
Assessment (EMA).44 Follow-up was by self-reported phone call. We enrolled 60 subjects in 
May 2014. Of all subjects, 30 (50%) were female, 27 (45%) were white, 33 (55%) nonwhite, 
mean age 40 years (SD 11), and insurance coverage of Medicaid, self-pay, or other, 
respectively, of 78%, 8%, 14%. All intervention subjects used the texting program, with 24/30 
(80%) using the program for all 28 days; 6 subjects opted out at some point. This pilot study 
showed evidence of efficacy: at one month, 14/30 subjects (47%) in the intervention arm 
reported tobacco abstinence, vs. 3/30 (10%) in the control arm (P=0.003). At 3 months, the self-
reported abstinence rates in the intervention and control arms was, respectively, 9/30 (30%) and 
4/30 (13%) (P=0.21). Thus, we found that a texting program, combined with pharmacotherapy 
and a quitline referral, shows promise to promote tobacco abstinence in ED smokers.
Relevance: This study is the first to demonstrate the feasibility of an ED-initiated tobacco 
dependence treatment intervention that includes texting. Although we cannot disaggregate the 
impact of texting from the other components, we have some evidence of effect, and have shown 
the feasibility of ED-initiated texting.
3. Qualitative research. In order to gain a deeper understanding of subjects’ attitudes 
about the acceptability and utility of SmokeFreeTXT, we analyzed qualitative data from 25 
subjects who had been randomized to the intervention arm. We developed a guide for the 
telephone interviews (see Appendix) and a preliminary coding schema covering the domains of 
Table 1. Component utilization.
Intervention 
Control 
Abstinent Meds 100% (80%)*
BNI 100%
QL 100% (25%)**
Booster 79%
Brochure 100%
Meds 31%
BNI 0%
QL 23%
Booster 0%
Brochure 100%
Not 
abstinent
Meds 100% (75%)*
BNI 100%
QL 100% (42%)**
Booster 72%
Brochure 100%
Meds 70%
BNI 0%
QL 24%
Booster 0%
Brochure 100%
*Numbers in parentheses refer to subject 
self-reported use of intervention 
**Numbers in parentheses are data from CT QL
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usability and acceptability of the program. The guide included several close-ended items with 
Likert response formats to assess subjects’ attitudes about the number and spacing of 
messages per day, clarity of wording, and helpfulness of the program.  Finally, subjects rated 11 
specific messages from the program, some of which the research team considered to be 
potentially problematic for our population (e.g., “dated,” unrealistic for subjects with limited 
financial resources).
All interviews were audio-recorded and transcribed. Data were analyzed thematically and 
iteratively. To expand and adapt the original conceptual framework, “negative” instances (i.e., 
comparative analysis that may not fit initial constructs) were also sought.
Most subjects viewed the program as helpful.  Common themes included having a sense of 
being emotionally supported in their efforts to quit, feeling “personally understood” by the 
program, and that the messages were non-judgmental. The number and spacing of messages 
per day was positively received; subjects considered the language to be very easily understood.  
Most subjects appeared to want to receive 2-4 messages per day, although some subjects 
preferred substantially more (i.e., 8-10 per day).  Two important themes to emerge concerning 
the timing of when to receive messages were convenience and at “trigger” times. Tailoring the 
timing to fit subjects’ daily routines appears to be important to consider in further refinement of 
the program.  
Relevance: Our group has the ability and experience to conduct mixed methods analyses, in 
order to identify facilitators and barriers to intervention implementation. This allows us to design 
interventions that are likely to be disseminated, implemented, and sustained across the diverse 
group of US EDs.
4. Other investigators. Benjamin Toll, PhD, is Associate Professor of Public Health 
Sciences, and Chief of Tobacco Cessation and Health Behaviors at the Hollings Cancer Center 
and the Medical University of South Carolina. His work examines the effects of message 
framing on the efficacy of quitline interventions. Drs. Toll and Bernstein continue their 
collaboration of 6+ years, even with Dr. Toll’s recent move from Yale to MUSC. Dr. Toll phones 
in to weekly meetings of Dr. Bernstein’s research group, and continues to co-author papers. 
James Dziura, PhD, is Associate Professor of Emergency Medicine, Associate Director of the 
Yale Center for Analytic Sciences and Biostatistics Core of the Yale Center for Clinical 
Investigation, the institution’s CTSA and Deputy Director of the Yale Data Coordinating Center. 
Dr. Dziura has collaborated with Dr. Bernstein for 4 years, and offers expertise in the design, 
coordination and quantitative analysis of clinical trials. Michael Pantalon, PhD, is a clinical 
psychologist and Research Scientist in Emergency Medicine at Yale. Dr. Pantalon will train the 
study’s research assistants to perform the brief negotiation interview, and review their taped 
interviews biweekly. He performed a similar function in Dr. Bernstein’s prior ED trial. Linda 
Collins, PhD, is Distinguished Professor of Human Development and Family Studies, and 
Professor of Statistics at Pennsylvania State University, and Director of the school’s 
Methodology Center. She pioneered the development and use of the Multiple Optimization 
Strategy (MOST) design for clinical trials. Lorien Abroms, ScD, MA, is Associate Professor of 
Prevention and Community Health at George Washington University’s School of Public Health 
and Health Services, and Director of George Washington University’s mHealth Collaborative. 
She pioneered the development and use of telephone-based texting to treat tobacco 
dependence. Ted Miller, PhD, is a Senior Scientist and health economist at the Pacific Institute 
for Research and Evaluation and frequent collaborator with Yale emergency physicians, 
including Dr. Bernstein, on cost-effectiveness studies. Lauretta Grau, PhD, is a Senior 
Research Scientist in the School of Public Health with rich experience in conducting qualitative 
research in individuals with substance use disorders, HIV, and hepatitis. She has collaborated 
with Dr. Bernstein for the past year on a qualitative analysis of the texting program to be used in 
this trial.Katrina Vickerman, PhD, is a Research Scientist with Consumer Wellness Solutions, 
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Inc. (formerly Alere, Inc.) who is an expert on the use of tobacco quitlines. She has collaborated 
with Dr. Bernstein on several projects.
D. OVERALL APPROACH
1. Overview. We propose to optimize the identification and treatment of adult smokers seen 
in a hospital ED. To do this we will employ the Multiple 
Optimization Strategy to develop a multicomponent 
intervention that will consist of some combination of the 
following: (1) a Brief Negotiation Interview (BNI, a 
variant of a motivational interview32), delivered by a 
trained research assistant; (2) provision of 6 weeks of 
nicotine patches and gum to the research participant, 
with application of the first patch in the ED; (3) active 
referral to the Connecticut Smokers’ Quitline; and (4) 
enrollment in the SmokefreeTXT short-messaging 
service (SMS) texting program for mobile phones. 
Using MOST principles, the first phase of the study will 
use a 2x2x2x2 full-factorial design to identify the 
components most likely to be efficacious in 
combination. Although the factorial design requires the 
allocation of participants to 16 different combinations of 
the 4 components (Table 1), evaluation of each 
individual component is performed comparing all of 
those receiving a component to all of those not 
receiving a component, making this an efficient design. 
For instance, evaluation of the BNI component will 
compare those randomized to arms 1 through 8 to 
those in arms 9 to 16.The second phase will consist of 
designing and proposing a  2-arm randomized clinical 
trial comparing the efficacy of the multicomponent 
intervention package to usual care; this will be 
conducted in a future application.
The primary outcome measure is the proportion of smokers in each group abstinent at 3 
months (verified by exhaled carbon monoxide). Secondary outcomes include the cost 
effectiveness of the intervention, as well as acceptability/feasibility. The BNI will be specified in 
a manual and provided to research assistants (RAs), who will be trained by experienced study 
personnel.  Patients will be screened for eligibility and enrolled by these RAs, with the proviso 
that the RA who enrolls a participant will not be the RA who performs the BNI. 
2. Setting. New Haven, Connecticut, is a poor city; 24.4% of its 350,000 residents live in 
poverty. YNHH is a tertiary care center. In 2013, women represented approximately 55% of the 
ED population; the mean age of
ED adults was 41 years. The racial mix of our patients reflects that of New Haven: 65% White, 
not Hispanic; 23% African-American, not Hispanic, 10% Hispanic; 2% other. Payor status for ED 
smokers is approximately 55% Medicaid, 5% Medicare, 30% private insurance, and 10% self-
pay.
Number of smokers. Based on work from prior studies at the YNHH ED, and assuming a 
conservative prevalence rate of smoking (at least 5 cigarettes/day) of 20% among uninsured or 
Medicaid patients, we estimate the YNHH ED treats 15,200 potentially eligible patients annually. 
(This estimate is conservative because low-income individuals smoke more than others. Data 
from the 2006 National Health Interview Survey found a smoking prevalence rate of 30.6% 
Table 2. Arms of the trial.
Green = condition is offered.
Red = condition is not.
Arm 
BNI
NRT
QL
Text
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
BNI = Brief Negotiated Interview.
NRT=Nicotine Replacement Therapy
QL=Quitline referral
Text=Smoke-Free Text
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among individuals with household incomes below the federal poverty level, compared to 20.4% 
for those with household incomes above the poverty level.45)
3. Participants. Inclusion criteria. Patients who present to the adult ED at Yale-New Haven 
Hospital (YNHH) will be eligible for the study if they are: (1) 18 years or older (2) have smoked 
>= 100 cigarettes lifetime (3) describe themselves as every or some day smokers (4) smoke at 
least 5 cigarettes/day (5) own a cellphone with texting capability, and (6) are able to give written 
informed consent (a draft is in the Appendix).
Exclusion criteria. Patients will be excluded for: (1) Inability to read or understand English; (2) 
currently receiving formal tobacco dependence treatment; (3) life-threatening or unstable 
medical, surgical, or psychobehavioral condition; (4) unable to provide at least one collateral 
contact; (5) live out-of-state; (6) leaving the ED against medical advice (7) being pregnant (self-
report or urine testing), nursing, or trying to conceive.
4. Entry into study and Randomization. Subjects will be recruited during all days of the week, 
from 7a-11p. Potential subjects will meet with a research assistant (RA) to be evaluated for 
eligibility. Patients will be asked for verbal consent to complete the 2-item tobacco screener 
used by the Behavioral Risk Factor Surveillance System (Do you currently smoke every day, 
some days, or not at all? Have you had more than 100 cigarettes in your lifetime?). Patients 
who report smoking < 5 cigarettes/day will not be enrolled, but will be given a handout 
recommending that they abstain from smoking, contact their primary care provider, and consider 
calling the quitline. Individuals who meet inclusion and exclusion criteria and consent to 
participate will have their baseline assessments performed, and then will be randomized to one 
of 16 combinations of components (Table 1). To assure equal intervention allocation and 
concealment of intervention allocation a random permuted block sequence will be generated 
and intervention assignments distributed through the clinical trial management system.  
5. Components of the Intervention. Our previous work employed a multicomponent 
approach to ED-initiated tobacco treatment, which used both pharmacologic and behavioral 
approaches. All components are evidence-based, and cited in the 2008 PHS clinical practice 
guideline, with the exception of the newest approach, SMS texting. Below we discuss these 
components, the rationale for each, and supportive evidence. Our intent is to use the MOST 
approach to identify the individual contributions of these components, and assemble them into 
an intervention that is effective, efficient, and scalable.
Brief negotiated interview (BNI). Brief Negotiated Intervention (BNI) is a manual-guided 
therapy that is designed to be feasible in the ED setting. The BNI manual for this study is based 
on one that we used in our previous trial. The purpose of the BNI is to assist patients in 
recognizing and changing their tobacco use.  It combines techniques based on motivational 
interviewing and a stage-model of change.32,46  The main goals of the interview are to decrease 
subjects’ ambivalence about engaging in tobacco dependence treatment and accepting ED-
initiated treatment, including NRT, texting, and QL referral.
The BNI will be delivered by a trained research assistant (RA), a bachelor’s-level individual, 
who will audiotape the encounters. Tapes will be reviewed biweekly by the RAs and Dr. 
Pantalon, to assess fidelity to protocol. In our prior work, the BNIs average 10-15 minutes in 
length. RAs will receive 10 hours of training by Dr. Pantalon in our manualized BNI, and by Dr. 
Bernstein in nicotine replacement pharmacotherapy. Next, RAs will role-play patient scenarios 
with Dr. Pantalon, followed by 1 week of shadowing an experienced RA performing BNIs on ED 
patients. We have used these procedures in all prior studies of ED SBIRT.
If, during the BNI or other interactions, the subject discloses to the RA risky behaviors such 
as suicidality, intimate partner violence, or use of other substances, the RA will notify the 
treating ED physician.
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Nicotine gum and patch, with initial dose applied in the ED. Subjects randomized to NRT will 
receive 6 weeks of patches (42 count) and gum (300 pieces of 2mg), free of charge. All NRT will 
be given to the subject in a small shopping bag. NRT dosing is tailored to the patient’s score on 
the Heavy Smoking Index.47 Patches come in 7, 14 and 21 mg doses. The first patch is applied 
by an ED nurse during the index visit. This allows us to demonstrate to the subject how to use 
the patch, its ease of use, and acceptability. It does bypass the traditional model of setting a quit 
date, although subjects may continue to reduce their tobacco use while using NRT. In our 
previous study, this approach was accepted enthusiastically by subjects. We employ 
combination NRT because of its generally greater efficacy than NRT monotherapy in promoting 
tobacco abstinence.48
Texting. We will use the SmokefreeTXT program, developed by NCI. SmokefreeTXT is a 
text messaging service designed for U.S. adults who are trying to quit smoking. The program 
provides 24/7 encouragement, advice, and tips to help smokers quit, and stay quit. It is a 6-8 
week program. Users receive 1-5 messages per day and can receive additional quit support by 
texting one of SmokefreeTXT's keywords. The service is free, other than the usual message 
and data rates per callers’ phone plans. SmokefreeTXT has shown evidence of efficacy. A 
recently completed randomized trial of 4000 smokers found a self-reported quit rate of 20% at 6 
months in the texting arms (E. Augustson, personal communication). Subjects received no other 
interventions.
The SmokefreeTXT library contains about 130 messages. In our pilot, we did some modest 
tailoring. We deleted texts that seemed less relevant to ED patients (e.g. “Jab, jab, punch! Visit 
your local gym or YMCA. Try taking boxing classes. Not only is it a great stress reliever but it's 
also an awesome workout”), and added some that were (e.g. “Remember that you can use the 
nicotine patch and gum at the same time to manage cravings.”) Based on our pilot qualitative 
work, we may offer additional tailoring, addressing the reason for visit (e.g. asthma attack). ICFI 
International, the SmokefreeTXT vendor, has worked with us already on tailoring.
Active quitline referral. Connecticut’s quitline services, provided by Consumer Wellness 
Solutions, Inc. (), combine individualized telephone counseling, written materials, and an 
interactive online program to complement phone-based treatment sessions. Participants receive 
up to 5 proactive counseling calls, designed to help develop problem-solving and coping skills, 
secure social support, and design a plan for cessation. Calls are scheduled at convenient times 
and at relapse-sensitive intervals, up to 50-51 days post-quit. Participants can also call a 1-800 
number for additional support between proactive calls. The effectiveness of the Quitline program 
has been validated by 3 randomized trials49-51, and several real-world evaluations52-54. In our 
prior study, 32% of subjects in the intervention arm engaged in >1 call with the QL.
Of note, future versions of Epic may contain functionality allowing the provider to send an 
electronic referral to the state quitline (mentioned at the Epic fall 2014 Users Group Meeting, 
attended by this proposal’s PI). That said, for now we will still have RAs fax the traditional paper 
referral form to Consumer Wellness Solutions, Inc., the QL vendor for CT.
Post-visit booster call. In our prior studies, intervention subjects received a phone call 2-3 
days after enrollment. The purpose of this call is to remind participants that they are enrolled in 
a trial, ask if they have questions about their treatment, reaffirm contact information, and thank 
them for participating. We reach about 70% of the subjects. Our experience suggests that these 
calls add little to the efficacy of the intervention. They do, however, require manpower and 
support which might be better spent on other activities, like recruiting. We have therefore 
decided not to perform booster calls in this proposal.
Smoking cessation brochure. In our work, all participants are provided with a brochure that 
reviews the health hazards of smoking, and provides the phone number for the state quitline. In 
Connecticut, this brochure is produced by the State Department of Public Health, printed in 
English and Spanish, and is available in bulk at low cost. We believe that distributing this 
brochure to all study participants is a reasonable maneuver for all subjects. That will not allow 
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us, of course, to isolate any discrete effect of the brochure on tobacco abstinence. In the 
parlance of MOST designs, that is known as “aliasing.”43 We believe this is an acceptable 
approach.
6. Measures. Overview. We will assess a range of pretreatment subject characteristics, 
process measures and treatment outcomes (Table 2).  Baseline assessments are designed to 
ensure that patients meet eligibility criteria and that important predictor variables are assessed.  
Process measures include utilization of health care and nicotine dependence treatment 
services, and adherence to the treatment manual and competence in performing the treatments.  
Primary outcome measures include tobacco use; secondary measures include engagement in 
treatment, health care service utilization, and cost indicators. Outcomes will be assessed from 
multiple sources, including patient self-report of treatment engagement, tobacco use, and 
objective measures such as Quitline verification regarding patient contact and exhaled carbon 
monoxide testing. 
Formal follow-up assessments are planned at 1 and 3 months. The 3-month follow-up is 
designed to capture our primary outcome of tobacco abstinence.  It is plausible that the effect of 
the BNI may be short lived and therefore we have scheduled an early initial follow-up (e.g., 30 
days).  To decrease respondent burden the 1 and 3 month assessments will be collected via 
telephone. Subjects self-reporting tobacco abstinence at 3 months will be asked to return to the 
ED to measure exhaled carbon monoxide, a validated measure of tobacco abstinence. In our 
prior ED study, we found that low-income subjects were easier to reach by phone earlier in the 
month rather than later, perhaps because of loss of cellphone service due to financial 
difficulties. Therefore, we will “front-load” our follow-up calls in the first half of each month.55
Baseline Assessments
Baseline instruments have been selected for their ability to test the specific study aims, for 
brevity, and ease of administration. Demographic and locator information in all groups will be 
collected by face-to-face interview.  
a. Demographic information: includes age, sex, racial/ethnic group, educational level and 
insurance status. 
b. Exhaled carbon monoxide (CO). All patients will receive biochemical verification of 
smoking status, via point-of-care measurement of exhaled CO. Testing will be performed by a 
trained research associate with the Bedfont Micro+® breath CO monitor (Bedfont Scientific 
Ltd.)  Calibration will be performed every 6 months, as recommended, by a research assistant. 
CO levels will be used to verify clinical equivalence of treatment groups at baseline. Consistent 
with standard practice, a cutoff of 10 ppm will indicate current smoking.56
Table 3. Baseline Assessments, 
Outcome and Process Measures 
Month
INSTRUMENT
Base-
line
1
3
BASELINE AND OUTCOME MEASURES
Intake History/Patient Demographics
X
Exhaled carbon monoxide level
X
X
PHQ-2 Depression Screen
X
Treatment engagement
X
X
Causal attribution scales
X
Wisconsin Predicting Patients’ Relapse 
X
X
X
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c. The Patient Health 
Questionnaire-2 (PHQ-2) will be 
used to assess depressive 
symptoms.57  This 2-item scale, 
which rates the frequency and 
duration of depressive symptoms 
during the past two weeks, has 
shown excellent reliability and 
validity.  Scores can range from 0-6, with scores of 1-4 indicative of possible depression and 
scores of 5-6 indicating probable depression.
d. Causal attribution assessments.11 Sentinel health events may be associated with changes 
in smoking behavior. These may include a visit to an ED for a tobacco-related illness, hospital 
admission, or surgery. Patients who perceive their acute health events as related to tobacco use 
are more likely to quit, as we found in our pilot trial. We will therefore assess patients’ beliefs re: 
the proximate reasons for their ED visit, using a 2-item measure co-developed by Dr. Bernstein.
e. Wisconsin Predicting Patients’ Relapse Questionnaire (WI-PREPARE).58 This 7-item 
scale will be used to assess patient’s likelihood of a relapse to smoking, after the ED visit. Two 
items of the WI-PREPARE, assessing time to first cigarette and daily consumption, constitute 
the Heavy Smoking Index (HSI), a subscale of the Fagerström Test for Nicotine Dependence 
(FTND).47,59 The HSI, a measure of the severity of nicotine dependence, will be used to guide 
the dosing of NRT.
f. Biochemical assessment. Exhaled carbon monoxide (CO) levels will be measured for each 
enrollee with the Bedfont Smokerlyzer. CO will be measured again at 3 months for subjects self-
reporting tobacco abstinence. Subjects endorsing abstinence by phone will be asked to return to 
the ED, or a mutually convenient location in New Haven, for CO measurement. In our last trial, 
92/97 (94%) such subjects returned.
h. Rapid Alcohol Problems Screen (RAPS).  The RAPS is a 4-item tool designed specifically 
for detecting problematic alcohol use in medical settings, and it has been well-validated for use 
in the ED setting.62,63  A “yes” response on any of the items places the participant in the “likely” 
group.  The RAPS has demonstrated good reliability and validity when validated against ICD-10 
and DSM-IV criteria for alcohol abuse or dependence, with an average sensitivity of 93% and 
specificity of 87%.  It generally outperforms other alcohol screening measures like the CAGE 
and the AUDIT in terms of test characteristics.63
i. Rapid Drug Problems Screen (RDPS).  The RDPS is a 4-item tool patterned after the 
RAPS.64  It is designed specifically for detecting drug use within medical settings.  It is a newer 
instrument and has less well-established test characteristics than the RAPS, but preliminary 
data for use in the ED setting are promising.64  A “yes” response on any of the items places the 
participant in the “likely” group.  For males, the RDPS has demonstrated good test 
characteristics when validated against ICD-10 and DSM-IV criteria for drug abuse or 
dependence, with a sensitivity of 93% and specificity of 96%. The validation study did not have 
enough subjects to adequately assess the RDPS’ test characteristics among females. 
Process measures
a. The Treatment Service Review (TSR),65 a brief, structured interview, will be 
administered to collect information on the type and amount of services received by subjects.  
This includes ED visits, hospitalizations, primary medical care visits, and self-help sources of 
support (e.g. quitline, web services). The TSR will be supplemented with questions on the use 
of smoking cessation medications.
Questionnaire
Heaviness of Smoking Index
X
X
X
Rapid Alcohol Problem Screen
X
X
Rapid Drug Problem Screen
X
X
Self-report of tobacco use
X
X
X
PROCESS/IMPLEMENTATION MEASURES
Treatment Service Review (TSR)
X
X
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b. Adherence to the BNI manual:  All BNIs will be audiotaped and reviewed by Dr. 
Pantalon and the RAs, to assess time with the patient, material reviewed, and proficiency of the 
provider at each session.
Outcome measures
a. Treatment engagement will be assessed by subject self-report, reports from 
Consumer Wellness Solutions, Inc. on QL use, and reports from ICFI International on texting 
engagement. Patients will be considered engaged in treatment if at 30-days after randomization 
the patient reports currently receiving care in a treatment program that addresses the patient’s 
nicotine dependence.
b. Self-report tobacco use at 1 and 3 months. Several measures will be assessed, as 
recommended by an expert panel.66 The primary endpoint is 7-day point prevalence abstinence; 
secondary endpoints are 30-day and continuous abstinence. A time-line follow-back (TLFB) 
technique67,68 will be used for all endpoints.
c. Exhaled carbon monoxide: will be collected in-personat baseline and in-person at 3 
months, for subjects self-reporting abstinence. In our prior study, 94% of self-reported 
abstainers returned for testing.
d. Use of cessation medications and services. Quitline use, NRT use, use of other 
pharmacotherapies such as bupropion and varenicline will be assessed by self-report and fax 
reports from the CT quitline.
e. The TSR will be administered by a research assistant at 1 and 3 months to assess 
changes in use of tobacco treatment services, including the Quitline, medical services and 
medications.  
11. Alternative strategies and methodologic considerations.
Why not perform the multicomponent randomized clinical trial shortly after 
completing the factorial trial, within the traditional 5-year duration of an R01? We explored 
a number of possible effect sizes, power and sample size calculations that might have allowed 
that. We chose not to do so for several reasons. First, it takes up to a year after completing 
enrollment in the factorial trial to identify components for the RCT. The time is spent completing 
follow-up (3 months in this proposal), gathering and analyzing the economic data, performing 
the cost effectiveness analyses, analyzing the qualitative data with subjects, and then planning 
the RCT. Given the effect size chosen for the factorial design, our expected accrual rate, and 
the need for the post-study analyses just described, we felt it most prudent to perform the 
factorial study as a stand-alone application, with a subsequent application for the follow-on 
randomized trial of the newly assembled package. That said, we are able to complete the 
proposed work in a cost-sensitive, accelerated 4-year design.
Why not follow participants up to 1 year after enrollment? In tobacco treatment trials, 
participant follow-up commonly lasts 6-12 months. Our prior study followed subjects for 12 
months, with the primary endpoint assessed at 3 months. We prefer the 3-month endpoint, with 
no extension of follow-up, because: (1) For a point-in-time intervention such as ours, the 
expectation of a treatment effect at 1 year is unrealistic, and probably not clinically sensible; (2) 
Viewing tobacco dependence as a chronic disease, with alternating periods of abstinence and 
relapse, is a more realistic model of addiction.90 In this model, treatment may need to be 
sustained for longer periods, as it is for other chronic diseases such as hypertension or 
diabetes. Therefore, one would not expect a single ED-initiated intervention to lead to sustained 
abstinence; (3) In practical terms, given our sample size, extending follow-up to 1 year would 
not be feasible in an accelerated l 4-year design.
That said, for our follow-on RCT that will test the complete multicomponent package, we will 
follow subjects up to 1 year, as part of an exploratory aim and hypothesis.
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 Why not a fractional factorial design? Our trial is comparable, in number of arms, to 
other studies done using MOST methods, including those assessing tobacco dependence 
treatment.42,43 We considered a fractional design, but were unsure which cells in the 4x4 matrix 
might be jettisoned. We know little about potential interactions among BNI, NRT, QL, and 
texting (other than there are additive effects when combining behavioral and pharmacologic 
modalities48). Therefore, our preference is to retain the full factorial design.
How will research staff maintain fidelity to protocol, with a 16-arm trial? We have an 
experienced group of RAs, and rigorous procedures for training and assessing fidelity to 
protocol. Intervention components are familiar to our study staff, physicians, nurses, and 
research pharmacist. All data, including assessments and treatment assignment, are captured 
using tablet computers which the RAs store in the ED. RAs are trained by a psychologist skilled 
in behavioral interventions, who meets with them biweekly to review taped subject encounters. 
RAs will first enroll a small number of subjects in a run-in period, to test our assessments and 
procedures, as we have done previously. We have an on-site automated, electronic medication 
dispensing system (Pyxis) dedicated to research, to store the NRT, with which our nurses are 
familiar from our prior trial. The project manager, who has worked with the PI for 5 years, will 
oversee all enrollments on a daily basis. 
Is this generalizable? Yes. The raison d’être of MOST is to design interventions that can 
be implemented broadly. All intervention components can be done now, at many EDs. Brief 
negotiated interview techniques are increasingly taught to medical students and EM residents; 
ED physicians can, and do, initiate NRT; quitline referrals are occasionally made; and texting is 
increasingly a focus of study for a variety of ED interventions in the domains of adherence and 
follow-up care.91-94 Of note, the 2015 version of the Epic EMR is likely to offer an electronic 
referral to tobacco quitlines; that will certainly facilitate our proposed intervention.
12. Next steps. In a follow-on study, we will perform a two-arm trial to test the efficacy of our 
newly assembled multicomponent package. The trial will be conducted at our ED at Yale-New 
Haven Hospital. Work beyond that will consist of a dissemination and implementation strategy to 
move the package into other EDs. 
4. Genetic Testing   N/A 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
Adults age 18 or over, who present to the adult ED at Yale New Haven Hospital (YNHH).
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements)
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7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
Inclusion criteria. Patients who present to the adult ED at YNHH will be eligible for the study if 
they are: (1) 18 years or older (2) have smoked >= 100 cigarettes lifetime (3) describe 
themselves as every or some day smokers (4) smoke at least 5 cigarettes/day (5) own a 
cellphone with texting capability, and (6) are able to give written informed consent (a draft is in 
the Appendix).
Exclusion criteria. Patients will be excluded for: (1) Inability to read or understand English; 
(2) currently receiving formal tobacco dependence treatment; (3) life-threatening or unstable 
medical, surgical, or psychobehavioral condition; (4) unable to provide at least one collateral 
contact; (5) live out-of-state; (6) leaving the ED against medical advice (7) being pregnant 
(self-report or urine testing), nursing, or trying to conceive.
8. How will eligibility be determined, and by whom? Trained research assistants will determine 
eligibility by first querying the medical records of patients currently being treated in the ED. 
Potential subjects will meet with a research assistant (RA) to be evaluated for eligibility. 
Patients will be asked for verbal consent to complete the 2-item tobacco screener used by 
the Behavioral Risk Factor Surveillance System (Do you currently smoke every day, some 
days, or not at all? Have you had more than 100 cigarettes in your lifetime?). 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.
 
Overall Risks
Because the procedures herein involve accepted forms of treatment interventions, rating scales 
and assessments, self-reports, and structured interviews, we foresee no special risks. The 
instruments have been used in similar projects in the past with no ill effects. The potential risks 
in this study are related to 1) nicotine replacement, 2) ratings scales and assessments, 3) breath 
collection, and 4) loss of confidentiality. The use of nicotine replacement involves minimal risk, 
and most risks are related to the use of the patch and discomfort at the site and difficulty 
sleeping. Blood samples may be collected as part of the standard of care in the ED; these 
results will not be utilized for this study. Breath samples are collected for research purposes and 
should add no risks other than those normally associated with the collection procedure. The 
rating scales and structured assessments are all non-invasive and have been utilized in clinical 
studies with no known negative outcomes and should also add no risks to subjects, as our past 
experience indicates. The main risk associated with the study is the possibility that confidential 
information obtained during the study will be disclosed. All efforts will be made to protect 
subjects’ confidentiality. The alternative to participation is for a potential subject to decide NOT 
to participate.
Risks Associated with Nicotine Replacement 
Under order of the treating physician, consenting patients will receive their first NRT product 
(patch and/or gum) in the ED, and a “starter kit” to take home which will include a 6-week supply 
of medication. Smokers admitted to inpatient units will have their treating physician contacted by 
the study team, to encourage continuation of pharmacotherapy while in hospital. The study 
team will follow up with admitted patients who, when, discharged, will receive sufficient 
medication to fulfill a 6-week course of treatment.
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There are minor, non-life-threatening risks associated with using the gum. The subject could 
use too much, or chew too quickly, which might lead to symptoms of nicotine toxicity.  This 
could also occur if the subject smokes while using the patch or gum. Symptoms associated with 
nicotine “overdose” include cold sweats, fainting, confusion, and pounding heart. Toxicity 
resolves in several hours. Cases of nicotine toxicity are extremely rare. In terms of the patch, 
nicotine continues to enter the bloodstream for several hours after removing it, as it leaches 
through the skin, so smoking within 12 hours of removing the patch is strongly discouraged One 
of the most common side effects of the patch is a localized skin rash due to a reaction to the 
adhesive on the patch or a reaction to the nicotine. A topical salve (such as 1% hydrocortisone 
cream) can relieve the discomfort. The second most common side effect is sleep disturbance. 
This side effect is common in people who use the 24-hour patch. Nicotine can lead to vivid, 
colorful dreams and difficulty sleeping. For this study, the 24-hour patch will be utilized.  
Switching to a 16-hour patch might alleviate this problem, but it often can result in nicotine 
cravings. Other potential side effects of NRT include dizziness, insomnia and abdominal 
discomfort. 
Nicotine gum has a peppery taste, which some participants may find unpleasant. (Note that we 
mitigate this by using mint-flavored gum.) It may cause a tingling sensation when chewed. 
During the first few days of using the medication, the participant may experience mouth 
soreness, jaw muscle aches, increased saliva production, indigestion, or headache. These 
effects should dissipate over time. There are some risks associated with chewing the gum too 
fast, in that it can cause lightheadedness, dizziness, hiccups, nausea, vomiting or insomnia. All 
participants will be asked to notify us if they develop symptoms of too much nicotine in their 
body. 
There is also a very small risk that the subject could have an allergic reaction to the drug in 
either product.  If this occurs in the ED, the RA will notify the treating physician at once. If this 
occurs after discharge, the subject will be directed to seek immediate medical attention. 
Symptoms of an allergic reaction include rash, itching, swelling, dizziness, and trouble 
breathing. 
Risks Associated with Breath Collection
Breath Collection - Subjects will have breath samples taken to measure CO to verify clinical 
equivalence of treatment groups at baseline. Testing will be performed by a trained research 
associate with the Bedfont Micro+® breath CO monitor (Bedfont Scientific Ltd., Rochester, 
UK). There are no known risks associated with this test. Subjects exhale into a disposable 
plastic sterile straw attached to the monitor; there should be no risk of infection.
Risks Associated with Rating Scales and Assessments
Other risks from the rating scales and assessments, self-reports, and interviews are not beyond 
usual research procedures. Research assessments are all non-invasive, and should add no 
risk. The major disadvantages are the time taken to complete them and possible breach of 
confidentiality. Our past experience with these measures indicates that they are acceptable to 
subjects. Any potential risks (e.g., discussion of upsetting events), however, will be minimized 
through the use of a trained, experienced Research Associates, supervised by Drs. Bernstein 
and Pantalon for screening, intervention, and appropriate referrals. In addition, the Yale-New 
Haven ED has an onsite, adjacent Crisis Intervention Unit (CIU) staffed by attending and 
resident psychiatrists 24 hours each day which can be accessed if necessary.  All adverse 
events will be immediately reported to the PI by research staff.  
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Risks Associated with Texting
The text messaging program will serve as a stand-alone health education program for quitting 
smoking. The program will not interface with the electronic health record, and therefore will be 
free of additional constraints imposed by HIPAA.  Nonetheless, text messaging is not a secure 
mode of communication. As part of the informed consent process, participants will be informed 
about the privacy risks associated with text messaging. Participants will also be informed that 
their interactions with the SmokefreeTXT computer system will be analyzed as a marker for their 
participation in the program.  
Risks Associated with Loss of Confidentiality
Confidentiality of the results are specifically protected by Federal laws, and all records will be 
identified by code number only, with the master file kept under lock by the Project Director. 
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
Protections Against Risks
Inclusion and exclusion criteria and the use of a trained Research Assistant will help to avoid 
the enrollment of subjects into this study who are either ineligible or who would be at greater risk 
for complications because of neurological, psychiatric, or medical illnesses.  
All patient interactions will be conducted in areas that are as private as possible in an ED 
setting. 
Once enrolled, subjects will be given a unique study number, to which only members of our 
research team will have access. Computerized subject data will be password protected. All 
identifiable information will be stored in a locked research cabinet in a locked office. All subjects 
will be assigned a study subject number. Subsequently, subjects will be identified in encrypted, 
secured tablet computers accessible only to study RAs only by that number and an encoded 
version of their initials (i.e., John Doe = JDO). A list of numbers and the corresponding names 
will be maintained by the Project Director. 
Any identifiable information that is obtained in connection with this study will be disclosed only 
with subject permission or as required by U.S. or State law. Individually identifiable health 
information will be protected in accordance with the Health Insurance Portability and 
Accountability Act of 1996. We will clearly explain our mandated obligation to report incidents, 
including suspicion of child or elder abuse or neglect, threats of harm to self and others, and 
threats of damage to property. Data will only be reported in aggregate. During an audit or 
program evaluation, representatives from the Yale Human Investigation Committee and from 
the National Institutes of Health may have access to subject data, but will strictly adhere to the 
rules of confidentiality. Upon completion of the study, all computerized subject datasets will be 
de-identified and stored in a password-protected study computer, to which only the PI and study 
personnel will have access.  Any paper files with subject information will remain in locked files in 
the study office of the Project Director, until they are destroyed, after all analyses are complete 
and after the federal requisite waiting period (7 years) to maintain records. 
Data will be collected using Filemaker for iPad. IPads are encrypted and stored in a locked safe 
in the RA’s locked office in the ED. The iPads are connected to a university-maintained server 
via an encrypted WiFi connection. This is a live connection; therefore, all data are immediately 
stored on the secure server.  The server is backed up hourly. No ePHI is stored on the iPads. 
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This system is compliant with HIPAA and regulations for the collection of ePHI. Computers are 
encrypted with PGP software. 
Any information published as a result of the study will be such that it will not permit identification 
of any subject.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a. 
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? Minimal
b.
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? N/A
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
 available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal
Data and Safety Monitoring Plan 
Monitoring for data integrity and safety will be the responsibility of the investigators and the Yale 
Human Investigation Committee (HIC). The principal investigator (PI) will be responsible for 
monitoring the data, assuring protocol compliance, conducting the safety reviews, and the 
specified frequency of the reviews at a minimum of every 6 months (including when reapproval 
of the protocol is sought). During the review process, the PI will evaluate whether the study 
should continue unchanged, require modification/amendment, continue or close to enrollment. 
Either the PI or the HIC have the authority to stop or suspend the study or require modifications. 
Based on our prior work, the risks associated with the proposed study are minimal. We view the 
risks associated with the combined use of nicotine patch and nicotine gum as minimal. Given 
the now-established safety and validity of nicotine replacement therapies in our prior work and 
others’, we do not view the proposed studies as high risk. In previous studies by our group, 
standard doses of NRT such as those proposed in this study were extremely well tolerated. 
Further, nicotine patch and gum are available over-the-counter, also attesting to their excellent 
safety profiles.
Although we have assessed the proposed study as one of minimal risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first-
hand experience with the proposed study methods. Therefore, we provide a plan for monitoring 
the data and safety of the proposed study.
Attribution of Adverse Events
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator (Steven L. Bernstein, MD) according to 
the following categories:
1.
Definite: Adverse event is clearly related to investigational agent.
2.
Probable: Adverse event is likely related to investigational agent.
3.
Possible: Adverse event may be related to investigational agent.
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4.
Unlikely: Adverse event is likely not to be related to the investigational agent.
5.
Unrelated: Adverse event is clearly not related to investigational agent.
Plan for Grading Adverse Events 
The following scale will be used in grading the severity of adverse events noted during the 
study:
1.
Mild adverse event
2.
Moderate adverse event
3.
Severe unanticipated adverse event resulting inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.
4.
Life-threatening adverse event
5.
Fatal adverse event
Plan for reporting serious AND unanticipated AND related adverse events and anticipated 
adverse events occurring at a greater frequency than expected to the HIC.
The investigator will report the following types of adverse events to the HIC: a) serious AND 
unanticipated AND possibly, probably or definitely related events; and b) anticipated adverse 
events occurring with a greater frequency than expected. These adverse events will be reported 
to the HIC within 48 hours of it becoming known to the investigator, using Yale HIC Form 6A. 
Adverse events will be deemed serious in nature if graded as 3 or higher according to the scale 
in item #4 above. 
Plan for Reporting Adverse Events to Co-Investigators
For this study, the following individuals, funding, and/or regulatory agencies will be notified: all 
co-Investigators listed on the protocol, the HIC, and the National Institutes of Health. The 
principal investigator (Steven L. Bernstein, MD) will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator and Dr. Toll will evaluate the 
frequency and severity of the adverse events and determine if modifications to the protocol or 
consent form are required.
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
Analytic strategy: overview. Intervention components will be analyzed over three domains, as 
outlined in Figure 2. First, components will be assessed for clinical efficacy, using traditional 
measures such as biochemically verified tobacco abstinence. If clinically effective, components 
will then be analyzed for cost-effectiveness and feasibility/acceptability to providers and 
subjects. For the economic analysis, we will use standard approaches that assess quality-
adjusted life years. For the qualitative assessments, we will interview research subjects to 
assess the feasibility and acceptability of the intervention components. Components that are 
clinically efficacious, cost-effective, and feasible and acceptable will be retained in the final 
package, which will be compared to a control condition in a follow-on randomized clinical trial. 
Analytic tactics are described in detail in the next few sections.
8. Biostatistical considerations. Primary Study Endpoints and Analyses. The primary efficacy 
endpoint for this study will be biochemically verified 7-day cessation rate at 3 months.66 Tobacco 
use will be assessed by self-report and confirmatory biochemical testing with exhaled carbon 
monoxide. Patients who assert abstinence by phone interview will be asked to return to hospital 
for assessment of exhaled carbon monoxide.
Baseline comparability. The adequacy of the randomization will be assessed by comparing the 
distribution of baseline demographic and clinical characteristics among the intervention groups. 
Comparability for continuous variables will be examined graphically and by summary statistics, 
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and categorical variables by calculating frequency distributions. Data analyses will be conducted 
using SAS 9.3 (SAS Institute, Cary, NC).  
Sample size and power calculations. The goal of this proposal is to identify individual tobacco 
dependence treatment interventions which show clinical efficacy, subject to constraints of cost 
effectiveness and acceptability. As each component is allocated to half the participants, the 
sample size to detect main effects in a full factorial MOST design is not depending on the 
number of components evaluated, but rather the smallest clinically important difference between 
the presence and absence of a component. In our previous trial, we found a difference of 7.3% 
in biochemically confirmed abstinence between the control and intervention arms at 3 months. It 
is reasonable to expect that, in this factorial trial, the effect of individual components will be less 
than that seen in the multicomponent trial.13,69 Therefore, we have chosen an absolute 
difference of 5% for the main effects of each component. (We considered a narrower absolute 
difference of 4%, but the sample size and resources needed become unfeasible.) With a two-
sided 0.05 significance level, and an average abstinence proportion of 4.9% in the absence of a 
component, a total sample size of 860 participants will provide 80% power to detect a 5% 
increase in the abstinence rate. We will enroll 1056 participants to account for up to a 15% 
dropout rate by 3 months. Although we will investigate whether the effect of a component is 
dependent on the levels of other components (i.e. interactions) our trial has not been powered 
with the intent to detect these interactions.
Data monitoring. Procedures for data collection, data management, monitoring of data quality 
and data analysis have been developed and refined in our previous ED studies. An experienced 
data manager and Dr. Dziura will supervise this process. Procedures include use of a 
computerized database system (OnCore) to monitor research activities, screening and 
enrollment, compliance with protocol and treatment interventions, completion of scheduled 
assessments, and data retrieval. Data quality will be assured by: 1) extensive 
training/supervision of RAs in data collection; 2) preliminary review of all assessment 
instruments prior to data entry and checks for completeness and coding errors; and 3) error-
checking statistical programs. No interim looks for efficacy are planned. Monthly reports will 
monitor accrual, randomization; data timeliness, quality, completeness, and overall event rates 
(e.g. abstinence). Error corrections will be documented.
Plan for missing data. Several strategies will be used to handle missing data.70,71 Prevention is 
the most obvious and effective means to control bias and loss of power. This protocol will follow 
the intent to treat principle.72 Telephone visit reminders will be delivered to participants prior to 
protocol-specified collection times. Alternative contact information will be identified on 
enrollment to minimize loss to follow-up. Timely data entry combined with weekly missing data 
reports will trigger protocols for tracking and obtaining missing data items or outcome 
assessments. We will describe the extent and patterns of missing data and use logistic 
regression to identify factors associated with non-response. For primary analysis, when data on 
tobacco abstinence are missing due to attrition or non-response, we will impute relapse to 
smoking, as is conventional. However, if missing abstinence data are more prevalent in the 
control group this could lead to a bias in favor of the intervention. While we do not expect 
differential rates of dropout between groups or high loss to follow-up, sensitivity analysis using 
pattern-mixture and selection models under missing not at random (MNAR) assumptions will be 
performed to examine the robustness of conclusions of the primary analysis.70,73 
Analysis for Aim 1. The primary outcome, abstinence at 3 months, will be compared between 
the presence and absence of each component using logistic regression. Per convention, in the 
primary analysis missing abstinence data will be imputed as relapse. For this full-factorial 
design, the model will include main effects for each of the 4 components as well as all 2, 3 and 
4-way interactions. The regression will also include baseline covariates: age, sex, race/ethnicity, 
and smoking characteristics. Main effects will be evaluated at the 0.05 significance level. 
Differences in proportions for the presence and absence of each component (i.e. main effects) 
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will be estimated along with 95% confidence intervals using the bootstrap method.74 A p-value 
of 0.10 will be used as a guide to flag potentially important interactions which will be explored 
graphically with a particular emphasis on identifying substantial synergistic effects or qualitative 
(i.e. where the impact of one component changes direction depending on the presence or 
absence of another component) effect modification. Similar analyses will be performed at 1-
month follow-up. Additionally, a logistic regression with parameters estimated by weighted 
Generalized Estimating Equations (GEE) will incorporate both 1 and 3-month outcome data 
without imputing non-responders as relapse.75 This analysis weights for the probability of 
response and is valid under the assumption that missing data are missing at random (MAR). 
Secondary outcomes at 1 and 3 months will also be evaluated by a generalized linear model 
with weighted GEE.
9. Economic analysis. Overview. We will perform a series of incremental cost effectiveness 
analyses (CEA) to determine whether the benefits of each component appear to be worth the 
added costs, partially accounting for the interactive effects of the components. Two outcomes 
will be considered: (1) number of abstinent smokers at 3 months (measured by biochemically 
verified 7-day tobacco abstinence) and (2) the cost 
per quality-adjusted life year (QALY) saved. Following CEA recommendations,76,77 baseline 
analyses will adopt a societal perspective, considering all economic costs regardless of source. 
We also will calculate incremental cost effectiveness ratios (ICERs) from the payer’s 
perspective, excluding patient costs and, in sensitivity analysis, QL costs. We will use CERs for 
other cessation interventions to select an acceptable maximum cost/quality-adjusted life year 
(QALY) saved for the tested program elements since we want to identify an ED cessation 
approach that is at least as cost-effective as approaches based in other settings.78-80 
Treatment Costs: We will include costs of all smoking cessation treatment received by 
participants, broken down by component (Table 3). Resource costs include costs of 
administering the BNI and medication, texting (a purchased item), and making the QL referral 
(i.e., IT costs, cost of clinician time to administer the intervention, medication delivered in 
Table 4. Components of economic analysis.
Component 
Health system cost
Subject cost
State 
costs
Screening
None. Screening information collected 
for all patients.
None.
None.
Motivational 
interview
Provider time performing motivational 
interview (wage X minutes). Average 
YNHH wage, conditional on provider 
training (i.e., MD, nurse practitioner, 
RA) will be used.  
None. No additional 
time in hospital due 
to motivational 
interview.
None.
Medication (6 
weeks)
Total price paid by hospital. In 
sensitivity analysis we will consider 
average wholesale price (AWP), since 
not all providers receive same 
medication discounts.
None. Assume all 
costs of medication 
borne by provider.
None. 
Quitline  
None. Provider bears no costs for quit 
line use.  
Cost of time on QL 
(avg. wage rate X 
minutes).
Marginal 
cost of QL 
user. 
Texting
None. Texting will be automated. Once 
developed marginal cost of texting is 
small. 
Cost of minutes to 
subject.
None.
Brochure
Printing costs of brochure. 
None.
None.
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hospital, incremental cost of longer follow-up booster phone call), costs related to QL use (i.e., 
counselor and patient time, cost of written materials, patient time on website), outpatient 
treatment costs, other medical costs, and patient costs (e.g., time, transportation). In evaluating 
a prior trial, we measured RA time for an ED-based BNI session. Clinician time costs will include 
wages, fringe benefits, and overhead. Cost of patient time will be calculated using the average 
wage rate in the geographic area. Relevant medication use will be obtained from the CPOE 
record; cost of medication will be based on the average of the current formulary price for the top 
5 health insurers in Connecticut. Quitline costs: We will get number of counseling calls 
completed and costs of written materials used directly from QL records, then calculate costs of 
counselor and patient time related to the calls (both scheduled QL calls and calls to toll-free 
number). We will collect patient time on the website at 1 and 3 month assessments. We will 
exclude research costs because these would not be incurred if our intervention were standard 
care. Training and texting program setup costs will be excluded from the main analyses. 
Although these startup costs may be incurred, when distributed across many patients over 
many years, they would be negligible. We will collect information on training and setup costs 
and include in publications/sensitivity analysis, as these may be of interest to decision makers. 
Measuring Effectiveness. We will assess effectiveness (i.e., abstinence) biochemically at 3 
months. With the MOST design, regression will estimate quit rates for the four potential 
intervention components, as well as the gains and losses that occur when combining them. 
Over time, abstinence reduces medical care utilization and improves quality of life. We will not 
track those savings in our patient cohort. Instead, we will update our adaptation of a popular 
model that simulates them.
Calculating C/E ratios: We will calculate ICERs in two passes. A naive first pass will array cost 
and regression-adjusted quit rate for each of the 16 MOST cells, ignoring if differences are 
statistically significant. This naive look will let us drop clearly dominated cells where higher cost 
is associated with a lower quit rate, as well as any cells that proved infeasible in the clinical 
setting or were unacceptable to staff. In a refined pass, we will define incremental component 
cost effectiveness as ΔC/ΔE, where ΔC is the cost a component adds and ΔE is the 
effectiveness associated with the component. This refined look at the remaining candidates will 
use two effectiveness measures, the 3-month quit rate and the simulated quality-adjusted life 
year (QALY) gain. A QALY is a standard measure of health-related quality of life, defined so that 
a year in perfect health is valued at 1.0 and death is valued at 0.0.77 Even if one component 
costs more per quitter than another, it still may be worthwhile if it helps more smokers to quit at 
an acceptable cost per QALY gained. By estimating QALYs gained per quitter, we get a 
measure that lets us judge the cost of cessation gains relative to other smoking interventions, 
with a tentative ceiling of $5000 per QALY gained that we will refine in year 4 by updating our 
literature review on cessation interventions regularly used in medical settings.
The analysis will require estimates of the QALY losses and medical costs averted by smoking 
cessation.  For QALY loss, the most recent estimates81-83 are better than older estimates.84,85 
For medical costs, we expect to use the latest update to CDC’s SAMMEC model1 which build 
from the methods pioneered by V. Miller.86 We will inflate all cost savings to the same year’s 
dollars as the program costs and compute present value of savings in future years at a 3% 
discount rate. To account for relapse, we will insert our chosen smoking costs and our observed 
quit rate pattern into the widely used BENESCO (benefits of smoking cessation on outcomes) 
Markov simulation model of cessation duration or a closely related model.78,79 These models 
stem from a 2002 World Health Organization model. The resulting estimates will let us answer 
the question, which efficacious ED-based interventions maximize quits while staying below the 
acceptable cost per QALY gained.
To better inform our package choice, we will estimate 95% CIs around the ICERs. To 
estimate ratio variance, we will start with roughly estimated standard errors or distributional data 
for each number in the cost-effectiveness equation. We will use bootstrapping simulation 
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methods that form an empirical probability distribution.87 To handle estimates with unknown 
variance, notably the discount rate, we will conduct sensitivity analyses. The sensitivity analyses 
examine if different input assumptions would change package selection.
10. Qualitative analysis. The final analytic strategy is a mixed methods analysis of those 
components found to be clinically efficacious. The goal of this analysis is to ensure that those 
components are considered feasible, practical, and acceptable by the patients who we wish to 
use the package in real-world settings. Intervention components scoring well in Likert 
assessments and found feasible and acceptable in interviews with subjects (that are also 
clinically efficacious and cost-effective) will be retained to study in the future randomized trial.
As we did previously, we will conduct phone interviews with study subjects to assess their 
views of the components, alone and in combination. Unlike our earlier qualitative work, which 
focused on the texting component only, we will assess subjects’ view of all components in the 
factorial design: texting, BNI, QL, and NRT. As before, Likert-type questions will be included. 
We will make sure to sample individuals who were randomized to each of these as a single 
intervention. We will also sample individuals who were in arms where we identify important 2-
way or 3-way interactions of efficacy.  
We will use a grounded theory approach, in which explanatory theories will emerge from 
inspection of themes derived from coded transcripts.88,89 All interviews will be audiotaped and 
professionally transcribed. Interviews will be coded by Dr. Grau and study personnel with 
experience in coding. Subjects will be interviewed until thematic saturation is reached. We 
anticipate this will mean 25-30 subjects. Dr. Grau will use ATLAS.ti (ATLAS.ti GmbH).
Telephone interviews will be conducted with subjects during their routine 3-month follow-up 
phone calls. Consent for the qualitative component will have already been given at study 
enrollment. We have used this method, with success, in our previous trial of ED-initiated texting. 
Calls are audiotaped and transcribed by a professional service, with subsequent coding and 
theming by the study team.
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s). 
Nicotine replacement therapy—patches and gum—all FDA approved—to be used for 
treatment of nicotine dependence.
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:  N/A
a. What is the Investigational New Drug (IND) number assigned by the FDA?
b. Who holds the IND? 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________
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Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies
 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.  
 Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
      product. 
 Yes  
 No
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product. 
 Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). 
 Yes  
 No
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
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 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
Subjects randomized to NRT will receive 6 weeks of patches (42 count) and gum (300 
pieces of 2mg), free of charge. All NRT will be given to the subject in a small shopping bag. 
NRT dosing is tailored to the patient’s score on the Heavy Smoking Index.47 Patches come in 7, 
14 and 21 mg doses. The first patch is applied by an ED nurse during the index visit. This allows 
us to demonstrate to the subject how to use the patch, its ease of use, and acceptability. It does 
bypass the traditional model of setting a quit date, although subjects may continue to reduce 
their tobacco use while using NRT. In our previous study, this approach was accepted 
enthusiastically by subjects. We employ combination NRT because of its generally greater 
efficacy than NRT monotherapy in promoting tobacco abstinence.48
All smokers will be offered combination treatment with nicotine patch (1/day) and gum (<1 
piece/hour), stepped to daily consumption. Smokers with the lightest levels of addiction—<10 
cigarettes/day—will be offered a 14 mg patch and 2 mg gum. Subjects may choose only 1 form 
of NRT, if preferred. Smokers experiencing withdrawal in the ED will be offered gum, 
irrespective of daily cigarette consumption, because it leads to a relatively rapid rise in serum 
nicotine levels. The dosing schedule will be determined by the RA in consultation with the 
patient. Drs. Bernstein and Toll will be available by pager or cell for consultation, as needed.
3. Source: a) Identify the source of the drug or biologic to be used. 
Nicotine replacement patch – 7 mg, 14 mg, and 21 mg
Nicotine replacement gum – 2 mg
b) Is the drug provided free of charge to subjects? 
 Yes  
 No
    If yes, by whom? 
To be purchased by YNHH Pharmacy – Investigational Drug Service using specified 
grant funding.
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
Nicotine patches and gum are ordered by YNHH IDS.  A research PYXIS machine was 
purchased by the department.  All NRT is stored in the PYXIS in the YNHH ED.
Check applicable Investigational Drug Service utilized:
     
   YNHH IDS                                                                      
   Yale Cancer Center 
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   CMHC Pharmacy                                                          
  West Haven VA
     
   PET Center                                                     
    None      
     
    Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
  
5. Use of Placebo: 
 Not applicable to this research project
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access. 
 
 No    If no, explain why this is acceptable.
 B.  DEVICES – N/A
1.      Are there any investigational devices used or investigational procedures performed at Yale-
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No    If Yes, please be aware of the following requirements:
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
  targeted for enrollment at Yale for this protocol 1056
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): RAs will query Epic to determine which patients currently in the YNHH ED are 
smokers.  They will then approach these patients to screen for study eligibility.
3.  Recruitment Procedures: 
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a.
Describe how potential subjects will be identified. RAs will query Epic to determine 
which patients currently in the YNHH ED are smokers.  They will then approach these 
patients to screen for study eligibility.
b.
Describe how potential subjects are contacted. RAs will approach patients who are 
smokers while they are being treated in the ED.
c. Who is recruiting potential subjects? Trained Research Assistants and Research 
Associates. 
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
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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.)
Choose one: 
☐ For entire study 
☒ For recruitment purposes only
☐ For inclusion of non-English speaking subject if short form is being used
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;
We are requesting a HIPAA waiver for recruitment purposes only. The RAs will 
review the ED Track Board in Epic and will then check the “Smoking Status” for each 
patient in the ED.  They will then approach the patients identified as current smokers 
or smoking status unknown to ask additional screening questions.  We do not have 
the time and resources to approach every ED patient and ascertain smoking status.  
Using Epic is more efficient for the RAs.
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. 
Teresa O’Leary, Kimberly Beauchemin, Elizabeth Jurczak.
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. 
Prospective subjects will be told that we are conducting a study on interventions for health risks 
and based on their answers to the screening questions they have been identified as eligible for 
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the study.  If patient is interested in hearing about the study, the RA will explain the study.  All 
eligible participants will be asked for written consent using the Yale HIC approved compound 
authorization form.  Consent will be obtained at patient bedside.  
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
Subjects must be awake, alert, and oriented, and have capacity to consent. Patients 
mechanically ventilated, clearly delirious or delusional will be excluded. We will not recruit from 
the CIU, which houses patients with clinically significant and active psychiatric illness.
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.
An electronic version of the Yale HIC-approved Compound Authorization and Consent Form will 
be used on a HIPAA-compliant tablet computer. The form is uploaded into the database and the 
patient is able to review the form on a tablet. The patient signs the form on the tablet with a stylus 
and the signature is captured in a signature field in the database. For patients uncomfortable with e-
consents, paper forms will be provided. An RA will be present throughout the consent process and 
a copy of the signed form will be printed out for the patient before he/she is discharged from the 
ED.
  
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use. 
Non-English speaking patients will be excluded as we do not have the ability to provide 
interventions in languages other than English.  Non-English speaking patients will be referred to 
CT Quitline, as appropriate. If we are fortunate to hire a bilingual RA, e.g. Spanish and English, 
we will recruit Spanish-speaking patients and use documents translated into Spanish.
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment? 
YES ☐  NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.
Several translated short form templates are found on our website at: 
 http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short form 
is not available on our website, then the translated short form needs to be submitted to the IRB 
office for approval via amendment prior to enrolling the subject. Please review the guidance and 
presentation on use of the short form available on the HRPP website.
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If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above. 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent – for Recruitment/Screening only
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
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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? 
It is not feasible to consent every ED patient in order to review the patient’s smoking 
status in Epic.  We will then ask smokers 3-5 very brief screening questions to determine 
eligibility.  We do not collect PHI on patients we do not enroll in the study.
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? N/A – no PHI is collected on patients we do not enroll in the 
study.
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research? 
Name, sex, race, education, employment, health care, insurance, legal issues, behaviors (such 
as: person safety, tobacco/alcohol/drug use and exercise), patient contact information, contact 
information of family and/or friends as alternate contacts, primary care providers and specialists 
will also be recorded to facilitate follow-up.
       
b. How will the research data be collected, recorded and stored?
Data will be collected using Filemaker for iPad. IPads are encrypted and stored in a locked 
safe in the RA’s locked office in the ED. The iPads are connected to a university-maintained 
server via an encrypted WiFi connection. This is a live connection; therefore, all data are 
immediately stored on the secure server.  The server is backed up hourly. No ePHI is stored 
on the iPads. This system is compliant with HIPAA and regulations for the collection of ePHI. 
Computers are encrypted with PGP software.
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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.
All paper files with subject information will remain in locked files in the study office of the PI. 
At the end of data collection, any identifiable data/PHI will be removed from the database. 
After this is done, only de-identified data will be maintained in a password-protected file on a 
password-protected network server to which only the PI, co-investigators and study personnel 
will have access. After publication, all remaining paper and electronic data will be destroyed.
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) 
Only the study team listed on the protocol will have access to PHI and the study database.
If a subject is randomized to one of the 8 arms with the texting component, we will receive 
information about the subject’s utilization of the texting program from ICF International, vendor 
for SmokefreeTxt. A Data Use Agreement has been executed specifying that ICF will send us 
unmasked reports of utilization (did subject opt out, subject’s responses to Ecological 
Momentary Assessment (EMA) questions, etc). We will be able to link ICF’s records back to the 
study subjects using subjects’ cell phone numbers. No other PHI will be exchanged between 
ICF and Yale.
g.   If appropriate, has a Certificate of Confidentiality been obtained? Yes
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. 
N/A
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.)
Subjects will receive a medical evaluation at no charge. In addition, subjects will receive 
potentially beneficial treatment for nicotine dependence free of charge. The medical counseling, 
quitline referral and nicotine replacement therapy that participants may receive are standard 
treatments that have been shown to be efficacious for smoking cessation. Mobile phone texting, 
a newer modality, shows promise as well. 
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         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
The alternative to study participation is to not participate.  If a patient expresses interest 
in smoking cessation but does not want to participate, the RA can give the 
patient a brochure for the CT Tobacco Quitline, a free service available to any 
resident of CT.  The Quitline offers counseling and cessation medications.
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. 
All subjects are eligible to receive up to $50 for enrollment and completion of 2 follow-up phone 
calls. All subjects will receive a $10 gift card at enrollment, a $20 gift card for completion of the 1 
month follow-up and a $20 gift card for completion of the 3 month follow-up.  Subjects 
randomized to the texting arm will receive an additional $20 gift card to cover the cost of 
minutes on their phone plans. For subjects reporting tobacco abstinence at 3 months, an 
additional $200 is offered for returning to the hospital to measure exhaled breath carbon 
monoxide. For subjects asked to complete the qualitative interviews, a $40 gift card will be 
offered.
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. 
Patients randomized to the texting arm who do not have unlimited texting on their cell phone 
plans may incur messaging charges associated with study enrollment.  We intend to give 
subjects in the texting arm an additional $20 gift card at enrollment to offset this potential cost.
   
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.     Will medical treatment be available if research-related injury occurs? Yes.
b.     Where and from whom may treatment be obtained? Routine sources of care.
c.     Are there any limits to the treatment being provided? Not anticipated.
d.     Who will pay for this treatment? None anticipated this is largely minimal risk.
e.     How will the medical treatment be accessed by subjects? Via PCP or YNHH.  Can be 
referred for treatment by PI, if needed.
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